WorldWideScience

Sample records for aged mdx mice

  1. Mutation types and aging differently affect revertant fiber expansion in dystrophic mdx and mdx52 mice.

    Directory of Open Access Journals (Sweden)

    Yusuke Echigoya

    Full Text Available Duchenne muscular dystrophy (DMD, one of the most common and lethal genetic disorders, and the mdx mouse myopathies are caused by a lack of dystrophin protein. These dystrophic muscles contain sporadic clusters of dystrophin-expressing revertant fibers (RFs, as detected by immunohistochemistry. RFs are known to arise from muscle precursor cells with spontaneous exon skipping (alternative splicing and clonally expand in size with increasing age through the process of muscle degeneration/regeneration. The expansion of revertant clusters is thought to represent the cumulative history of muscle regeneration and proliferation of such precursor cells. However, the precise mechanisms by which RFs arise and expand are poorly understood. Here, to test the effects of mutation types and aging on RF expansion and muscle regeneration, we examined the number of RFs in mdx mice (containing a nonsense mutation in exon 23 and mdx52 mice (containing deletion mutation of exon 52 with the same C57BL/6 background at 2, 6, 12, and 18months of age. Mdx mice displayed a significantly higher number of RFs compared to mdx52 mice in all age groups, suggesting that revertant fiber expansion largely depends on the type of mutation and/or location in the gene. A significant increase in the expression and clustering levels of RFs was found beginning at 6months of age in mdx mice compared with mdx52 mice. In contrast to the significant expansion of RFs with increasing age, the number of centrally nucleated fibers and embryonic myosin heavy chain-positive fibers (indicative of cumulative and current muscle regeneration, respectively decreased with age in both mouse strains. These results suggest that mutation types and aging differently affect revertant fiber expansion in mdx and mdx52 mice.

  2. SERCA2a gene transfer improves electrocardiographic performance in aged mdx mice

    Directory of Open Access Journals (Sweden)

    Hajjar Roger

    2011-08-01

    Full Text Available Abstract Background Cardiomyocyte calcium overloading has been implicated in the pathogenesis of Duchenne muscular dystrophy (DMD heart disease. The cardiac isoform of sarcoplasmic reticulum calcium ATPase (SERCA2a plays a major role in removing cytosolic calcium during heart muscle relaxation. Here, we tested the hypothesis that SERCA2a over-expression may mitigate electrocardiography (ECG abnormalities in old female mdx mice, a murine model of DMD cardiomyopathy. Methods 1 × 1012 viral genome particles/mouse of adeno-associated virus serotype-9 (AAV-9 SERCA2a vector was delivered to 12-m-old female mdx mice (N = 5 via a single bolus tail vein injection. AAV transduction and the ECG profile were examined eight months later. Results The vector genome was detected in the hearts of all AAV-injected mdx mice. Immunofluorescence staining and western blot confirmed SERCA2a over-expression in the mdx heart. Untreated mdx mice showed characteristic tachycardia, PR interval reduction and QT interval prolongation. AAV-9 SERCA2a treatment corrected these ECG abnormalities. Conclusions Our results suggest that AAV SERCA2a therapy may hold great promise in treating dystrophin-deficient heart disease.

  3. Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice

    DEFF Research Database (Denmark)

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M;

    2007-01-01

    ADAM12 could be a candidate for nonreplacement gene therapy of Duchenne muscular dystrophy. We therefore evaluated the long-term effect of ADAM12 overexpression in muscle. Surprisingly, we observed loss of skeletal muscle and accelerated fibrosis and adipogenesis in 1-year-old mdx mice transgenically......Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed...... regeneration as a possible factor in development of muscular dystrophy....

  4. Transgenic Overexpression of ADAM12 Suppresses Muscle Regeneration and Aggravates Dystrophy in Aged mdx Mice

    OpenAIRE

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M.; Schrøder, Henrik Daa

    2007-01-01

    Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed effect of ADAM12 was suggested to be mediated via a membrane-stabilizing up-regulation of utrophin, α7B integrin, and dystroglycans. Ectopic ADAM12 expression in normal mouse skeletal muscle also imp...

  5. Evidence of hypoxic tolerance in weak upper airway muscle from young mdx mice.

    Science.gov (United States)

    Burns, David P; O'Halloran, Ken D

    2016-06-01

    Duchenne muscular dystrophy (DMD) is a genetic disease characterised by deficiency in the protein dystrophin. The respiratory system is weakened and patients suffer from sleep disordered breathing and hypoventilation culminating in periods of hypoxaemia. We examined the effects of an acute (6h) hypoxic stress on sternohyoid muscle function (representative pharyngeal dilator). 8 week old male, wild-type (WT; C57BL/10ScSnJ; n=18) and mdx (C57BL/10ScSn-Dmd(mdx)/J; n=16) mice were exposed to sustained hypoxia (FIO2=0.10) or normoxia. Muscle functional properties were examined ex vivo. Additional WT (n=5) and mdx (n=5) sternohyoid muscle was exposed to an anoxic challenge. Sternohyoid dysfunction was observed in mdx mice with significant reductions in force and power. Following exposure to the acute in vivo hypoxic stress, WT sternohyoid muscle showed evidence of functional impairment (reduced force, work and power). Conversely, mdx sternohyoid showed an apparent tolerance to the acute hypoxic stress. This tolerance was not maintained for mdx following a severe hypoxic stress. A dysfunctional upper airway muscle phenotype is present at 8 weeks of age in the mdx mouse, which may have implications for the control of airway patency in DMD. Hypoxic tolerance in mdx respiratory muscle is suggestive of adaptation to chronic hypoxia, which could be present due to respiratory morbidity. We speculate a role for hypoxia in mdx respiratory muscle morbidity. PMID:26691169

  6. Chronic Dosing with Membrane Sealant Poloxamer 188 NF Improves Respiratory Dysfunction in Dystrophic Mdx and Mdx/Utrophin-/- Mice.

    Directory of Open Access Journals (Sweden)

    Bruce E Markham

    Full Text Available Poloxamer 188 NF (national formulary (NF grade of P-188 improves cardiac muscle function in the mdx mouse and golden retriever muscular dystrophy models. However in vivo effects on skeletal muscle have not been reported. We postulated that P-188 NF might protect diaphragm muscle membranes from contraction-induced injury in mdx and mdx/utrophin-/- (dko muscular dystrophy models. In the first study 7-month old mdx mice were treated for 22 weeks with subcutaneous (s.c. injections of saline or P-188 NF at 3 mg/Kg. In the second, dkos were treated with saline or P-188 NF (1 mg/Kg for 8 weeks beginning at age 3 weeks. Prednisone was the positive control in both studies. Respiratory function was monitored using unrestrained whole body plethysmography. P-188 NF treatment affected several respiratory parameters including tidal volume/BW and minute volume/BW in mdx mice. In the more severe dko model, P-188 NF (1 mg/Kg significantly slowed the decline in multiple respiratory parameters compared with saline-treated dko mice. Prednisone's effects were similar to those seen with P-188 NF. Diaphragms from P-188 NF or prednisone treated mdx and dko mice showed signs of muscle fiber protection including less centralized nuclei, less variation in fiber size, greater fiber density, and exhibited a decreased amount of collagen deposition. P-188 NF at 3 mg/Kg s.c. also improved parameters of systolic and diastolic function in mdx mouse hearts. These results suggest that P-188 NF may be useful in treating respiratory and cardiac dysfunction, the leading causes of death in Duchenne muscular dystrophy patients.

  7. uPA deficiency exacerbates muscular dystrophy in MDX mice

    OpenAIRE

    Suelves, Mònica; Vidal, Berta; Serrano, Antonio L.; Tjwa, Marc; Roma, Josep; López-Alemany, Roser; Luttun, Aernout; de Lagrán, María Martínez; Díaz, Maria Àngels; Jardí, Mercè; Roig, Manuel; Dierssen, Mara; Dewerchin, Mieke; Carmeliet, Peter; Muñoz-Cánoves, Pura

    2007-01-01

    Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (...

  8. Dysfunctional muscle and liver glycogen metabolism in mdx dystrophic mice.

    Directory of Open Access Journals (Sweden)

    David I Stapleton

    Full Text Available Duchenne muscular dystrophy (DMD is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD patients and mdx mice (an animal model of DMD exhibit altered metabolic disturbances that cannot be attributed to the loss of dystrophin directly. We tested the hypothesis that glycogen metabolism is defective in mdx dystrophic mice.Dystrophic mdx mice had increased skeletal muscle glycogen (79%, (P<0.01. Skeletal muscle glycogen synthesis is initiated by glycogenin, the expression of which was increased by 50% in mdx mice (P<0.0001. Glycogen synthase activity was 12% higher (P<0.05 but glycogen branching enzyme activity was 70% lower (P<0.01 in mdx compared with wild-type mice. The rate-limiting enzyme for glycogen breakdown, glycogen phosphorylase, had 62% lower activity (P<0.01 in mdx mice resulting from a 24% reduction in PKA activity (P<0.01. In mdx mice glycogen debranching enzyme expression was 50% higher (P<0.001 together with starch-binding domain protein 1 (219% higher; P<0.01. In addition, mdx mice were glucose intolerant (P<0.01 and had 30% less liver glycogen (P<0.05 compared with control mice. Subsequent analysis of the enzymes dysregulated in skeletal muscle glycogen metabolism in mdx mice identified reduced glycogenin protein expression (46% less; P<0.05 as a possible cause of this phenotype.We identified that mdx mice were glucose intolerant, and had increased skeletal muscle glycogen but reduced amounts of liver glycogen.

  9. Lack of Dystrophin Affects Bronchial Epithelium in mdx Mice.

    Science.gov (United States)

    Morici, Giuseppe; Rappa, Francesca; Cappello, Francesco; Pace, Elisabetta; Pace, Andrea; Mudò, Giuseppa; Crescimanno, Grazia; Belluardo, Natale; Bonsignore, Maria R

    2016-10-01

    Mild exercise training may positively affect the course of Duchenne Muscular Dystrophy (DMD). Training causes mild bronchial epithelial injury in both humans and mice, but no study assessed the effects of exercise in mdx mice, a well known model of DMD. The airway epithelium was examined in mdx (C57BL/10ScSn-Dmdmdx) mice, and in wild type (WT, C57BL/10ScSc) mice either under sedentary conditions (mdx-SD, WT-SD) or during mild exercise training (mdx-EX, WT-EX). At baseline, and after 30 and 45 days of training (5 d/wk for 6 weeks), epithelial morphology and markers of regeneration, apoptosis, and cellular stress were assessed. The number of goblet cells in bronchial epithelium was much lower in mdx than in WT mice under all conditions. At 30 days, epithelial regeneration (PCNA positive cells) was higher in EX than SD animals in both groups; however, at 45 days, epithelial regeneration decreased in mdx mice irrespective of training, and the percentage of apoptotic (TUNEL positive) cells was higher in mdx-EX than in WT-EX mice. Epithelial expression of HSP60 (marker of stress) progressively decreased, and inversely correlated with epithelial apoptosis (r = -0.66, P = 0.01) only in mdx mice. Lack of dystrophin in mdx mice appears associated with defective epithelial differentiation, and transient epithelial regeneration during mild exercise training. Hence, lack of dystrophin might impair repair in bronchial epithelium, with potential clinical consequences in DMD patients. J. Cell. Physiol. 231: 2218-2223, 2016. © 2016 Wiley Periodicals, Inc. PMID:26868633

  10. Muscle structure influences utrophin expression in mdx mice.

    Directory of Open Access Journals (Sweden)

    Glen B Banks

    2014-06-01

    Full Text Available Duchenne muscular dystrophy (DMD is a severe muscle wasting disorder caused by mutations in the dystrophin gene. To examine the influence of muscle structure on the pathogenesis of DMD we generated mdx4cv:desmin double knockout (dko mice. The dko male mice died of apparent cardiorespiratory failure at a median age of 76 days compared to 609 days for the desmin-/- mice. An ∼ 2.5 fold increase in utrophin expression in the dko skeletal muscles prevented necrosis in ∼ 91% of 1a, 2a and 2d/x fiber-types. In contrast, utrophin expression was reduced in the extrasynaptic sarcolemma of the dko fast 2b fibers leading to increased membrane fragility and dystrophic pathology. Despite lacking extrasynaptic utrophin, the dko fast 2b fibers were less dystrophic than the mdx4cv fast 2b fibers suggesting utrophin-independent mechanisms were also contributing to the reduced dystrophic pathology. We found no overt change in the regenerative capacity of muscle stem cells when comparing the wild-type, desmin-/-, mdx4cv and dko gastrocnemius muscles injured with notexin. Utrophin could form costameric striations with α-sarcomeric actin in the dko to maintain the integrity of the membrane, but the lack of restoration of the NODS (nNOS, α-dystrobrevin 1 and 2, α1-syntrophin complex and desmin coincided with profound changes to the sarcomere alignment in the diaphragm, deposition of collagen between the myofibers, and impaired diaphragm function. We conclude that the dko mice may provide new insights into the structural mechanisms that influence endogenous utrophin expression that are pertinent for developing a therapy for DMD.

  11. Imatinib attenuates skeletal muscle dystrophy in mdx mice

    OpenAIRE

    HUANG, PING; Zhao, Xinyu S.; Fields, Matthew; Ransohoff, Richard M.; Zhou, Lan

    2009-01-01

    Duchenne-Meryon muscular dystrophy (DMD) is the most common and lethal genetic muscle disease. Ameliorating muscle necrosis, inflammation, and fibrosis represents an important therapeutic approach for DMD. Imatinib, an antineoplastic agent, demonstrated antiinflammatory and antifibrotic effects in liver, kidney, lung, and skin of various animal models. This study tested antiinflammatory and antifibrotic effects of imatinib in mdx mice, a DMD mouse model. We treated mdx mice with intraperitone...

  12. Transgenic overexpression of γ-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice

    Directory of Open Access Journals (Sweden)

    Baltgalvis Kristen A

    2011-10-01

    Full Text Available Abstract Background γ-cytoplasmic (γ-cyto actin levels are elevated in dystrophin-deficient mdx mouse skeletal muscle. The purpose of this study was to determine whether further elevation of γ-cyto actin levels improve or exacerbate the dystrophic phenotype of mdx mice. Methods We transgenically overexpressed γ-cyto actin, specifically in skeletal muscle of mdx mice (mdx-TG, and compared skeletal muscle pathology and force-generating capacity between mdx and mdx-TG mice at different ages. We investigated the mechanism by which γ-cyto actin provides protection from force loss by studying the role of calcium channels and stretch-activated channels in isolated skeletal muscles and muscle fibers. Analysis of variance or independent t-tests were used to detect statistical differences between groups. Results Levels of γ-cyto actin in mdx-TG skeletal muscle were elevated 200-fold compared to mdx skeletal muscle and incorporated into thin filaments. Overexpression of γ-cyto actin had little effect on most parameters of mdx muscle pathology. However, γ-cyto actin provided statistically significant protection against force loss during eccentric contractions. Store-operated calcium entry across the sarcolemma did not differ between mdx fibers compared to wild-type fibers. Additionally, the omission of extracellular calcium or the addition of streptomycin to block stretch-activated channels did not improve the force-generating capacity of isolated extensor digitorum longus muscles from mdx mice during eccentric contractions. Conclusions The data presented in this study indicate that upregulation of γ-cyto actin in dystrophic skeletal muscle can attenuate force loss during eccentric contractions and that the mechanism is independent of activation of stretch-activated channels and the accumulation of extracellular calcium.

  13. Muscle genome-wide expression profiling during disease evolution in mdx mice.

    Science.gov (United States)

    Marotta, Mario; Ruiz-Roig, Claudia; Sarria, Yaris; Peiro, Jose Luis; Nuñez, Fatima; Ceron, Julian; Munell, Francina; Roig-Quilis, Manuel

    2009-04-10

    Mdx mice show a milder phenotype than Duchenne patients despite bearing an analogous genetic defect. Our aim was to sort out genes, differentially expressed during the evolution of skeletal muscle mdx mouse disease, to elucidate the mechanisms by which these animals overcome the lack of dystrophin. Genome-wide microarray-based gene expression analysis was carried out at 3 wk and 1.5 and 3 mo of life. Candidate genes were selected by comparing: 1) mdx vs. controls at each point in time, and 2) mdx mice and 3) control mice among the three points in time. The first analysis showed a strong upregulation (96%) of inflammation-related genes and in >75% of genes related to cell adhesion, muscle structure/regeneration, and extracellular matrix remodeling during mdx disease evolution. Lgals3, Postn, Ctss, and Sln genes showed the strongest variations. The analysis performed among points in time demonstrated significant changes in Ecm1, Spon1, Thbs1, Csrp3, Myo10, Pde4b, and Adamts-5 exclusively during mdx mice lifespan. RT-PCR analysis of Postn, Sln, Ctss, Thbs1, Ecm1, and Adamts-5 expression from 3 wk to 9 mo, confirmed microarray data and demonstrated variations beyond 3 mo of age. A high-confidence functional network analysis demonstrated a strong relationship between them and showed two main subnetworks, having Dmd-Utrn-Myo10 and Adamts5-Thbs1-Spon1-Postn as principal nodes, which are functionally linked to Abca1, Actn4, Crebbp, Csrp3, Lama1, Lama3, Mical2, Mical3, Myf6, Pxn, and Sparc genes. Candidate genes may participate in the decline of muscle necrosis in mdx mice and could be considered potential therapeutic targets for Duchenne patients. PMID:19223608

  14. Myogenin regulates exercise capacity but is dispensable for skeletal muscle regeneration in adult mdx mice.

    Directory of Open Access Journals (Sweden)

    Eric Meadows

    Full Text Available Duchenne muscular dystrophy (DMD is the most prevalent inherited childhood muscle disorder in humans. mdx mice exhibit a similar pathophysiology to the human disorder allowing for an in-depth investigation of DMD. Myogenin, a myogenic regulatory factor, is best known for its role in embryonic myogenesis, but its role in adult muscle maintenance and regeneration is still poorly understood. Here, we generated an mdx:Myog(flox/flox mouse harboring a tamoxifen-inducible Cre recombinase transgene, which was used to conditionally delete Myog during adult life. After tamoxifen treatment, three groups of mice were created to study the effects of Myog deletion: mdx:Myog(flox/flox mice (mdx, Myog(flox/flox mice (wild-type, and mdx:Myog(floxΔ/floxΔ:Cre-ER mice (mdx:Myog-deleted. mdx:Myog-deleted mice exhibited no adverse phenotype and behaved normally. When run to exhaustion, mdx:Myog-deleted mice demonstrated an enhanced capacity for exercise compared to mdx mice, running nearly as far as wild-type mice. Moreover, these mice showed the same signature characteristics of muscle regeneration as mdx mice. Unexpectedly, we found that myogenin was dispensable for muscle regeneration. Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity. Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function.

  15. Analyses of the differentiation potential of satellite cells from myoD-/-, mdx, and PMP22 C22 mice

    Directory of Open Access Journals (Sweden)

    Huxley Clare

    2005-03-01

    Full Text Available Abstract Background Sporadic and sometimes contradictory studies have indicated changes in satellite cell behaviour associated with the progressive nature of human Duchenne muscular dystrophy (DMD. Satellite cell proliferation and number are reportedly altered in DMD and the mdx mouse model. We recently found that satellite cells in MSVski transgenic mice, a muscle hypertrophy model showing progressive muscle degeneration, display a severe ageing-related differentiation defect in vitro. We tested the hypothesis that similar changes contribute to the gradual loss of muscle function with age in mdx and PMP22 mice, a model of human motor and sensory neuropathy type 1A (HMSN1A. Methods Single extensor digitorum longus muscle fibres were cultured from mdx and PMP22 mice and age- and genetic background-matched controls. Mice at several ages were compared with regard to the differentiation of satellite cells, assayed as the proportion of desmin-expressing cells that accumulated sarcomeric myosin heavy chain. Results Satellite cells of 2 month, 6 month, and 12 month old mdx mice were capable of differentiating to a similar extent to age-matched wild type control animals in an in vitro proliferation/differentiation model. Strikingly, differentiation efficiency in individual 6 month and 12 month old mdx animals varies to a much higher extent than in age-matched controls, younger mdx animals, or PMP22 mice. In contrast, differentiation of myoblasts from all myoD null mice assayed was severely impaired in this assay system. The defect in satellite cell differentiation that occurs in some mdx animals arises from a delay in differentiation that is not overcome by IGF-1 treatment at any phase of cultivation. Conclusion Overall, a defect in satellite cell differentiation above that arising through normal ageing does not occur in mdx or PMP22 mouse models of human disease. Nonetheless, the impaired differentiation of satellite cells from some mdx animals

  16. Inhibition of myosatellite cell proliferation by gamma irradiation does not prevent the age-related increase of the number of dystrophin-positive fibers in soleus muscles of mdx female heterozygote mice.

    OpenAIRE

    Weller, B; Karpati, G.; Lehnert, S.; Carpenter, S.; Ajdukovic, B.; Holland, P

    1991-01-01

    In skeletal muscles of young mdx female heterozygote mice, there is a mosaic of dystrophin-positive and dystrophin-negative fiber segments. In older animals, there is a marked decline in the number of dystrophin-negative fiber segments. This phenomenon might be due to a fusion of dystrophin-competent satellite cells into the originally dystrophin-negative fiber segments during growth. To study this possibility, soleus muscles of 10-day-old mdx female heterozygotes were gamma irradiated (2000 ...

  17. Blastocyst Injection of Wild Type Embryonic Stem Cells Induces Global Corrections in Mdx Mice

    OpenAIRE

    Stillwell, Elizabeth; Vitale, Joseph; Zhao, Qingshi; Beck, Amanda; Schneider, Joel; Khadim, Farah; Elson, Genie; Altaf, Aneela; Yehia, Ghassan; Dong, Jia-hui; Liu, Jing; Mark, Willie; Bhaumik, Mantu; Grange, Robert; Fraidenraich, Diego

    2009-01-01

    Duchenne muscular dystrophy (DMD) is an incurable neuromuscular degenerative disease, caused by a mutation in the dystrophin gene. Mdx mice recapitulate DMD features. Here we show that injection of wild-type (WT) embryonic stem cells (ESCs) into mdx blastocysts produces mice with improved pathology and function. A small fraction of WT ESCs incorporates into the mdx mouse nonuniformly to upregulate protein levels of dystrophin in the skeletal muscle. The chimeric muscle shows reduced regenerat...

  18. Inhibiting TGF-β Activity Improves Respiratory Function in mdx Mice

    OpenAIRE

    Nelson, Carol A.; Hunter, R. Bridge; Quigley, Lindsay A.; Girgenrath, Stefan; Weber, William D.; McCullough, Jennifer A.; Dinardo, Carol J.; Keefe, Kelly A.; Ceci, Lorena; Clayton, Nicholas P.; McVie-Wylie, Alison; Cheng, Seng H.; Leonard, John P.; Wentworth, Bruce M.

    2011-01-01

    Respiratory function is the main cause of mortality in patients with Duchenne muscular dystrophy (DMD). Elevated levels of TGF-β play a key role in the pathophysiology of DMD. To determine whether therapeutic attenuation of TGF-β signaling improves respiratory function, mdx mice were treated from 2 weeks of age to 2 months or 9 months of age with either 1D11 (a neutralizing antibody to all three isoforms of TGF-β), losartan (an angiotensin receptor antagonist), or a combination of the two age...

  19. Selective modulation through the glucocorticoid receptor ameliorates muscle pathology in mdx mice.

    Science.gov (United States)

    Huynh, Tony; Uaesoontrachoon, Kitipong; Quinn, James L; Tatem, Kathleen S; Heier, Christopher R; Van Der Meulen, Jack H; Yu, Qing; Harris, Mark; Nolan, Christopher J; Haegeman, Guy; Grounds, Miranda D; Nagaraju, Kanneboyina

    2013-10-01

    The over-expression of NF-κB signalling in both muscle and immune cells contribute to the pathology in dystrophic muscle. The anti-inflammatory properties of glucocorticoids, mediated predominantly through monomeric glucocorticoid receptor inhibition of transcription factors such as NF-κB (transrepression), are postulated to be an important mechanism for their beneficial effects in Duchenne muscular dystrophy. Chronic glucocorticoid therapy is associated with adverse effects on metabolism, growth, bone mineral density and the maintenance of muscle mass. These detrimental effects result from direct glucocorticoid receptor homodimer interactions with glucocorticoid response elements of the relevant genes. Compound A, a non-steroidal selective glucocorticoid receptor modulator, is capable of transrepression without transactivation. We confirm the in vitro NF-κB inhibitory activity of compound A in H-2K(b) -tsA58 mdx myoblasts and myotubes, and demonstrate improvements in disease phenotype of dystrophin deficient mdx mice. Compound A treatment in mdx mice from 18 days of post-natal age to 8 weeks of age increased the absolute and normalized forelimb and hindlimb grip strength, attenuated cathepsin-B enzyme activity (a surrogate marker for inflammation) in forelimb and hindlimb muscles, decreased serum creatine kinase levels and reduced IL-6, CCL2, IFNγ, TNF and IL-12p70 cytokine levels in gastrocnemius (GA) muscles. Compared with compound A, treatment with prednisolone, a classical glucocorticoid, in both wild-type and mdx mice was associated with reduced body weight, reduced GA, tibialis anterior and extensor digitorum longus muscle mass and shorter tibial lengths. Prednisolone increased osteopontin (Spp1) gene expression and osteopontin protein levels in the GA muscles of mdx mice and had less favourable effects on the expression of Foxo1, Foxo3, Fbxo32, Trim63, Mstn and Igf1 in GA muscles, as well as hepatic Igf1 in wild-type mice. In conclusion, selective

  20. Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

    Directory of Open Access Journals (Sweden)

    D. Feder

    2014-11-01

    Full Text Available Erythropoietin (EPO has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1, and tumor necrosis factor-α (TNF-α was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11. On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16 and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09. These results may help to clarify some of the direct actions of EPO on skeletal muscle.

  1. Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

    Energy Technology Data Exchange (ETDEWEB)

    Feder, D.; Rugollini, M.; Santomauro, A. Jr; Oliveira, L.P.; Lioi, V.P. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Santos, R. dos; Ferreira, L.G.; Nunes, M.T.; Carvalho, M.H. [Universidade de São Paulo, Instituto de Ciências Biomédicas, São Paulo, SP (Brazil); Delgado, P.O.; Carvalho, A.A.S. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Fonseca, F.L.A. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Universidade Federal de São Paulo, Ambientais e Farmacêuticas, Instituto de Ciências Químicas, Diadema, SP (Brazil)

    2014-09-05

    Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16) and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle.

  2. Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

    International Nuclear Information System (INIS)

    Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16) and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle

  3. Combined Effect of AMPK/PPAR Agonists and Exercise Training in mdx Mice Functional Performance

    OpenAIRE

    Carlos R. Bueno Júnior; Pantaleão, Lucas C; Voltarelli, Vanessa A.; Bozi, Luiz Henrique M.; Brum, Patricia Chakur; Zatz, Mayana

    2012-01-01

    The present investigation was undertaken to test whether exercise training (ET) associated with AMPK/PPAR agonists (EM) would improve skeletal muscle function in mdx mice. These drugs have the potential to improve oxidative metabolism. This is of particular interest because oxidative muscle fibers are less affected in the course of the disease than glycolitic counterparts. Therefore, a cohort of 34 male congenic C57Bl/10J mdx mice included in this study was randomly assigned into four groups:...

  4. Blastocyst injection of wild type embryonic stem cells induces global corrections in mdx mice.

    Directory of Open Access Journals (Sweden)

    Elizabeth Stillwell

    Full Text Available Duchenne muscular dystrophy (DMD is an incurable neuromuscular degenerative disease, caused by a mutation in the dystrophin gene. Mdx mice recapitulate DMD features. Here we show that injection of wild-type (WT embryonic stem cells (ESCs into mdx blastocysts produces mice with improved pathology and function. A small fraction of WT ESCs incorporates into the mdx mouse nonuniformly to upregulate protein levels of dystrophin in the skeletal muscle. The chimeric muscle shows reduced regeneration and restores dystrobrevin, a dystrophin-related protein, in areas with high and with low dystrophin content. WT ESC injection increases the amount of fat in the chimeras to reach WT levels. ESC injection without dystrophin does not prevent the appearance of phenotypes in the skeletal muscle or in the fat. Thus, dystrophin supplied by the ESCs reverses disease in mdx mice globally in a dose-dependent manner.

  5. Gastric emptying, small intestinal transit and fecal output in dystrophic (mdx) mice.

    Science.gov (United States)

    Mulè, Flavia; Amato, Antonella; Serio, Rosa

    2010-01-01

    Duchenne muscular dystrophy (DMD), which results from deficiency in dystrophin, a sarcolemma protein of skeletal, cardiac and smooth muscle, is characterized by progressive striated muscle degeneration, but various gastrointestinal clinical manifestations have been observed. The aim was to evaluate the possible impact of the dystrophin loss on the gastrointestinal propulsion in mdx mice (animal model for DMD). The gastric emptying of a carboxymethyl cellulose/phenol red dye non-nutrient meal was not significantly different at 20 min from gavaging between wild-type and mdx mice. The intestinal transit and the fecal output were significantly decreased in mdx versus normal animals, although the length of the intestine was similar in both animals. The present results provide evidence for motor intestinal alterations in mdx mice in in vivo conditions. PMID:19784719

  6. Low Six4 and Six5 gene dosage improves dystrophic phenotype and prolongs life span of mdx mice.

    Science.gov (United States)

    Yajima, Hiroshi; Kawakami, Kiyoshi

    2016-08-01

    Muscle regeneration is an important process for skeletal muscle growth and recovery. Repair of muscle damage is exquisitely programmed by cellular mechanisms inherent in myogenic stem cells, also known as muscle satellite cells. We demonstrated previously the involvement of homeobox transcription factors, SIX1, SIX4 and SIX5, in the coordinated proliferation and differentiation of isolated satellite cells in vitro. However, their roles in adult muscle regeneration in vivo remain elusive. To investigate SIX4 and SIX5 functions during muscle regeneration, we introduced knockout alleles of Six4 and Six5 into an animal model of Duchenne Muscular Dystrophy (DMD), mdx (Dmd(mdx) /Y) mice, characterized by frequent degeneration-regeneration cycles in muscles. A lower number of small myofibers, higher number of thick ones and lower serum creatine kinase and lactate dehydrogenase activities were noted in 50-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice than Dmd(mdx) /Y mice, indicating improvement of dystrophic phenotypes of Dmd(mdx) /Y mice. Higher proportions of cells positive for MYOD1 and MYOG (markers of regenerating myonuclei) and SIX1 (a marker of regenerating myoblasts and newly regenerated myofibers) in 12-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice suggested enhanced regeneration, compared with Dmd(mdx) /Y mice. Although grip strength was comparable in Six4(+/-) 5(+/-) Dmd(mdx) /Y and Dmd(mdx) /Y mice, treadmill exercise did not induce muscle weakness in Six4(+/-) 5(+/-) Dmd(mdx) /Y mice, suggesting higher regeneration capacity. In addition, Six4(+/-) 5(+/-) Dmd(mdx) /Y mice showed 33.8% extension of life span. The results indicated that low Six4 and Six5 gene dosage improved dystrophic phenotypes of Dmd(mdx) /Y mice by enhancing muscle regeneration, and suggested that SIX4 and SIX5 are potentially useful de novo targets in therapeutic applications against muscle disorders, including DMD. PMID:27224259

  7. Normal myogenic cells from newborn mice restore normal histology to degenerating muscles of the mdx mouse

    International Nuclear Information System (INIS)

    Dystrophin deficiency in skeletal muscle of the x-linked dystrophic (mdx) mouse can be partially remedied by implantation of normal muscle precursor cells (mpc). However, it is difficult to determine whether this biochemical rescue results in any improvement in the structure or function of the treated muscle, because the vigorous regeneration of mdx muscle more than compensates for the degeneration. By using x-ray irradiation to prevent mpc proliferation, it is possible to study loss of mdx muscle fibers without the complicating effect of simultaneous fiber regeneration. Thus, improvements in fiber survival resulting from any potential therapy can be detected easily. Here, we have implanted normal mpc, obtained from newborn mice, into such preirradiated mdx muscles, finding that it is far more extensively permeated and replaced by implanted mpc than is nonirradiated mdx muscle; this is evident both from analysis of glucose-6-phosphate isomerase isoenzyme markers and from immunoblots and immunostaining of dystrophin in the treated muscles. Incorporation of normal mpc markedly reduces the loss of muscle fibers and the deterioration of muscle structure which otherwise occurs in irradiated mdx muscles. Surprisingly, the regenerated fibers are largely peripherally nucleated, whereas regenerated mouse skeletal muscle fibers are normally centrally nucleated. We attribute this regeneration of apparently normal muscle to the tendency of newborn mouse mpc to recapitulate their neonatal ontogeny, even when grafted into 3-wk-old degenerating muscle

  8. Inhibition of myosatellite cell proliferation by gamma irradiation does not prevent the age-related increase of the number of dystrophin-positive fibers in soleus muscles of mdx female heterozygote mice

    International Nuclear Information System (INIS)

    In skeletal muscles of young mdx female heterozygote mice, there is a mosaic of dystrophin-positive and dystrophin-negative fiber segments. In older animals, there is a marked decline in the number of dystrophin-negative fiber segments. This phenomenon might be due to a fusion of dystrophin-competent satellite cells into the originally dystrophin-negative fiber segments during growth. To study this possibility, soleus muscles of 10-day-old mdx female heterozygotes were gamma irradiated (2000 rads) to inhibit subsequent myosatellite cell proliferation and fusion. In the irradiated soleus muscles of animals at 60 days, the relative amount of dystrophin measured by quantitative immunoblots was not significantly different from that of the contralateral nonirradiated muscles. The prevalence of dystrophin-negative fibers in the 60-day-old irradiated solei was not higher than in the nonirradiated contralateral muscles, implying that dystrophin-competent satellite cell fusion was not a significant factor in the observed conversion. A longitudinal expansion of the cytoplasmic domain of the original dystrophin-competent myonuclei during growth could explain the observed conversion phenomenon

  9. Fetal muscle-derived cells can repair dystrophic muscles in mdx mice

    International Nuclear Information System (INIS)

    We have previously reported that CD34+ cells purified from mouse fetal muscles can differentiate into skeletal muscle in vitro and in vivo when injected into muscle tissue of dystrophic mdx mice. In this study, we investigate the ability of such donor cells to restore dystrophin expression, and to improve the functional muscle capacity of the extensor digitorum longus muscle (EDL) of mdx mice. For this purpose green fluorescent-positive fetal GFP+/CD34+ cells or desmin+/-LacZ/CD34+ cells were transplanted into irradiated or non-irradiated mdx EDL muscle. Donor fetal muscle-derived cells predominantly fused with existing fibers. Indeed more than 50% of the myofibers of the host EDL contained donor nuclei delivering dystrophin along 80-90% of the length of their sarcolemma. The presence of significant amounts of dystrophin (about 60-70% of that found in a control wild-type mouse muscle) was confirmed by Western blot analyses. Dystrophin expression also outcompeted that of utrophin, as revealed by a spatial shift in the distribution of utrophin. At 1 month post-transplant, the recipient muscle appeared to have greater resistance to fatigue than control mdx EDL muscle during repeated maximal contractions

  10. Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice.

    Science.gov (United States)

    Han, Gang; Gu, Ben; Cao, Limin; Gao, Xianjun; Wang, Qingsong; Seow, Yiqi; Zhang, Ning; Wood, Matthew J A; Yin, HaiFang

    2016-01-01

    Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD) mdx mice. We identify a glucose-fructose (GF) formulation that potentiates PMO activity, completely corrects aberrant Dmd transcripts, restores dystrophin levels in skeletal muscles and achieves functional rescue without detectable toxicity. This activity is attributed to enhancement of GF-mediated PMO uptake in the muscle. We demonstrate that PMO cellular uptake is energy dependent, and that ATP from GF metabolism contributes to enhanced cellular uptake of PMO in the muscle. Collectively, we show that GF potentiates PMO activity by replenishing cellular energy stores under energy-deficient conditions in mdx mice. Our findings provide mechanistic insight into hexose-mediated oligonucleotide delivery and have important implications for the development of DMD exon-skipping therapy. PMID:26964641

  11. Truncated dystrophins reduce muscle stiffness in the extensor digitorum longus muscle of mdx mice

    OpenAIRE

    Hakim, Chady H.; Duan, Dongsheng

    2012-01-01

    Muscle stiffness is a major clinical feature in Duchenne muscular dystrophy (DMD). DMD is the most common lethal inherited muscle-wasting disease in boys, and it is caused by the lack of the dystrophin protein. We recently showed that the extensor digitorum longus (EDL) muscle of mdx mice (a DMD mouse model) exhibits disease-associated muscle stiffness. Truncated micro- and mini-dystrophins are the leading candidates for DMD gene therapy. Unfortunately, it has never been clear whether these t...

  12. Effects of Dantrolene Therapy on Disease Phenotype in Dystrophin Deficient mdx Mice.

    Science.gov (United States)

    Quinn, James L; Huynh, Tony; Uaesoontrachoon, Kitipong; Tatem, Kathleen; Phadke, Aditi; Van der Meulen, Jack H; Yu, Qing; Nagaraju, Kannaboyina

    2013-01-01

    Dystrophin deficiency causes contraction-induced injury and damage to the muscle fiber, resulting in sustained increase in intracellular calcium levels, activation of calcium-dependent proteases and cell death. It is known that the Ryanodine receptor (RyR1) on the sarcoplasmic reticular (SR) membrane controls calcium release. Dantrolene, an FDA approved skeletal muscle relaxant, inhibits the release of calcium from the SR during excitation-contraction and suppresses uncontrolled calcium release by directly acting on the RyR complex to limit its activation. This study examines whether Dantrolene can reduce the disease phenotype in the mdx mouse model of muscular dystrophy. We treated mdx mice (4 weeks old) with daily intraperitoneal injections of 40mg/kg of Dantrolene for 6 weeks and measured functional (grip strength, in vitro force contractions), behavioral (open field digiscan), imagining (optical imaging for inflammation), histological (H&E), and molecular (protein and RNA) endpoints in a blinded fashion. We found that treatment with Dantrolene resulted in decreased grip strength and open field behavioral activity in mdx mice. There was no significant difference in inflammation either by optical imaging analysis of cathepsin activity or histological (H&E) analysis. In vitro force contraction measures showed no changes in EDL muscle-specific force, lengthening-contraction force deficit, or fatigue resistance. We found Dantrolene treatment significantly reduces serum CK levels. Further, Dantrolene-treated mice showed decreased SERCA1 but not RyR1 expression in skeletal muscle. These results suggest that Dantrolene treatment alone has no significant beneficial effects at the tested doses in young mdx mice. PMID:24270550

  13. Adeno-Associated Virus Serotype-9 Microdystrophin Gene Therapy Ameliorates Electrocardiographic Abnormalities in mdx Mice

    OpenAIRE

    Bostick, Brian; Yue, Yongping; Lai, Yi; Long, Chun; Li, Dejia; Duan, Dongsheng

    2008-01-01

    Adeno-associated virus (AAV)-mediated microdystrophin gene therapy holds great promise for treating Duchenne muscular dystrophy (DMD). Previous studies have revealed excellent skeletal muscle protection. Cardiac muscle is also compromised in DMD patients. Here we show that a single intravenous injection of AAV serotype-9 (AAV-9) microdystrophin vector efficiently transduced the entire heart in neonatal mdx mice, a dystrophin-deficient mouse DMD model. Furthermore, microdystrophin therapy norm...

  14. Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice

    OpenAIRE

    Han, Gang; Gu, Ben; Cao, Limin; Gao, Xianjun; Wang, Qingsong; Seow, Yiqi; Zhang, Ning; Matthew J A Wood; Yin, HaiFang

    2016-01-01

    Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD) mdx mice. We identify a glucose–fructose (GF) formulation that potentiates PMO activity, completely corrects aberrant Dmd transcripts, restores dystrophin levels in skeletal muscles and achieves functional rescue without detectable toxicity. This activity is a...

  15. Polyethylenimine-modified Pluronics (PCMs) Improve Morpholino Oligomer Delivery in Cell Culture and Dystrophic mdx Mice

    OpenAIRE

    Wang, Mingxing; Wu, Bo; Lu, Peijuan; Cloer, Caryn; Tucker, Jay D; Lu, Qilong

    2012-01-01

    We investigated a series of small-sized polyethylenimine (PEI, 0.8/1.2 k)-conjugated pluronic copolymers (PCMs) for their potential to enhance delivery of an antisense phosphorodiamidate morpholino oligomer (PMO) in vitro and in dystrophic mdx mice. PCM polymers containing pluronics of molecular weight (Mw) ranging 2–6 k, with hydrophilic-lipophilic balance (HLB) 7–23, significantly enhanced PMO-induced exon-skipping in a green fluorescent protein (GFP) reporter-based myoblast culture system....

  16. Sulforaphane mitigates muscle fibrosis in mdx mice via Nrf2-mediated inhibition of TGF-β/Smad signaling.

    Science.gov (United States)

    Sun, Chengcao; Li, Shujun; Li, Dejia

    2016-02-15

    Sulforaphane (SFN), an activator of NF-E2-related factor 2 (Nrf2), has been found to have an antifibrotic effect on liver and lung. However, its effects on dystrophic muscle fibrosis remain unknown. This work was undertaken to evaluate the effects of SFN-mediated activation of Nrf2 on dystrophic muscle fibrosis. Male mdx mice (age 3 mo) were treated with SFN by gavage (2 mg/kg body wt per day) for 3 mo. Experimental results demonstrated that SFN remarkably attenuated skeletal and cardiac muscle fibrosis as indicated by reduced Sirius Red staining and immunostaining of the extracellular matrix. Moreover, SFN significantly inhibited the transforming growth factor-β (TGF-β)/Smad signaling pathway and suppressed profibrogenic gene and protein expressions such as those of α-smooth muscle actin (α-SMA), fibronectin, collagen I, plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor metalloproteinase-1 (TIMP-1) in an Nrf2-dependent manner. Furthermore, SFN significantly decreased the expression of inflammatory cytokines CD45, TNF-α, and IL-6 in mdx mice. In conclusion, these results show that SFN can attenuate dystrophic muscle fibrosis by Nrf2-mediated inhibition of the TGF-β/Smad signaling pathway, which indicates that Nrf2 may represent a new target for dystrophic muscle fibrosis. PMID:26494449

  17. Nifedipine treatment reduces resting calcium concentration, oxidative and apoptotic gene expression, and improves muscle function in dystrophic mdx mice.

    Directory of Open Access Journals (Sweden)

    Francisco Altamirano

    Full Text Available Duchenne Muscular Dystrophy (DMD is a recessive X-linked genetic disease, caused by mutations in the gene encoding dystrophin. DMD is characterized in humans and in mdx mice by a severe and progressive destruction of muscle fibers, inflammation, oxidative/nitrosative stress, and cell death. In mdx muscle fibers, we have shown that basal ATP release is increased and that extracellular ATP stimulation is pro-apoptotic. In normal fibers, depolarization-induced ATP release is blocked by nifedipine, leading us to study the potential therapeutic effect of nifedipine in mdx muscles and its relation with extracellular ATP signaling. Acute exposure to nifedipine (10 µM decreased [Ca(2+]r, NF-κB activity and iNOS expression in mdx myotubes. In addition, 6-week-old mdx mice were treated with daily intraperitoneal injections of nifedipine, 1 mg/Kg for 1 week. This treatment lowered the [Ca(2+]r measured in vivo in the mdx vastus lateralis. We demonstrated that extracellular ATP levels were higher in adult mdx flexor digitorum brevis (FDB fibers and can be significantly reduced after 1 week of treatment with nifedipine. Interestingly, acute treatment of mdx FDB fibers with apyrase, an enzyme that completely degrades extracellular ATP to AMP, reduced [Ca(2+]r to a similar extent as was seen in FDB fibers after 1-week of nifedipine treatment. Moreover, we demonstrated that nifedipine treatment reduced mRNA levels of pro-oxidative/nitrosative (iNOS and gp91(phox/p47(phox NOX2 subunits and pro-apoptotic (Bax genes in mdx diaphragm muscles and lowered serum creatine kinase (CK levels. In addition, nifedipine treatment increased muscle strength assessed by the inverted grip-hanging test and exercise tolerance measured with forced swimming test in mdx mice. We hypothesize that nifedipine reduces basal ATP release, thereby decreasing purinergic receptor activation, which in turn reduces [Ca(2+]r in mdx skeletal muscle cells. The results in this work open new

  18. ADAM12 alleviates the skeletal muscle pathology in mdx dystrophic mice

    DEFF Research Database (Denmark)

    Kronqvist, Pauliina; Kawaguchi, Nobuko; Albrechtsen, Reidar; Xu, Xiufeng; Schrøder, Henrik Daa; Moghadaszadeh, Behzad; Nielsen, Finn Cilius; Frohlich, Camilla; Engvall, Eva; Wewer, Ulla M

    2002-01-01

    Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study...... we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx mice alleviated the muscle pathology in these animals, as...

  19. Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice.

    Science.gov (United States)

    Betts, Corinne A; Saleh, Amer F; Carr, Carolyn A; Hammond, Suzan M; Coenen-Stass, Anna M L; Godfrey, Caroline; McClorey, Graham; Varela, Miguel A; Roberts, Thomas C; Clarke, Kieran; Gait, Michael J; Wood, Matthew J A

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes to mortality. Antisense oligonucleotides (AOs) are a promising DMD therapy, restoring functional dystrophin protein by exon skipping. However, a major limitation with current AOs is the absence of dystrophin correction in heart. Pip peptide-AOs demonstrate high activity in cardiac muscle. To determine their therapeutic value, dystrophic mdx mice were subject to forced exercise to model the DMD cardiac phenotype. Repeated peptide-AO treatments resulted in high levels of cardiac dystrophin protein, which prevented the exercised induced progression of cardiomyopathy, normalising heart size as well as stabilising other cardiac parameters. Treated mice also exhibited significantly reduced cardiac fibrosis and improved sarcolemmal integrity. This work demonstrates that high levels of cardiac dystrophin restored by Pip peptide-AOs prevents further deterioration of cardiomyopathy and pathology following exercise in dystrophic DMD mice. PMID:25758104

  20. CRISPR-mediated Genome Editing Restores Dystrophin Expression and Function in mdx Mice.

    Science.gov (United States)

    Xu, Li; Park, Ki Ho; Zhao, Lixia; Xu, Jing; El Refaey, Mona; Gao, Yandi; Zhu, Hua; Ma, Jianjie; Han, Renzhi

    2016-03-01

    Duchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by genetic mutations that lead to the disruption of dystrophin in muscle fibers. There is no curative treatment for this devastating disease. Clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) has emerged as a powerful tool for genetic manipulation and potential therapy. Here we demonstrate that CRIPSR-mediated genome editing efficiently excised a 23-kb genomic region on the X-chromosome covering the mutant exon 23 in a mouse model of DMD, and restored dystrophin expression and the dystrophin-glycoprotein complex at the sarcolemma of skeletal muscles in live mdx mice. Electroporation-mediated transfection of the Cas9/gRNA constructs in the skeletal muscles of mdx mice normalized the calcium sparks in response to osmotic shock. Adenovirus-mediated transduction of Cas9/gRNA greatly reduced the Evans blue dye uptake of skeletal muscles at rest and after downhill treadmill running. This study provides proof evidence for permanent gene correction in DMD. PMID:26449883

  1. Polyethylenimine-modified pluronics (PCMs) improve morpholino oligomer delivery in cell culture and dystrophic mdx mice.

    Science.gov (United States)

    Wang, Mingxing; Wu, Bo; Lu, Peijuan; Cloer, Caryn; Tucker, Jay D; Lu, Qilong

    2013-01-01

    We investigated a series of small-sized polyethylenimine (PEI, 0.8/1.2 k)-conjugated pluronic copolymers (PCMs) for their potential to enhance delivery of an antisense phosphorodiamidate morpholino oligomer (PMO) in vitro and in dystrophic mdx mice. PCM polymers containing pluronics of molecular weight (Mw) ranging 2-6 k, with hydrophilic-lipophilic balance (HLB) 7-23, significantly enhanced PMO-induced exon-skipping in a green fluorescent protein (GFP) reporter-based myoblast culture system. Application of optimized formulations of PCMs with PMO targeted to dystrophin exon 23 demonstrated a significant increase in exon-skipping efficiency in dystrophic mdx mice. Consistent with our observations in vitro, optimization of molecular size and the HLB of pluronics are important factors for PCMs to achieve enhanced PMO delivery in vivo. Observed cytotoxicity of the PCMs was lower than Endo-porter and PEI 25 k. Tissue toxicity of PCMs in muscle was not clearly detected with the concentrations used, indicating the potential of the PCMs as effective and safe PMO carriers for treating diseases such as muscular dystrophy. PMID:23164938

  2. PRECLINICAL DRUG TRIALS IN THE mdx MOUSE: ASSESSMENT OF RELIABLE AND SENSITIVE OUTCOME MEASURES

    OpenAIRE

    SPURNEY, CHRISTOPHER F.; Gordish-Dressman, Heather; Alfredo D Guerron; Sali, Arpana; Gouri S Pandey; Rawat, Rashmi; van der Meulen, Jack H; Cha, Hee-Jae; Pistilli, Emidio E.; Partridge, Terence A.; Hoffman, Eric P; Nagaraju, Kanneboyina

    2009-01-01

    The availability of animal models for Duchenne muscular dystrophy has led to extensive preclinical research on potential therapeutics. Few studies have focused on reliability and sensitivity of endpoints for mdx mouse drug trials. Therefore, we sought to compare a wide variety of reported and novel endpoint measures in exercised mdx and normal control mice at 10, 20, and 40 weeks of age. Statistical analysis as well as power calculations for expected effect sizes in mdx preclinical drug trial...

  3. The proton pump inhibitor lansoprazole improves the skeletal phenotype in dystrophin deficient mdx mice.

    Directory of Open Access Journals (Sweden)

    Arpana Sali

    Full Text Available BACKGROUND: In Duchenne muscular dystrophy (DMD, loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology. METHODOLOGY/PRINCIPAL FINDINGS: We designed a preclinical trial to investigate the effects of lansoprazole (LANZO administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n = 12 per group: (1 vehicle control; (2 5 mg/kg/day LANZO; (3 5 mg/kg/day prednisolone; and (4 combined treatment of 5 mg/kg/day prednisolone (PRED and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan and functional outcomes (grip strength and Rotarod were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions. CONCLUSIONS/SIGNIFICANCE: Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings

  4. Fructose Promotes Uptake and Activity of Oligonucleotides With Different Chemistries in a Context-dependent Manner in mdx Mice.

    Science.gov (United States)

    Cao, Limin; Han, Gang; Lin, Caorui; Gu, Ben; Gao, Xianjun; Moulton, Hong M; Seow, Yiqi; Yin, HaiFang

    2016-01-01

    Antisense oligonucleotide (AO)-mediated exon-skipping therapeutics shows great promise in correcting frame-disrupting mutations in the DMD gene for Duchenne muscular dystrophy. However, insufficient systemic delivery limits clinical adoption. Previously, we showed that a glucose/fructose mixture augmented AO delivery to muscle in mdx mice. Here, we evaluated if fructose alone could enhance the activities of AOs with different chemistries in mdx mice. The results demonstrated that fructose improved the potency of AOs tested with the greatest effect on phosphorodiamidate morpholino oligomer (PMO), resulted in a 4.25-fold increase in the number of dystrophin-positive fibres, compared to PMO in saline in mdx mice. Systemic injection of lissamine-labeled PMO with fructose at 25 mg/kg led to increased uptake and elevated dystrophin expression in peripheral muscles, compared to PMO in saline, suggesting that fructose potentiates PMO by enhancing uptake. Repeated intravenous administration of PMO in fructose at 50 mg/kg/week for 3 weeks and 50 mg/kg/month for 5 months restored up to 20% of wild-type dystrophin levels in skeletal muscles with improved functions without detectable toxicity, compared to untreated mdx controls. Collectively, we show that fructose can potentiate AOs of different chemistries in vivo although the effect diminished over repeated administration. PMID:27351681

  5. Superpulsed low-level laser therapy protects skeletal muscle of mdx mice against damage, inflammation and morphological changes delaying dystrophy progression

    OpenAIRE

    Ernesto Cesar Pinto Leal-Junior; Patrícia de Almeida; Shaiane Silva Tomazoni; Paulo de Tarso Camillo de Carvalho; Rodrigo Álvaro Brandão Lopes-Martins; Lucio Frigo; Jon Joensen; Johnson, Mark I; Jan Magnus Bjordal

    2014-01-01

    Aim: To evaluate the effects of preventive treatment with low-level laser therapy (LLLT) on progression of dystrophy in mdx mice. Methods: Ten animals were randomly divided into 2 experimental groups treated with superpulsed LLLT (904 nm, 15 mW, 700 Hz, 1 J) or placebo-LLLT at one point overlying the tibialis anterior muscle (bilaterally) 5 times per week for 14 weeks (from 6th to 20th week of age). Morphological changes, creatine kinase (CK) activity and mRNA gene expression were assesse...

  6. ADAM12 alleviates the skeletal muscle pathology in mdx dystrophic mice

    DEFF Research Database (Denmark)

    Kronqvist, Pauliina; Kawaguchi, Nobuko; Albrechtsen, Reidar;

    2002-01-01

    Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study...... evidenced by less muscle cell necrosis and inflammation, lower levels of serum creatine kinase, and less uptake of Evans Blue dye into muscle fibers. These studies demonstrate that ADAM12 directly or indirectly contributes to muscle cell regeneration, stability, and survival....... we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx mice alleviated the muscle pathology in these animals, as...

  7. Myogenic Akt signaling attenuates muscular degeneration, promotes myofiber regeneration and improves muscle function in dystrophin-deficient mdx mice

    OpenAIRE

    Kim, Michelle H.; Kay, Danielle I.; Rudra, Renuka T.; Chen, Bo Ming; Hsu, Nigel; Izumiya, Yasuhiro; Martinez, Leonel; Spencer, Melissa J.; Walsh, Kenneth; Grinnell, Alan D.; Crosbie, Rachelle H.

    2011-01-01

    Duchenne muscular dystrophy, the most common form of childhood muscular dystrophy, is caused by X-linked inherited mutations in the dystrophin gene. Dystrophin deficiencies result in the loss of the dystrophin–glycoprotein complex at the plasma membrane, which leads to structural instability and muscle degeneration. Previously, we induced muscle-specific overexpression of Akt, a regulator of cellular metabolism and survival, in mdx mice at pre-necrotic (6 weeks) similarly increased the abunda...

  8. Combination Antisense Treatment for Destructive Exon Skipping of Myostatin and Open Reading Frame Rescue of Dystrophin in Neonatal mdx Mice.

    Science.gov (United States)

    Lu-Nguyen, Ngoc B; Jarmin, Susan A; Saleh, Amer F; Popplewell, Linda; Gait, Michael J; Dickson, George

    2015-08-01

    The fatal X-linked Duchenne muscular dystrophy (DMD), characterized by progressive muscle wasting and muscle weakness, is caused by mutations within the DMD gene. The use of antisense oligonucleotides (AOs) modulating pre-mRNA splicing to restore the disrupted dystrophin reading frame, subsequently generating a shortened but functional protein has emerged as a potential strategy in DMD treatment. AO therapy has recently been applied to induce out-of-frame exon skipping of myostatin pre-mRNA, knocking-down expression of myostatin protein, and such an approach is suggested to enhance muscle hypertrophy/hyperplasia and to reduce muscle necrosis. Within this study, we investigated dual exon skipping of dystrophin and myostatin pre-mRNAs using phosphorodiamidate morpholino oligomers conjugated with an arginine-rich peptide (B-PMOs). Intraperitoneal administration of B-PMOs was performed in neonatal mdx males on the day of birth, and at weeks 3 and 6. At week 9, we observed in treated mice (as compared to age-matched, saline-injected controls) normalization of muscle mass, a recovery in dystrophin expression, and a decrease in muscle necrosis, particularly in the diaphragm. Our data provide a proof of concept for antisense therapy combining dystrophin restoration and myostatin inhibition for the treatment of DMD. PMID:25959011

  9. Myofiber branching rather than myofiber hyperplasia contributes to muscle hypertrophy in mdx mice

    OpenAIRE

    Faber, Rachel M; Hall, John K; Chamberlain, Jeffrey S.; Banks, Glen B.

    2014-01-01

    Background Muscle hypertrophy in the mdx mouse model of Duchenne muscular dystrophy (DMD) can partially compensate for the loss of dystrophin by maintaining peak force production. Histopathology examination of the hypertrophic muscles suggests the hypertrophy primarily results from the addition of myofibers, and is accompanied by motor axon branching. However, it is unclear whether an increased number of innervated myofibers (myofiber hyperplasia) contribute to muscle hypertrophy in the mdx m...

  10. Effects of Mechanical Over-Loading on the Properties of Soleus Muscle Fibers, with or without Damage, in Wild Type and Mdx Mice

    OpenAIRE

    Terada, Masahiro; Kawano, Fuminori; Ohira, Takashi; Nakai, Naoya; Nishimoto, Norihiro; Ohira, Yoshinobu

    2012-01-01

    Effects of mechanical over-loading on the characteristics of regenerating or normal soleus muscle fibers were studied in dystrophin-deficient (mdx) and wild type (WT) mice. Damage was also induced in WT mice by injection of cardiotoxin (CTX) into soleus muscle. Over-loading was applied for 14 days to the left soleus muscle in mdx and intact and CTX-injected WT mouse muscles by ablation of the distal tendons of plantaris and gastrocnemius muscles. All of the myonuclei in normal muscle of WT mi...

  11. Comparative study of myocytes from normal and mdx mice iPS cells.

    Science.gov (United States)

    Chen, Fei; Cao, Jiqing; Liu, Qiang; Qin, Jie; Kong, Jie; Wang, Yanyun; Li, Yaqin; Geng, Jia; Li, Qiuling; Yang, Liqing; Xiang, Andy Peng; Zhang, Cheng

    2012-02-01

    Recently, induced pluripotent stem cells (iPS cells) have been derived from various techniques and show great potential for therapy of human diseases. Furthermore, the iPS technique can be used to provide cell models to explore pathological mechanisms of many human diseases in vitro, such as Duchenne muscular dystrophy (DMD), which is a severe recessive X-linked form of muscular dystrophy without effective treatment. In this study, we try to determine whether there are different characteristics of myocytes from mdx iPS cells and C57BL/10 iPS cells. Our results showed that both of mdx and C57BL/10 cells could be induced into iPS cells in vitro, whereas colony-forming ability of mdx iPS cells was much weaker than that of C57BL/10 iPS cells. Meanwhile, mdx iPS cells could be induced to differentiate into myocytes, whereas their differentiation efficiency was much lower than that of C57BL/10 iPS cells. And, the number of apoptotic cells in differentiated myocytes from mdx iPS cells was significantly higher than that from C57BL/10 iPS cells. More importantly, treatment of a pan-caspase inhibitor (Z-VAD) produced a significant decrease in apoptotic cells. This study might add some insight to the biology study of dystrophin gene. PMID:21976068

  12. Correlation analysis of inorganic elements in biological tissue if DMD{sup mdx}/J mice using INAA

    Energy Technology Data Exchange (ETDEWEB)

    Metairon, Sabrina; Zamboni, Cibele B.; Suzuki, Miriam F., E-mail: metairon@usp.b, E-mail: czamboni@ipen.b, E-mail: mfsuzuki@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Bueno Junior, Carlos R. [Universidade de Sao Paulo (USP), SP (Brazil). Inst. de Biociencias. Centro de Estudos do Genoma Humano; Sant' Anna, Osvaldo A., E-mail: gbrazil@usp.b [Instituto Butantan, Sao Paulo, SP (Brazil)

    2011-07-01

    Instrumental neutron activation analysis technique (INAA) has been used to determine Br, Ca, Cl, K, Mg, Na and S concentrations in bone and other organs samples from DMD{sup mdx}/J dystrophic mice as well as C57BL/6J control group mice. The DMD{sup mdx}/J mouse strain is relevant as an experimental model for Duchenne Muscular Dystrophy (DMD), which is the most severe and prevalent type of muscular dystrophy. Muscle weakness, premature death and instability of the membrane that involves the muscle fibers - causing functional/structural abnormalities and cell death - are main characteristics of this genetic disease. To show in more details the alterations that this disease may cause in bones (tibiae) and organs (quadriceps and heart), correlations matrixes were generated for both strains permitting a comparison between these groups. A significant change was observed in the analysis of the heart of dystrophic mice suggesting that this dysfunction affects severely the heart muscle. The results emphasize physiologic differences for Na, Ca and Mg and suggest that Br and S results are altered, emphasizing a constant monitoring needs. Other than that, these results may help the researchers to evaluate the efficiency of new treatments and to compare the advantages of different treatment approaches before performing tests in patients with muscular dystrophy. (author)

  13. Enhancing translation: guidelines for standard pre-clinical experiments in mdx mice

    OpenAIRE

    Willmann, Raffaella; De Luca, Annamaria; Benatar, Michael; Grounds, Miranda; Dubach, Judith; Raymackers, Jean-Marc; Nagaraju, Kanneboyina

    2011-01-01

    Duchenne Muscular Dystrophy is an X-linked disorder that affects boys and leads to muscle wasting and death due to cardiac involvement and respiratory complications. The cause is the absence of dystrophin, a large structural protein indispensable for muscle cell function and viability. Neither an effective treatment nor a cure is available at the present time. The mdx mouse has become the standard animal model for pre-clinical evaluation of potential therapeutic treatments. Recent years have ...

  14. Elements determination of clinical relevance in biological tissues Dmd{sup mdx}/J dystrophic mice strains investigated by NAA; Determinacao de elementos de relevancia clinica em tecidos biologicos de camundongos distroficos Dmd{sup mdx}/J por AAN

    Energy Technology Data Exchange (ETDEWEB)

    Metairon, Sabrina

    2012-07-01

    In this work the determination of chemistry elements in biological tissues (whole blood, bones and organs) of dystrophic mice, used as animal model of Duchenne Muscular Dystrophy (DMD), was performed using analytical nuclear technique. The aim of this work was to determine reference values of elements of clinical (Ca, Cl, K, Mg, Na) and nutritional (Br and S) relevance in whole blood, tibia, quadriceps and hearts from Dmdmdx/J (10 males and 10 females) dystrophic mice and C57BL/6J (10 males) control group mice, using Neutron Activation Analysis technique (NAA). To show in more details the alterations that this disease may cause in these biological tissues, correlations matrixes of the DMD{sup mdx}/J mouse strain were generated and compared with C57BL/6J control group. For this study 119 samples of biological tissue were irradiated in the IEA-R1 nuclear reactor at IPEN (Sao Paulo, Brazil). The concentrations of these elements in biological tissues of Dmd{sup mdx}/J and C57B/6J mice are the first indicative interval for reference values. Moreover, the alteration in some correlation coefficients data among the elements in the health status and in the diseased status indicates a connection between these elements in whole blood, tibia, quadriceps and heart. These results may help the researchers to evaluate the efficiency of new treatments and to compare the advantages of different treatment approaches before performing tests in patients with muscular dystrophy. (author)

  15. Long-Term Blocking of Calcium Channels in mdx Mice Results in Differential Effects on Heart and Skeletal Muscle

    DEFF Research Database (Denmark)

    Jørgensen, Louise Helskov; Blain, Alison; Greally, Elizabeth;

    2011-01-01

    The disease mechanisms underlying dystrophin-deficient muscular dystrophy are complex, involving not only muscle membrane fragility, but also dysregulated calcium homeostasis. Specifically, it has been proposed that calcium channels directly initiate a cascade of pathological events by allowing...... calcium ions to enter the cell. The objective of this study was to investigate the effect of chronically blocking calcium channels with the aminoglycoside antibiotic streptomycin from onset of disease in the mdx mouse model of Duchenne muscular dystrophy (DMD). Treatment in utero onwards delayed onset of...... older mice. However, streptomycin treatment did not show positive effects in diaphragm or heart muscle, and heart pathology was worsened. Thus, blocking calcium channels even before disease onset does not prevent dystrophy, making this an unlikely treatment for DMD. These findings highlight the...

  16. iNOS ablation does not improve specific force of the extensor digitorum longus muscle in dystrophin-deficient mdx4cv mice.

    Directory of Open Access Journals (Sweden)

    Dejia Li

    Full Text Available Nitrosative stress compromises force generation in Duchenne muscular dystrophy (DMD. Both inducible nitric oxide synthase (iNOS and delocalized neuronal NOS (nNOS have been implicated. We recently demonstrated that genetic elimination of nNOS significantly enhanced specific muscle forces of the extensor digitorum longus (EDL muscle of dystrophin-null mdx4cv mice (Li D et al J. Path. 223:88-98, 2011. To determine the contribution of iNOS, we generated iNOS deficient mdx4cv mice. Genetic elimination of iNOS did not alter muscle histopathology. Further, the EDL muscle of iNOS/dystrophin DKO mice yielded specific twitch and tetanic forces similar to those of mdx4cv mice. Additional studies suggest iNOS ablation did not augment nNOS expression neither did it result in appreciable change of nitrosative stress markers in muscle. Our results suggest that iNOS may play a minor role in mediating nitrosative stress-associated force reduction in DMD.

  17. Superpulsed low-level laser therapy protects skeletal muscle of mdx mice against damage, inflammation and morphological changes delaying dystrophy progression.

    Directory of Open Access Journals (Sweden)

    Ernesto Cesar Pinto Leal-Junior

    Full Text Available AIM: To evaluate the effects of preventive treatment with low-level laser therapy (LLLT on progression of dystrophy in mdx mice. METHODS: Ten animals were randomly divided into 2 experimental groups treated with superpulsed LLLT (904 nm, 15 mW, 700 Hz, 1 J or placebo-LLLT at one point overlying the tibialis anterior muscle (bilaterally 5 times per week for 14 weeks (from 6th to 20th week of age. Morphological changes, creatine kinase (CK activity and mRNA gene expression were assessed in animals at 20th week of age. RESULTS: Animals treated with LLLT showed very few morphological changes in skeletal muscle, with less atrophy and fibrosis than animals treated with placebo-LLLT. CK was significantly lower (p=0.0203 in animals treated with LLLT (864.70 U.l-1, SEM 226.10 than placebo (1708.00 U.l-1, SEM 184.60. mRNA gene expression of inflammatory markers was significantly decreased by treatment with LLLT (p<0.05: TNF-α (placebo-control=0.51 µg/µl [SEM 0.12], - LLLT=0.048 µg/µl [SEM 0.01], IL-1β (placebo-control=2.292 µg/µl [SEM 0.74], - LLLT=0.12 µg/µl [SEM 0.03], IL-6 (placebo-control=3.946 µg/µl [SEM 0.98], - LLLT=0.854 µg/µl [SEM 0.33], IL-10 (placebo-control=1.116 µg/µl [SEM 0.22], - LLLT=0.352 µg/µl [SEM 0.15], and COX-2 (placebo-control=4.984 µg/µl [SEM 1.18], LLLT=1.470 µg/µl [SEM 0.73]. CONCLUSION: Irradiation of superpulsed LLLT on successive days five times per week for 14 weeks decreased morphological changes, skeletal muscle damage and inflammation in mdx mice. This indicates that LLLT has potential to decrease progression of Duchenne muscular dystrophy.

  18. Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

    OpenAIRE

    Bonuccelli, Gloria; Sotgia, Federica; Schubert, William; Park, David S.; Frank, Philippe G.; Woodman, Scott E.; Insabato, Luigi; Cammer, Michael; Minetti, Carlo; Lisanti, Michael P.

    2003-01-01

    Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is absent in the skeletal muscle of DMD patients and mdx mice. At the plasma membrane of skeletal muscle fibers, dystrophin associates with a multimeric protein complex, termed the dystrophin-glycoprotein complex (DGC). Protein members of this complex are normally absent or greatly reduced in dystrophin-deficient skeletal muscle fibers, and are thought to undergo degradation through an unknown pathway. As such, we ...

  19. Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the ??M??2 leukocyte integrin receptor

    OpenAIRE

    Vidal, B.; Ardite, E.; Suelves, M.; Ruiz-Bonilla, V.; Janue, A.; Flick, M. J.; Degen, J L; Serrano, A. L.; Munoz-Canoves, P.

    2012-01-01

    In Duchenne muscular dystrophy (DMD), a persistently altered and reorganizing extracellular matrix (ECM) within inflamed muscle promotes damage and dysfunction. However, the molecular determinants of the ECM that mediate inflammatory changes and faulty tissue reorganization remain poorly defined. Here, we show that fibrin deposition is a conspicuous consequence of muscle-vascular damage in dystrophic muscles of DMD patients and mdx mice and that elimination of fibrin(ogen) attenuated dystroph...

  20. D-Amino Acid Substitution of Peptide-Mediated NF-κB Suppression in mdx Mice Preserves Therapeutic Benefit in Skeletal Muscle, but Causes Kidney Toxicity.

    Science.gov (United States)

    Reay, Daniel P; Bastacky, Sheldon I; Wack, Kathryn E; Stolz, Donna B; Robbins, Paul D; Clemens, Paula R

    2015-01-01

    In Duchenne muscular dystrophy (DMD) patients and the mdx mouse model of DMD, chronic activation of the classical nuclear factor-κB (NF-κB) pathway contributes to the pathogenesis that causes degeneration of muscle fibers, inflammation and fibrosis. Prior studies demonstrate that inhibition of inhibitor of κB kinase (IKK)-mediated NF-κB activation using L-isomer NF-κB essential modulator (NEMO)-binding domain (NBD) peptide-based approaches reduce muscle pathology in the mdx mouse. For our studies, the NBD peptide is synthesized as a fusion peptide with an eight-lysine (8K) protein transduction domain to facilitate intracellular delivery. We hypothesized that the d-isoform peptide could have a greater effect than the naturally occurring L-isoform peptide due to the longer persistence of the D-isoform peptide in vivo. In this study, we compared systemic treatment with low (1 mg/kg) and high (10 mg/kg) doses of L- and D-isomer 8K-wild-type-NBD peptide in mdx mice. Treatment with both L- or D-isoform 8K-wild-type-NBD peptide resulted in decreased activation of NF-κB and improved histology in skeletal muscle of the mdx mouse. However, we observed kidney toxicity (characterized by proteinuria), increased serum creatinine, activation of NF-κB and pathological changes in kidney cortex that were most severe with treatment with the D-isoform of 8K-wild-type-NBD peptide. The observed toxicity was also seen in normal mice. PMID:26018805

  1. Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice

    OpenAIRE

    Martin, Paul T.; Xu, Rui; Rodino-Klapac, Louise R.; Oglesbay, Elaine; Camboni, Marybeth; Montgomery, Chrystal L; Shontz, Kim; Chicoine, Louis G.; Clark, K Reed; Sahenk, Zarife; Mendell, Jerry R; Janssen, Paul M.L.

    2008-01-01

    The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:β1,4-N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcβ1,4[NeuAc(orGc)α2, 3]Galβ1,4GlcNAcβ-}. Overexpression of Galgt2 in the skeletal muscles of transgenic mice inhibits the development of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. Here, we provide physiological evidence as...

  2. Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice

    Directory of Open Access Journals (Sweden)

    Sirsi Shashank R

    2008-04-01

    Full Text Available Abstract Background Exon skipping oligonucleotides (ESOs of 2'O-Methyl (2'OMe and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD. However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine (PEI and poly(ethylene glycol (PEG are regarded as effective agents for enhanced delivery of nucleic acids in various applications. Results We examined whether PEG-PEI copolymers can facilitate ESO-mediated dystrophin expression after intramuscular injections into tibialis anterior (TA muscles of mdx mice. We utilized a set of PEG-PEI copolymers containing 2 kDa PEI and either 550 Da or 5 kDa PEG, both of which bind 2'OMe ESOs with high affinity and form stable nanoparticulates with a relatively low surface charge. Three weekly intramuscular injections of 5 μg of ESO complexed with PEI2K-PEG550 copolymers resulted in about 500 dystrophin-positive fibers and about 12% of normal levels of dystrophin expression at 3 weeks after the initial injection, which is significantly greater than for injections of ESO alone, which are known to be almost completely ineffective. In an effort to enhance biocompatibility and cellular uptake, the PEI2K-PEG550 and PEI2K-PEG5K copolymers were functionalized by covalent conjugation with nanogold (NG or adsorbtion of colloidal gold (CG, respectively. Surprisingly, using the same injection and dosing regimen, we found no significant difference in dystrophin expression by Western blot between the NG-PEI2K-PEG550, CG-PEI2K-PEG5K, and non-functionalized PEI2K-PEG550 copolymers. Dose-response experiments using the CG-PEI2K-PEG5K copolymer with total ESO ranging from 3–60 μg yielded a maximum of about 15% dystrophin expression. Further improvements in dystrophin expression up to 20% of normal

  3. Metabolic profile of dystrophic mdx mouse muscles analyzed with in vitro magnetic resonance spectroscopy (MRS).

    Science.gov (United States)

    Martins-Bach, Aurea B; Bloise, Antonio C; Vainzof, Mariz; Rahnamaye Rabbani, Said

    2012-10-01

    Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy characterized by progressive and irreversible degeneration of the muscles. The mdx mouse is the classical animal model for DMD, showing similar molecular and protein defects. The mdx mouse, however, does not show significant muscle weakness, and the diaphragm muscle is significantly more degenerated than skeletal muscles. In this work, (1)H magnetic resonance spectroscopy (MRS) was used to study the metabolic profile of quadriceps and diaphragm muscles from mdx and control mice. Using principal components analysis (PCA), the animals were separated into groups according to age and lineages. The classification was compared to histopathological analysis. Among the 24 metabolites identified from the nuclear MR spectra, only 19 were used by the PCA program for classification purposes. These can be important key biomarkers associated with the progression of degeneration in mdx muscles and with natural aging in control mice. Glutamate, glutamine, succinate, isoleucine, acetate, alanine and glycerol were increased in mdx samples as compared to control mice, in contrast to carnosine, taurine, glycine, methionine and creatine that were decreased. These results suggest that MRS associated with pattern recognition analysis can be a reliable tool to assess the degree of pathological and metabolic alterations in the dystrophic tissue, thereby affording the possibility of evaluation of beneficial effects of putative therapies. PMID:22673895

  4. Dystropathology increases energy expenditure and protein turnover in the mdx mouse model of duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Hannah G Radley-Crabb

    Full Text Available The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the dietary requirements for these macronutrients at different stages of the disease, are not well-understood. This study used juvenile (4- to 5- wk-old and adult (12- to 14-wk-old male dystrophic C57BL/10ScSn-mdx/J and age-matched C57BL/10ScSn/J control male mice to measure total and resting energy expenditure, food intake, spontaneous activity, body composition, whole body protein turnover, and muscle protein synthesis rates. In juvenile mdx mice that have extensive muscle damage, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were higher than in age-matched controls. Adaptations in food intake and decreased activity were insufficient to meet the increased energy and protein needs of juvenile mdx mice and resulted in stunted growth. In (non-growing adult mdx mice with less severe dystropathology, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were also higher than in age-matched controls. Food intake was sufficient to meet their protein and energy needs, but insufficient to result in fat deposition. These data show that dystropathology impacts the protein and energy needs of mdx mice and that tailored dietary interventions are necessary to redress this imbalance. If not met, the resultant imbalance blunts growth, and may limit the benefits of therapies designed to protect and repair dystrophic muscles.

  5. Serotonin and Histamine Therapy Increases Tetanic Forces of Myoblasts, Reduces Muscle Injury, and Improves Grip Strength Performance of Dmd(mdx) Mice.

    Science.gov (United States)

    Gurel, Volkan; Lins, Jeremy; Lambert, Kristyn; Lazauski, Joan; Spaulding, James; McMichael, John

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a recessive X-linked fatal disorder caused by a mutation in the dystrophin gene. Although several therapeutic approaches have been studied, none has led to substantial long-term effects in patients. The aim of this study was to test a serotonin and histamine (S&H) combination on human skeletal myoblasts and Dmd(mdx) mice for its effects on muscle strength and injury. Normal human bioartificial muscles (BAMs) were treated, and muscle tetanic forces and muscle injury tests were performed using the MyoForce Analysis System. Dmd(mdx) mice, the murine model of DMD, were administered serotonin, histamine, or S&H combination twice daily for 6 weeks, and functional performance tests were conducted once a week. The S&H combination treatment caused significant increases in tetanic forces at all time points and concentrations tested as compared to the saline controls. Dose response of the BAMs to the treatment demonstrated a significant increase in force generation at all concentrations compared to the controls after 3 to 4 days of drug treatment. The highest 3 concentrations had a significant effect on lowering contractile-induced injury as measured by a reduction in the release of adenylate kinase. Histamine-only and S&H treatments improved grip strength of Dmd(mdx) mice, whereas serotonin-only treatment resulted in no significant improvement in muscle strength. The results of this study indicate that S&H therapy might be a promising new strategy for muscular dystrophies and that the mechanism should be further investigated. PMID:26740813

  6. Biodistribution and Molecular Studies on Orally Administered Nanoparticle-AON Complexes Encapsulated with Alginate Aiming at Inducing Dystrophin Rescue in mdx Mice

    Directory of Open Access Journals (Sweden)

    Maria Sofia Falzarano

    2013-01-01

    Full Text Available We have previously demonstrated that intraperitoneal injections of 2′-O-methyl-phosphorothioate (2′OMePS antisense oligoribonucleotides adsorbed onto a cationic core-shell nanoparticles (NPs, termed ZM2, provoke dystrophin restoration in the muscles of mdx mice. The aim of the present work was to evaluate the oral route as an alternative way of administration for ZM2-antisense oligoribonucleotides complexes. The biodistribution and elimination of nanoparticles were evaluated after single and multiple oral doses of IR-dye conjugated nanoparticles. Labeled nanoparticles were tracked in vivo as well as in tissue cryosections, urines and feces by Odyssey infrared imaging system, and revealed a permanence in the intestine and abdominal lymph nodes for 72 hours to 7 days before being eliminated. We subsequently tested alginate-free and alginate-encapsulated ZM2-antisense oligoribonucleotides (AON complexes orally administered 2 and 3 times per week, respectively, in mdx mice for a total of 12 weeks. Treatment with alginate ZM2-AON induced a slight dystrophin rescue in diaphragm and intestine smooth muscles, while no dystrophin was detected in alginate-free ZM2-AON treated mice. These data encourage further experiments on oral administration testing of NP and AON complexes, possibly translatable in oligoribonucleotides-mediated molecular therapies.

  7. Poly(ester amine) Composed of Polyethylenimine and Pluronic Enhance Delivery of Antisense Oligonucleotides In Vitro and in Dystrophic mdx Mice.

    Science.gov (United States)

    Wang, Mingxing; Wu, Bo; Tucker, Jason D; Bollinger, Lauren E; Lu, Peijuan; Lu, Qilong

    2016-01-01

    A series of poly(esteramine)s (PEAs) constructed from low molecular weight polyethyleneimine (LPEI) and Pluronic were evaluated for the delivery of antisense oligonuclotides (AOs), 2'-O-methyl phosphorothioate RNA (2'-OMePS) and phosphorodiamidate morpholino oligomer (PMO) in cell culture and dystrophic mdx mice. Improved exon-skipping efficiency of both 2'-OMePS and PMO was observed in the C2C12E50 cell line with all PEA polymers compared with PEI 25k or LF-2k. The degree of efficiency was found in the order of PEA 01, PEA 04 > PEA 05 > others. The in vivo study in mdx mice demonstrated enhanced exon-skipping of 2'-OMePS with the order of PEA 06 > PEA 04, PEA 07 > PEA 03 > PEA 01 > others, and much higher than PEI 25k formulated 2'-OMePS. Exon-skipping efficiency of PMO in formulation with the PEAs were significantly enhanced in the order of PEA 02 > PEA 10 > PEA 01, PEA 03 > PEA 05, PEA 07, PEA 08 > others, with PEA 02 reaching fourfold of Endo-porter formulated PMO. PEAs improve PMO delivery more effectively than 2'-OMePS delivery in vivo, and the systemic delivery evaluation further highlight the efficiency of PEA for PMO delivery in all skeletal muscle. The results suggest that the flexibility of PEA polymers could be explored for delivery of different AO chemistries, especially for antisense therapy. PMID:27483024

  8. Isobaric Tagging-Based Quantification for Proteomic Analysis: A Comparative Study of Spared and Affected Muscles from mdx Mice at the Early Phase of Dystrophy.

    Directory of Open Access Journals (Sweden)

    Cintia Yuri Matsumura

    Full Text Available Duchenne muscular dystrophy (DMD is the most common childhood myopathy, characterized by muscle loss and cardiorespiratory failure. While the genetic basis of DMD is well established, secondary mechanisms associated with dystrophic pathophysiology are not fully clarified yet. In order to obtain new insights into the molecular mechanisms of muscle dystrophy during earlier stages of the disease, we performed a comparative proteomic profile of the spared extraocular muscles (EOM vs. affected diaphragm from the mdx mice, using a label based shotgun proteomic approach. Out of the 857 identified proteins, 42 to 62 proteins had differential abundance of peptide ions. The calcium-handling proteins sarcalumenin and calsequestrin-1 were increased in control EOM compared with control DIA, reinforcing the view that constitutional properties of EOM are important for their protection against myonecrosis. The finding that galectin-1 (muscle regeneration, annexin A1 (anti-inflammatory and HSP 47 (fibrosis were increased in dystrophic diaphragm provides novel insights into the mechanisms through which mdx affected muscles are able to counteract dystrophy, during the early stage of the disease. Overall, the shotgun technique proved to be suitable to perform quantitative comparisons between distinct dystrophic muscles and allowed the suggestion of new potential biomarkers and drug targets for dystrophinopaties.

  9. Dystrophin Delivery to Muscles of mdx Mice Using Lentiviral Vectors Leads to Myogenic Progenitor Targeting and Stable Gene Expression

    OpenAIRE

    Kimura, En; Li, Sheng; Gregorevic, Paul; Fall, Brent M; Jeffrey S. Chamberlain

    2009-01-01

    To explore whether stable transduction of myogenic stem cells using lentiviral vectors could be of benefit for treating dystrophic muscles, we generated vectors expressing a functional microdystrophin/enhanced green fluorescence protein fusion (µDys/eGFP) gene. Lentiviral vector injection into neonatal mdx4cv muscles resulted in widespread and stable expression of dystrophin for at least 2 years. This expression resulted in a significant amelioration of muscle pathophysiology as assessed by a...

  10. AAV micro-dystrophin gene therapy alleviates stress-induced cardiac death but not myocardial fibrosis in >21-m-old mdx mice, an end-stage model of Duchenne muscular dystrophy cardiomyopathy

    OpenAIRE

    Bostick, Brian; Shin, Jin-Hong; Yue, Yongping; Wasala, Nalinda B.; Lai, Yi; Duan, Dongsheng

    2012-01-01

    Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by the absence of the sarcolemmal protein dystrophin. Dilated cardiomyopathy leading to heart failure is a significant source of morbidity and mortality in DMD. We recently demonstrated amelioration of DMD heart disease in 16 to 20-m-old dystrophin-null mdx mice using adeno-associated virus (AAV) mediated micro-dystrophin gene therapy. DMD patients show severe heart disease near the end of their life expectancy. Similarly, md...

  11. Bubble liposomes and ultrasound exposure improve localized morpholino oligomer delivery into the skeletal muscles of dystrophic mdx mice.

    Science.gov (United States)

    Negishi, Yoichi; Ishii, Yuko; Shiono, Hitomi; Akiyama, Saki; Sekine, Shoko; Kojima, Takuo; Mayama, Sayaka; Kikuchi, Taiki; Hamano, Nobuhito; Endo-Takahashi, Yoko; Suzuki, Ryo; Maruyama, Kazuo; Aramaki, Yukihiko

    2014-03-01

    Duchenne muscular dystrophy (DMD) is a genetic disorder that is caused by mutations in the DMD gene that lead to an absence of functional protein. The mdx dystrophic mouse contains a nonsense mutation in exon 23 of the dystrophin gene; a phosphorodiamidate morpholino oligomer (PMO) designed to skip this mutated exon in the mRNA induces dystrophin expression. However, an efficient PMO delivery method is needed to improve treatment strategies for DMD. We previously developed polyethylene glycol (PEG)-modified liposomes (Bubble liposomes) that entrap ultrasound contrast gas and demonstrated that the combination of Bubble liposomes with ultrasound exposure is an effective gene delivery tool in vitro and in vivo. In this study, to evaluate the ability of Bubble liposomes as a PMO delivery tool, we tested the potency of the Bubble liposomes combined with ultrasound exposure to boost the delivery of PMO and increase the skipping of the mutated exon in the mdx mouse. The results indicated that the combination of Bubble liposomes and ultrasound exposure increased the uptake of the PMO targeting a nonsense mutation in exon 23 of the dystrophin gene and consequently increased the PMO-mediated exon-skipping efficiency compared with PMO injection alone, leading to significantly enhanced dystrophin expression. This increased efficiency indicated the potential of the combination of Bubble liposomes with ultrasound exposure to enhance PMO delivery for treating DMD. Thus, this ultrasound-mediated Bubble liposome technique may provide an effective, noninvasive, nonviral method for PMO therapy for DMD muscle as well as for other muscular dystrophies. PMID:24433046

  12. 骨髓干细胞移植后mdx鼠腓肠肌病理变化%Pathologic change in mdx mice gastrocnemius muscle after bone marrow stem cells transplantation

    Institute of Scientific and Technical Information of China (English)

    卢锡林; 冯善伟; 姚晓黎; 张为西; 于美娟; 张成

    2008-01-01

    Objective To investigate the pathologic change in mdx mice gastrecnemius muscle after the bone marrow stem cells transplantation. Methods Twenty mdx mice (7 to 9 weeks old) preconditioned with 7 Gy γ-ray were divided into 4 groups and bone marrow stem ceils from C57 mice (6 to 8 weeks old) were injected intravenously into the mdx mice. Morphology and centrally nucleated fibers (CNF)were observed by HE stain and the rate of CNF was calculated 4 weeks ,8 weeks ,12 weeks and 16 weeks after transplantation respectively. Five C57 mice and 5 mdx mice were acted as positive and negative controls. Results The myocytes of normal C57 mice were polygon and uniform in size with nuclei localized in borderline. No inflammation was found in intraceilular substance. The myocytes of treated and untreated mdx mice were round in shape and various in size. The obvious abnormality was nucleus centralized. The rate of CNF in untreated mdx mice was highest, up to 70%. The rate of CNF decreased to 55%,50% and 44% at the 4th, 12th, 16th week after transplantation. Condusion CNF of mdx mice gastrecnemias muscle decreases gradually after bone marrow stem cells transplantation, which indicates that the bone marrow stem cells can participate in the repair and regeneration of the injured tissues permanently and constantly.%目的 研究骨髓干细胞移植后mdx鼠腓肠肌组织病理变化. 方法 7~9周龄mdx鼠20只平均分为4组,放射处理后移植1.2×107细胞/只同种异基因全骨髓干细胞,于移植后4、8、12及16周用HE染色观察腓肠肌组织细胞形态及核中心移位纤维(CNF).C57鼠和未治疗mdx鼠各5只作阳性和阴性对照. 结果 CS7鼠腓肠肌横切面可见肌细胞大小形态基本一致,无核中心移位现象.各细胞移植治疗组和阴性对照组mdx鼠均有大量的炎细胞浸润,核中心移位明显.未治疗mdx鼠CNF最高,约达70%;移植后4、12和16周,CNF分别为55%、50%和44%. 结论 骨髓干细胞移植后mdx鼠腓肠

  13. Practical pathology of aging mice

    Directory of Open Access Journals (Sweden)

    Piper M. M. Treuting

    2011-06-01

    Full Text Available Old mice will have a subset of lesions as part of the progressive decline in organ function that defines aging. External and palpable lesions will be noted by the research, husbandry, or veterinary staff during testing, cage changing, or physical exams. While these readily observable lesions may cause alarm, not all cause undue distress or are life-threatening. In aging research, mice are maintained until near end of life that, depending on strain and genetic manipulation, can be upwards of 33 months. Aging research has unique welfare issues related to age-related decline, debilitation, fragility, and associated pain of chronic diseases. An effective aging research program includes the collaboration and education of the research, husbandry, and veterinary staff, and of the members of the institution animal care and use committee. This collaborative effort is critical to humanely maintaining older mice and preventing excessive censorship due to non-lethal diseases. Part of the educational process is becoming familiar with how old mice appear clinically, at necropsy and histopathologically. This baseline knowledge is important in making the determination of humane end points, defining health span, contributing causes of death and effects of interventions. The goal of this paper is to introduce investigators to age-associated diseases and lesion patterns in mice from clinical presentation to pathologic assessment. To do so, we present and illustrate the common clinical appearances, necropsy and histopathological lesions seen in subsets of the aging colonies maintained at the University of Washington.

  14. Cationic polyelectrolyte-mediated delivery of antisense morpholino oligonucleotides for exon-skipping in vitro and in mdx mice

    Directory of Open Access Journals (Sweden)

    Wang M

    2015-09-01

    Full Text Available Mingxing Wang, Bo Wu, Jason D Tucker, Peijuan Lu, Qilong Lu Department of Neurology, McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, NC, USA Abstract: In this study, we investigated a series of cationic polyelectrolytes (PEs with different size and composition for their potential to improve delivery of an antisense phosphorodiamidate morpholino oligomer (PMO both in vitro and in vivo. The results showed that the poly(diallyldimethylammonium chloride (PDDAC polymer series, especially PE-3 and PE-4, improves the delivery efficiency of PMO, comparable with Endoporter-mediated PMO delivery in vitro. The enhanced PMO delivery and targeting to dystrophin exon 23 was further observed in mdx mice, up to fourfold with the PE-4, compared with PMO alone. The cytotoxicity of the PEs was lower than that of Endoporter and polyethylenimine 25,000 Da in vitro, and was not clearly detected in muscle in vivo under the tested concentrations. Together, these results demonstrate that optimization of PE molecular size, composition, and distribution of cationic charge are key factors to achieve enhanced PMO exon-skipping efficiency. The increased efficiency and lower toxicity show this PDDAC series to be capable gene/antisense oligonucleotide delivery-enhancing agents for treating muscular dystrophy and other diseases. Keywords: cationic polyelectrolytes, antisense delivery, exon-skipping, PMO, muscular dystrophy

  15. Long-term efficacy of systemic multiexon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice.

    Science.gov (United States)

    Echigoya, Yusuke; Aoki, Yoshitsugu; Miskew, Bailey; Panesar, Dharminder; Touznik, Aleksander; Nagata, Tetsuya; Tanihata, Jun; Nakamura, Akinori; Nagaraju, Kanneboyina; Yokota, Toshifumi

    2015-01-01

    Antisense-mediated exon skipping, which can restore the reading frame, is a most promising therapeutic approach for Duchenne muscular dystrophy. Remaining challenges include the limited applicability to patients and unclear function of truncated dystrophin proteins. Multiexon skipping targeting exons 45-55 at the mutation hotspot of the dystrophin gene could overcome both of these challenges. Previously, we described the feasibility of exons 45-55 skipping with a cocktail of Vivo-Morpholinos in vivo; however, the long-term efficacy and safety of Vivo-Morpholinos remains to be determined. In this study, we examined the efficacy and toxicity of exons 45-55 skipping by intravenous injections of 6 mg/kg 10-Vivo-Morpholino cocktail (0.6 mg/kg each vPMO) every 2 weeks for 18 weeks to dystrophic exon-52 knockout (mdx52) mice. Systemic skipping of the entire exons 45-55 region was induced, and the Western blot analysis exhibited the restoration of 5-27% of normal levels of dystrophin protein in skeletal muscles, accompanied by improvements in histopathology and muscle strength. No obvious immune response and renal and hepatic toxicity were detected at the end-point of the treatment. We demonstrate our new regimen with the 10-Vivo-Morpholino cocktail is effective and safe for long-term repeated systemic administration in the dystrophic mouse model. PMID:25647512

  16. Pluronic-PEI copolymers enhance exon-skipping of 2'-O-methyl phosphorothioate oligonucleotide in cell culture and dystrophic mdx mice.

    Science.gov (United States)

    Wang, M; Wu, B; Lu, P; Tucker, J D; Milazi, S; Shah, S N; Lu, Q L

    2014-01-01

    A series of small-size polyethylenimine (PEI)-conjugated pluronic polycarbamates (PCMs) have been investigated for the ability to modulate the delivery of 2'-O-methyl phosphorothioate RNA (2'-OMePS) in vitro and in dystrophic mdx mice. The PCMs retain strong binding capacity to negatively charged oligomer as demonstrated by agarose gel retardation assay, with the formation of condensed polymer/oligomer complexes at a wide-range weight ratio from 1:1 to 20:1. The condensed polymer/oligomer complexes form 100-300 nm nanoparticles. Exon-skipping effect of 2'-OMePS was dramatically enhanced with the use of the most effective PCMs in comparison with 2'-OMePS alone in both cell culture and in vivo, respectively. More importantly, the effective PCMs, especially those composed of moderate size (2k-5kDa) and intermediate hydrophilic-lipophilic balance (7-23) of pluronics, enhanced exon-skipping of 2'-OMePS with low toxicity as compared with Lipofectamine-2000 in vitro or PEI 25k in vivo. The variability of individual PCM for delivery of antisense oligomer and plasmid DNA indicate the complexity of interaction between polymer and their cargos. Our data demonstrate the potential of PCMs to mediate delivery of modified antisense oligonucleotides to the muscle for treating muscular dystrophy or other appropriate myodegenerative diseases. PMID:24131982

  17. d-Amino Acid Substitution of Peptide-Mediated NF-κB Suppression in mdx Mice Preserves Therapeutic Benefit in Skeletal Muscle, but Causes Kidney Toxicity

    OpenAIRE

    Reay, Daniel P.; Bastacky, Sheldon I; Wack, Kathryn E; Stolz, Donna B.; Paul D Robbins; Clemens, Paula R

    2015-01-01

    In Duchenne muscular dystrophy (DMD) patients and the mdx mouse model of DMD, chronic activation of the classical nuclear factor-κB (NF-κB) pathway contributes to the pathogenesis that causes degeneration of muscle fibers, inflammation and fibrosis. Prior studies demonstrate that inhibition of inhibitor of κB kinase (IKK)-mediated NF-κB activation using l-isomer NF-κB essential modulator (NEMO)-binding domain (NBD) peptide-based approaches reduce muscle pathology in the mdx mouse. For our stu...

  18. MDX with SSAS 2012 cookbook

    CERN Document Server

    Li, Sherry

    2013-01-01

    This book is written in a recipe-based style packed full of practical tips and techniques to help you analyse multidimensional data stored in SSAS 2012 cubes. If you need to master MDX queries in SSAS, then this book is for you!If you are a Microsoft SQL Server Analysis Services developer and want to improve your solutions using MDX, then this book is for you. This book is also an essential resource for report developers who need to access the multidimensional cubes through the MDX language. The book assumes you have some basic working knowledge of MDX and a basic understanding of dimensional

  19. X-irradiation improves mdx mouse muscle as a model of myofiber loss in DMD

    International Nuclear Information System (INIS)

    The mdx mouse, although a genetic and biochemical homologue of human Duchenne muscular dystrophy (DMD), presents a comparatively mild histopathological and clinical phenotype. These differences are partially attributable to the greater efficacy of regeneration in the mdx mouse than in DMD muscle. To lessen this disparity, we have used a single dose of X-irradiation (16 Gy) to inhibit regeneration in one leg of mdx mice. The result is an almost complete block of muscle fiber regeneration leading to progressive loss of muscle fibers and their replacement by loose connective tissue. Surviving fibers are mainly peripherally nucleated and, surprisingly, of large diameter. Thus, X-irradiation converts mdx muscle to a model system in which the degenerative process can be studied in isolation from the complicating effect of myofiber regeneration. This system should be of use for testing methods of alleviating the myofiber degeneration which is common to mdx and DMD

  20. Evaluation of Tris[2-(Acryloyloxy)Ethyl]Isocyanurate Cross-Linked Polyethylenimine as Antisense Morpholino Oligomer Delivery Vehicle in Cell Culture and Dystrophic mdx Mice

    OpenAIRE

    Wang, Mingxing; Wu, Bo; Tucker, Jay D.; Lu, Peijuan; Cloer, Caryn; Lu, Qi Long

    2014-01-01

    Hyperbranched poly(ester amine)s (PEAs) based on tris[2-(acryloyloxy)ethyl]isocyanurate (TAEI) cross-linked low-molecular-weight polyethylenimine (Mw: 0.8k/1.2k/2.0k) have been evaluated for delivering antisense phosphorodiamidate morpholino oligomer (PMO) in vitro and in vivo in the dystrophic mdx mouse. The results show that the PEAs constructed with polyethylenimine (PEI) 2.0k (C series) improved PMO delivery more efficiently than those constructed with PEI 0.8k (A series) or 1.2k (B serie...

  1. Testosterone and Dihydrotestosterone Differentially Improve Cognition in Aged Female Mice

    Science.gov (United States)

    Benice, Ted S.; Raber, Jacob

    2009-01-01

    Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to…

  2. Abnormal GABAA-mediated metabolic response in the MDX mouse - an explanation for the mental deficit in Duchenne muscular dystrophy?

    International Nuclear Information System (INIS)

    Full text: Duchenne muscular dystrophy is an X-linked disorder associated with lack of the 728 kDa protein dystrophin. In addition to the well-known muscle wasting, sufferers also experience a 15 point downshift in IQ. Recently reduced clustering of GABAA receptors in cerebellar Purkinje and hippocampal CA1 neurons has been shown in the murine homologue of DMD, the mdx mouse. In this work, the functional efficacy of GABAA receptors in mdx mice (C57B1/10Sc-Sn-mdx) and control was tested by examining the metabolism of [1- 13C]D-glucose under both normoxic and hypoxic conditions and also by examining the metabolic response to the GABAA agonist muscimol (5-aminomethyl-3-hydroxyisoxazole). Although total measured [13C] was identical in mdx cf. control mice, the fractional enrichment of all metabolites was increased in mdx mice, suggesting decreased inhibitory input in these animals. Further, although flux into metabolites from [1-13C]D-glucose decreased as expected in control mice in the presence of muscimol, the GABAa agonist had weaker effect in mdx mice, consistent with weaker GABAA activation. Finally, the response of mdx mouse brain tissue slices to mild hypoxia (partially mediated by GABAA) was altered cf. control mice, with increased production of lactate and decreased flux into Krebs cycle intermediates. These data are consistent with a functional lesion of a subset of GABAA receptors in DMD

  3. Prophylactic pamidronate partially protects from glucocorticoid-induced bone loss in the mdx mouse model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Yoon, Sung-Hee; Chen, Jinghan; Grynpas, Marc D; Mitchell, Jane

    2016-09-01

    Glucocorticoids are extensively used to treat patients with Duchenne muscular dystrophy because of their ability to delay muscle damage, prolong ambulation and extend life. However, use of glucocorticoids significantly increases bone loss, fragility and fractures. To determine if antiresorptive bisphosphonates could prevent the effects of glucocorticoids on bone quality, we used dystrophic mdx mice treated with the glucocorticoid prednisone during 8weeks of rapid bone growth from 5 to 13weeks of age and treated some mice with the bisphosphonate pamidronate during the first two weeks of prednisone administration. Prednisone reduced long bone growth, decreased cortical bone thickness and area and decreased the strength of the femurs. Pamidronate treatment protected mice from cortical bone loss but did not increase bone strength. The combination of prednisone and pamidronate inhibited remodeling of metaphyseal trabecular bone with large numbers of trabeculae containing remnants of calcified cartilage. Prednisone improved muscle strength in the mdx mice and decreased serum creatine kinase with evidence of improved muscle histology and these effects were maintained in mice treated with pamidronate. PMID:27373502

  4. Effectiveness of BCG vaccination to aged mice

    Directory of Open Access Journals (Sweden)

    Ito Tsukasa

    2010-09-01

    Full Text Available Abstract Background The tuberculosis (TB still increases in the number of new cases, which is estimated to approach 10 million in 2010. The number of aged people has been growing all over the world. Ageing is one of risk factors in tuberculosis because of decreased immune responses in aged people. Mycobacterium bovis Bacillus Calmette Guérin (BCG is a sole vaccine currently used for TB, however, the efficacy of BCG in adults is still a matter of debate. Emerging the multidrug resistant Mycobacterium tuberculosis (MDR-TB make us to see the importance of vaccination against TB in new light. In this study, we evaluated the efficacy of BCG vaccination in aged mice. Results The Th1 responses, interferon-γ production and interleukin 2, in BCG inoculated aged mice (24-month-old were comparable to those of young mice (4- to 6-week-old. The protection activity of BCG in aged mice against Mycobacterium tuberculosis H37Rv was also the same as young mice. Conclusion These findings suggest that vaccination in aged generation is still effective for protection against tuberculosis.

  5. IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse

    Directory of Open Access Journals (Sweden)

    Kostek Matthew C

    2012-06-01

    Full Text Available Abstract Background IL-6 is a pleiotropic cytokine that modulates inflammatory responses and plays critical roles in muscle maintenance and remodeling. In the mouse model (mdx of Duchenne Muscular Dystrophy, IL-6 and muscle inflammation are elevated, which is believed to contribute to the chronic inflammation and failure of muscle regeneration in DMD. The purpose of the current study was to examine the effect of blocking IL-6 signaling on the muscle phenotype including muscle weakness and pathology in the mdx mouse. Methods A monoclonal antibody against the IL-6 receptor (IL-6r mAb that blocks local and systemic IL-6 signaling was administered to mdx and BL-10 mice for 5 weeks and muscle function, histology, and inflammation were examined. Results IL-6r mAb treatment increased mdx muscle inflammation including total inflammation score and ICAM-1 positive lumens in muscles. There was no significant improvement in muscle strength nor muscle pathology due to IL-6r mAb treatment in mdx mice. Conclusions These results showed that instead of reducing inflammation, IL-6 signaling blockade for 5 weeks caused an increase in muscle inflammation, with no significant change in indices related to muscle regeneration and muscle function. The results suggest a potential anti-inflammatory instead of the original hypothesized pro-inflammatory role of IL-6 signaling in the mdx mice.

  6. Testosterone and dihydrotestosterone differentially improve cognition in aged female mice

    OpenAIRE

    Benice, Ted S.; Raber, Jacob

    2009-01-01

    Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to 24-mo-old gonadally intact female mice treated for 6 wk with silastic capsules containing either testosterone (T) or dihydrotestosterone (DHT) or empty c...

  7. Taurine increases hippocampal neurogenesis in aging mice

    OpenAIRE

    Elias Gebara; Florian Udry; Sébastien Sultan; Nicolas Toni

    2015-01-01

    Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the d...

  8. Major alteration of the pathological phenotype in gamma irradiated mdx soleus muscles

    International Nuclear Information System (INIS)

    Two thousand rads of gamma irradiation delivered to the lower legs of ten day old normal and x-chromosome linked muscular dystrophy (mdx) mice caused significant inhibition of tibial bone and soleus muscle fiber growth. In the irradiated mdx solei, there was a major loss of muscle fibers, lack of central nucleation, and some endomysial fibrosis. These features were caused by a failure of regeneration of muscle fibers due to impaired proliferative capacity of satellite cells. Gamma irradiation transforms the late pathological phenotype of mdx muscles, so that in one major aspect (muscle fiber loss) they resemble muscles in Duchenne muscular dystrophy. However, extensive endomysial fibrosis which is another characteristic feature of Duchenne muscular dystrophy did not develop. This experimental model could be useful for the functional investigation of possible beneficial effects of therapeutic interventions in mdx dystrophy

  9. Unexpected regeneration in middle-aged mice.

    Science.gov (United States)

    Reines, Brandon; Cheng, Lily I; Matzinger, Polly

    2009-02-01

    Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age. Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5-11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes. These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight. PMID:19226206

  10. Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis.

    Science.gov (United States)

    Cea, Luis A; Puebla, Carlos; Cisterna, Bruno A; Escamilla, Rosalba; Vargas, Aníbal A; Frank, Marina; Martínez-Montero, Paloma; Prior, Carmen; Molano, Jesús; Esteban-Rodríguez, Isabel; Pascual, Ignacio; Gallano, Pía; Lorenzo, Gustavo; Pian, Héctor; Barrio, Luis C; Willecke, Klaus; Sáez, Juan C

    2016-07-01

    Skeletal muscles of patients with Duchenne muscular dystrophy (DMD) show numerous alterations including inflammation, apoptosis, and necrosis of myofibers. However, the molecular mechanism that explains these changes remains largely unknown. Here, the involvement of hemichannels formed by connexins (Cx HCs) was evaluated in skeletal muscle of mdx mouse model of DMD. Fast myofibers of mdx mice were found to express three connexins (39, 43 and 45) and high sarcolemma permeability, which was absent in myofibers of mdx Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice (deficient in skeletal muscle Cx43/Cx45 expression). These myofibers did not show elevated basal intracellular free Ca(2+) levels, immunoreactivity to phosphorylated p65 (active NF-κB), eNOS and annexin V/active Caspase 3 (marker of apoptosis) but presented dystrophin immunoreactivity. Moreover, muscles of mdx Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice exhibited partial decrease of necrotic features (big cells and high creatine kinase levels). Accordingly, these muscles showed similar macrophage infiltration as control mdx muscles. Nonetheless, the hanging test performance of mdx Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice was significantly better than that of control mdx Cx43(fl/fl)Cx45(fl/fl) mice. All three Cxs found in skeletal muscles of mdx mice were also detected in fast myofibers of biopsy specimens from patients with muscular dystrophy. Thus, reduction of Cx expression and/or function of Cx HCs may be potential therapeutic approaches to abrogate myofiber apoptosis in DMD. PMID:26803842

  11. Taurine increases hippocampal neurogenesis in aging mice

    Directory of Open Access Journals (Sweden)

    Elias Gebara

    2015-05-01

    Full Text Available Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors. Taurine had a direct effect on stem/progenitor cells proliferation, as observed in vitro, and also reduced activated microglia. Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis. Together, these results show that taurine increases several steps of adult neurogenesis and support a beneficial role of taurine on hippocampal neurogenesis in the context of brain aging.

  12. Functional and molecular effects of arginine butyrate and prednisone on muscle and heart in the mdx mouse model of Duchenne Muscular Dystrophy.

    Directory of Open Access Journals (Sweden)

    Alfredo D Guerron

    Full Text Available BACKGROUND: The number of promising therapeutic interventions for Duchenne Muscular Dystrophy (DMD is increasing rapidly. One of the proposed strategies is to use drugs that are known to act by multiple different mechanisms including inducing of homologous fetal form of adult genes, for example utrophin in place of dystrophin. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have treated mdx mice with arginine butyrate, prednisone, or a combination of arginine butyrate and prednisone for 6 months, beginning at 3 months of age, and have comprehensively evaluated the functional, biochemical, histological, and molecular effects of the treatments in this DMD model. Arginine butyrate treatment improved grip strength and decreased fibrosis in the gastrocnemius muscle, but did not produce significant improvement in muscle and cardiac histology, heart function, behavioral measurements, or serum creatine kinase levels. In contrast, 6 months of chronic continuous prednisone treatment resulted in deterioration in functional, histological, and biochemical measures. Arginine butyrate-treated mice gene expression profiling experiments revealed that several genes that control cell proliferation, growth and differentiation are differentially expressed consistent with its histone deacetylase inhibitory activity when compared to control (saline-treated mdx mice. Prednisone and combination treated groups showed alterations in the expression of genes that control fibrosis, inflammation, myogenesis and atrophy. CONCLUSIONS/SIGNIFICANCE: These data indicate that 6 months treatment with arginine butyrate can produce modest beneficial effects on dystrophic pathology in mdx mice by reducing fibrosis and promoting muscle function while chronic continuous treatment with prednisone showed deleterious effects to skeletal and cardiac muscle. Our results clearly indicate the usefulness of multiple assays systems to monitor both beneficial and toxic effects of drugs with

  13. Inhaled Anesthetic Potency in Aged Alzheimer Mice

    Science.gov (United States)

    Bianchi, Shannon L.; Caltagarone, Breanna M.; LaFerla, Frank M.; Eckenhoff, Roderic G.; Kelz, Max B.

    2016-01-01

    BACKGROUND The number of elderly patients with frank or incipient Alzheimer’s disease (AD) requiring surgery is growing as the population ages. General anesthesia may exacerbate symptoms of and the pathology underlying AD, so minimizing anesthetic exposure may be important. This requires knowledge of whether the continuing AD pathogenesis alters anesthetic potency. METHODS We determined the induction potency and emergence time for isoflurane, halothane, and sevoflurane using the minimum alveolar anesthetic concentration for loss of righting reflex as an end point in 12- to 14-mo-old triple transgenic Alzheimer (3xTgAD) mice and wild type C57BL6 controls. 3xTgAD mice model AD by harboring three distinct mutations: the APPSwe, Tau, and PS1 human transgenes, each of which has been associated with familial forms of human AD. RESULTS The 3xTgAD mice exhibited mild resistance (from 8% to 30%) to volatile anesthetics but displayed indistinguishable emergence patterns from all three inhaled anesthetics. CONCLUSIONS These results show that the genetic vulnerabilities and neuropathology associated with AD produce a small but significant decrease in sensitivity to the hypnotic actions of three inhaled anesthetics. Emergence times were not altered. PMID:19820240

  14. Young Little Mice Express a Premature Cardiovascular Aging Phenotype

    OpenAIRE

    Reddy, Anilkumar K.; Hartley, Craig J.; Pham, Thuy T.; Darlington, Gretchen; Entman, Mark L.; Taffet, George E.

    2013-01-01

    To investigate the effect of growth hormone and insulin-like growth factor 1 deficiency on the aging mouse arterial system, we compared the hemodynamics in young (4 months) and old (30 months) growth hormone–releasing hormone receptor null dwarf (Little) mice and their wild-type littermates. Young Little mice had significantly lower peak and mean aortic velocity and significantly higher aortic impedance than young wild-type mice. However, unlike the wild-type mice, there were no significant c...

  15. Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model

    Directory of Open Access Journals (Sweden)

    Jahnke Vanessa E

    2012-08-01

    Full Text Available Abstract Background Duchenne muscular dystrophy is a genetic disease involving a severe muscle wasting that is characterized by cycles of muscle degeneration/regeneration and culminates in early death in affected boys. Mitochondria are presumed to be involved in the regulation of myoblast proliferation/differentiation; enhancing mitochondrial activity with exercise mimetics (AMPK and PPAR-delta agonists increases muscle function and inhibits muscle wasting in healthy mice. We therefore asked whether metabolic remodeling agents that increase mitochondrial activity would improve muscle function in mdx mice. Methods Twelve-week-old mdx mice were treated with two different metabolic remodeling agents (GW501516 and AICAR, separately or in combination, for 4 weeks. Extensive systematic behavioral, functional, histological, biochemical, and molecular tests were conducted to assess the drug(s' effects. Results We found a gain in body and muscle weight in all treated mice. Histologic examination showed a decrease in muscle inflammation and in the number of fibers with central nuclei and an increase in fibers with peripheral nuclei, with significantly fewer activated satellite cells and regenerating fibers. Together with an inhibition of FoXO1 signaling, these results indicated that the treatments reduced ongoing muscle damage. Conclusions The three treatments produced significant improvements in disease phenotype, including an increase in overall behavioral activity and significant gains in forelimb and hind limb strength. Our findings suggest that triggering mitochondrial activity with exercise mimetics improves muscle function in dystrophin-deficient mdx mice.

  16. Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice

    OpenAIRE

    van Praag, Henriette; Shubert, Tiffany; Zhao, Chunmei; GAGE, FRED H.

    2005-01-01

    Aging causes changes in the hippocampus that may lead to cognitive decline in older adults. In young animals, exercise increases hippocampal neurogenesis and improves learning. We investigated whether voluntary wheel running would benefit mice that were sedentary until 19 months of age. Specifically, young and aged mice were housed with or without a running wheel and injected with bromodeoxyuridine or retrovirus to label newborn cells. After 1 month, learning was tested in the Morris water ma...

  17. A metabolic signature predicts biological age in mice

    OpenAIRE

    Tomás-Loba, Antonia; Bernardes de Jesus, Bruno; Mato, Jose M.; Blasco, Maria A.

    2012-01-01

    Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8-129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice. In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ag...

  18. Age-related retinopathy in NRF2-deficient mice.

    Directory of Open Access Journals (Sweden)

    Zhenyang Zhao

    Full Text Available BACKGROUND: Cumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD. Nuclear factor erythroid 2-related factor 2 (NRF2 is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine whether NRF2-deficient mice would develop AMD-like retinal pathology with aging and to explore the underlying mechanisms. METHODS AND FINDINGS: Eyes of both wild type and Nrf2(-/- mice were examined in vivo by fundus photography and electroretinography (ERG. Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2(-/- mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE. Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV and sub-RPE deposition of inflammatory proteins were present in Nrf2(-/- mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microscopy both within the RPE and in Bruch's membrane of aged Nrf2(-/- mice. CONCLUSIONS: Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2(-/- mice can provide a novel model for mechanistic and translational research on AMD.

  19. Altered Allogeneic Immune Responses in Middle-Aged Mice

    Institute of Scientific and Technical Information of China (English)

    YiminSun; HanhanLi; AlanN.Langnas

    2004-01-01

    It is well known that leukocyte composition, T cell phenotypes and immune function change in aged mice and humans. However, limited and conflicting results on the age-related immune changes in middle-aged mice were reported. Identification of the characteristics of allogeneic immune responses in aging mice may offer important information for transplantation immunology. The major age-related changes in the immune cell phenotypes and function of 12 months old mice include: 1) the significantly decreased CD4+ cell population in the peripheral blood, the major peripheral CD4+ cells is CD45RBlowCD62Llow memory phenotype; 2) the in vitro responses to alloantigens and Con A of splenocytes markedly reduced; 3) the in vivo secondary humoral immune responses to alloantigens significantly declined; 4) the age-related alteration in the thymus mainly occurred in CD4/CD8 double positive (DP) stage; and 5) increased CD80+ and MHC class II+ cell population in spleens. Thus, the major age-related immune changes in 12 months old mice occurred in CD4+ T cells in the periphery and DP stage in the thymus, which may subsequently lead to the decreased allogeneic immune responses and the different sensitivity to immunosuppressive drugs and treatments. Further studies on the characteristics of allogeneic immunity in aging individuals may help to determine the appropriated treatment for transplant aging individuals. Cellular & Molecular Immunology. 2004;1(6):440-446.

  20. Altered Allogeneic Immune Responses in Middle-Aged Mice

    Institute of Scientific and Technical Information of China (English)

    Yimin Sun; Hanhan Li; Alan N. Langnas; Yong Zhao

    2004-01-01

    It is well known that leukocyte composition, T cell phenotypes and immune function change in aged mice and humans. However, limited and conflicting results on the age-related immune changes in middle-aged mice were reported. Identification of the characteristics of allogeneic immune responses in aging mice may offer important information for transplantation immunology. The major age-related changes in the immune cell phenotypes and function of 12 months old mice include: 1) the significantly decreased CD4+ cell population in the peripheral blood, the major peripheral CD4+ cells is CD45RBlowCD62Llow memory phenotype; 2) the in vitro responses to alloantigens and Con A of splenocytes markedly reduced; 3) the in vivo secondary humoral immune responses to alloantigens significantly declined; 4) the age-related alteration in the thymus mainly occurred in CD4/CD8 double positive (DP) stage; and 5) increased CD80+ and MHC class Ⅱ+ cell population in spleens. Thus, the major age-related immune changes in 12 months old mice occurred in CD4+ T cells in the periphery and DP stage in the thymus, which may subsequently lead to the decreased allogeneic immune responses and the different sensitivity to immunosuppressive drugs and treatments. Further studies on the characteristics of allogeneic immunity in aging individuals may help to determine the appropriated treatment for transplant aging individuals. Cellular & Molecular Immunology. 2004; 1(6) :440-446.

  1. Instant MDX queries for SQL Server 2012

    CERN Document Server

    Emond, Nicholas

    2013-01-01

    Get to grips with a new technology, understand what it is and what it can do for you, and then get to work with the most important features and tasks. This short, focused guide is a great way to get stated with writing MDX queries. New developers can use this book as a reference for how to use functions and the syntax of a query as well as how to use Calculated Members and Named Sets.This book is great for new developers who want to learn the MDX query language from scratch and install SQL Server 2012 with Analysis Services

  2. Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Michelle Wehling-Henricks

    Full Text Available BACKGROUND: Duchenne muscular dystrophy (DMD is the most common, lethal disease of childhood. One of 3500 new-born males suffers from this universally-lethal disease. Other than the use of corticosteroids, little is available to affect the relentless progress of the disease, leading many families to use dietary supplements in hopes of reducing the progression or severity of muscle wasting. Arginine is commonly used as a dietary supplement and its use has been reported to have beneficial effects following short-term administration to mdx mice, a genetic model of DMD. However, the long-term effects of arginine supplementation are unknown. This lack of knowledge about the long-term effects of increased arginine metabolism is important because elevated arginine metabolism can increase tissue fibrosis, and increased fibrosis of skeletal muscles and the heart is an important and potentially life-threatening feature of DMD. METHODOLOGY: We use both genetic and nutritional manipulations to test whether changes in arginase metabolism promote fibrosis and increase pathology in mdx mice. Our findings show that fibrotic lesions in mdx muscle are enriched with arginase-2-expressing macrophages and that muscle macrophages stimulated with cytokines that activate the M2 phenotype show elevated arginase activity and expression. We generated a line of arginase-2-null mutant mdx mice and found that the mutation reduced fibrosis in muscles of 18-month-old mdx mice, and reduced kyphosis that is attributable to muscle fibrosis. We also observed that dietary supplementation with arginine for 17-months increased mdx muscle fibrosis. In contrast, arginine-2 mutation did not reduce cardiac fibrosis or affect cardiac function assessed by echocardiography, although 17-months of dietary supplementation with arginine increased cardiac fibrosis. Long-term arginine treatments did not decrease matrix metalloproteinase-2 or -9 or increase the expression of utrophin, which have

  3. Proteomic study on gender differences in aging kidney of mice

    OpenAIRE

    Cristobal Susana; Amelina Hanna

    2009-01-01

    Abstract Background This study aims to analyze sex differences in mice aging kidney. We applied a proteomic technique based on subfractionation, and liquid chromatography coupled with 2-DE. Samples from male and female CD1-Swiss outbred mice from 28 weeks, 52 weeks, and 76 weeks were analysed by 2-DE, and selected proteins were identified by matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Results This proteomic analysis detected age-related changes...

  4. Peripheral surgical wounding and age-dependent neuroinflammation in mice.

    Directory of Open Access Journals (Sweden)

    Zhipeng Xu

    Full Text Available Post-operative cognitive dysfunction is associated with morbidity and mortality. However, its neuropathogenesis remains largely to be determined. Neuroinflammation and accumulation of β-amyloid (Aβ have been reported to contribute to cognitive dysfunction in humans and cognitive impairment in animals. Our recent studies have established a pre-clinical model in mice, and have found that the peripheral surgical wounding without the influence of general anesthesia induces an age-dependent Aβ accumulation and cognitive impairment in mice. We therefore set out to assess the effects of peripheral surgical wounding, in the absence of general anesthesia, on neuroinflammation in mice with different ages. Abdominal surgery under local anesthesia was established in 9 and 18 month-old mice. The levels of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, Iba1 positive cells (the marker of microglia activation, CD33, and cognitive function in mice were determined. The peripheral surgical wounding increased the levels of TNF-α, IL-6, and Iba1 positive cells in the hippocampus of both 9 and 18 month-old mice, and age potentiated these effects. The peripheral surgical wounding increased the levels of CD33 in the hippocampus of 18, but not 9, month-old mice. Finally, anti-inflammatory drug ibuprofen ameliorated the peripheral surgical wounding-induced cognitive impairment in 18 month-old mice. These data suggested that the peripheral surgical wounding could induce an age-dependent neuroinflammation and elevation of CD33 levels in the hippocampus of mice, which could lead to cognitive impairment in aged mice. Pending further studies, anti-inflammatory therapies may reduce the risk of postoperative cognitive dysfunction in elderly patients.

  5. Functional correction of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length dystrophin

    OpenAIRE

    DelloRusso, Christiana; Scott, Jeannine M.; Hartigan-O'Connor, Dennis; Salvatori, Giovanni; Barjot, Catherine; Robinson, Ann S.; Robert W Crawford; Brooks, Susan V; Jeffrey S. Chamberlain

    2002-01-01

    Duchenne muscular dystrophy is a lethal X-linked recessive disorder caused by mutations in the dystrophin gene. Delivery of functionally effective levels of dystrophin to immunocompetent, adult mdx (dystrophin-deficient) mice has been challenging because of the size of the gene, immune responses against viral vectors, and inefficient infection of mature muscle. Here we show that high titer stocks of three different gutted adenoviral vectors carrying full-length, muscle-specific, dystrophin ex...

  6. Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

    OpenAIRE

    Rooney, Jachinta E.; Gurpur, Praveen B.; Burkin, Dean J.

    2009-01-01

    Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The α7β1-integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the α7-integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological ...

  7. Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model

    OpenAIRE

    Denti, Michela Alessandra; Rosa, Alessandro; D’Antona, Giuseppe; Sthandier, Olga; De Angelis, Fernanda Gabriella; Nicoletti, Carmine; Allocca, Mariacarmela; Pansarasa, Orietta; Parente, Valeria; Musarò, Antonio; Auricchio, Alberto; Bottinelli, Roberto; Bozzoni, Irene

    2006-01-01

    Duchenne muscular dystrophy is an X-linked muscle disease characterized by mutations in the dystrophin gene. Many of these can be corrected at the posttranscriptional level by skipping the mutated exon. We have obtained persistent exon skipping in mdx mice by tail vein injection with an adeno-associated viral (AAV) vector expressing antisense sequences as part of the stable cellular U1 small nuclear RNA. Systemic delivery of the AAV construct resulted in effective body-wide colonization, sign...

  8. A new immuno-, dystrophin-deficient model, the NSG-mdx(4Cv) mouse, provides evidence for functional improvement following allogeneic satellite cell transplantation.

    Science.gov (United States)

    Arpke, Robert W; Darabi, Radbod; Mader, Tara L; Zhang, Yu; Toyama, Akira; Lonetree, Cara-Lin; Nash, Nardina; Lowe, Dawn A; Perlingeiro, Rita C R; Kyba, Michael

    2013-08-01

    Transplantation of a myogenic cell population into an immunodeficient recipient is an excellent way of assessing the in vivo muscle-generating capacity of that cell population. To facilitate both allogeneic and xenogeneic transplantations of muscle-forming cells in mice, we have developed a novel immunodeficient muscular dystrophy model, the NSG-mdx(4Cv) mouse. The IL2Rg mutation, which is linked to the Dmd gene on the X chromosome, simultaneously depletes NK cells and suppresses thymic lymphomas, issues that limit the utility of the SCID/mdx model. The NSG-mdx(4Cv) mouse presents a muscular dystrophy of similar severity to the conventional mdx mouse. We show that this animal supports robust engraftment of both pig and dog muscle mononuclear cells. The question of whether satellite cells prospectively isolated by flow cytometry can confer a functional benefit upon transplantation has been controversial. Using allogeneic Pax7-ZsGreen donors and NSG-mdx(4Cv) recipients, we demonstrate definitively that as few as 900 FACS-isolated satellite cells can provide functional regeneration in vivo, in the form of an increased mean maximal force-generation capacity in cell-transplanted muscles, compared to a sham-injected control group. These studies highlight the potency of satellite cells to improve muscle function and the utility of the NSG-mdx(4Cv) model for studies on muscle regeneration and Duchenne muscular dystrophy therapy. PMID:23606600

  9. Age-related changes in antral endocrine cells in mice

    OpenAIRE

    Sandstrom, O.; Mahdavi, J.; El-Salhy, M.

    1999-01-01

    Antral endocrine cells in four age groups of mice, namely prepubertal (1 month old), young (3 months old), ageing (12 months old) and senescent (24 months old), were detected by immunocytochemistry and quantified by computerized image analysis. A statistical difference was detected between the different age groups regarding the numbers of gastrin-, somatostatin-, and serotonin-immunoreactive cells. The number of gastrin-immunoreactive cells significantly increa...

  10. Long-term treatment with naproxcinod significantly improves skeletal and cardiac disease phenotype in the mdx mouse model of dystrophy.

    Science.gov (United States)

    Uaesoontrachoon, Kitipong; Quinn, James L; Tatem, Kathleen S; Van Der Meulen, Jack H; Yu, Qing; Phadke, Aditi; Miller, Brittany K; Gordish-Dressman, Heather; Ongini, Ennio; Miglietta, Daniela; Nagaraju, Kanneboyina

    2014-06-15

    In Duchenne muscular dystrophy (DMD) patients and the mouse model of DMD, mdx, dystrophin deficiency causes a decrease and mislocalization of muscle-specific neuronal nitric oxide synthase (nNOSμ), leading to functional impairments. Previous studies have shown that nitric oxide (NO) donation associated with anti-inflammatory action has beneficial effects in dystrophic mouse models. In this study, we have systematically investigated the effects of naproxcinod, an NO-donating naproxen derivative, on the skeletal and cardiac disease phenotype in mdx mice. Four-week-old mdx and C57BL/10 mice were treated with four different concentrations (0, 10, 21 and 41 mg/kg) of naproxcinod and 0.9 mg/kg of prednisolone in their food for 9 months. All mice were subjected to twice-weekly treadmill sessions, and functional and behavioral parameters were measured at 3, 6 and 9 months of treatment. In addition, we evaluated in vitro force contraction, optical imaging of inflammation, echocardiography and blood pressure (BP) at the 9-month endpoint prior to sacrifice. We found that naproxcinod treatment at 21 mg/kg resulted in significant improvement in hindlimb grip strength and a 30% decrease in inflammation in the fore- and hindlimbs of mdx mice. Furthermore, we found significant improvement in heart function, as evidenced by improved fraction shortening, ejection fraction and systolic BP. In addition, the long-term detrimental effects of prednisolone typically seen in mdx skeletal and heart function were not observed at the effective dose of naproxcinod. In conclusion, our results indicate that naproxcinod has significant potential as a safe therapeutic option for the treatment of muscular dystrophies. PMID:24463621

  11. Importância do camundongo mdx na fisiopatologia da distrofia muscular de Duchenne The importance of mdx mouse in the pathophysiology of Duchenne's muscular distrophy

    Directory of Open Access Journals (Sweden)

    Sandra Lopes Seixas

    1997-09-01

    Full Text Available O camundongo mdx desenvolve distrofia muscular recessiva ligada ao cromossoma X (locus Xp21.1 e não expressa distrofina. Embora não apresente intensa fibrose do tecido muscular e acúmulo de tecido adiposo, é considerado o modelo animal mais adequado da distrofia muscular de Duchenne. As alterações estruturais no tecido muscular associadas à mionecrose e presença do infiltrado inflamatório com predomínio de linfócitos e monócitos/macrófagos sugerem uma participação do sistema imunológico nesta miopatia. Além disso a modulação na expressão dos componentes da matriz extracelular no microambiente muscular nas várias fases da doença (início, mionecrose, regeneração indicam um papel importante do conjuntivo no direcionamento das células inflamatórias para o foco da lesão muscular. O camundongo mdx coloca-se como um excelente modelo para o estudo dos mecanismos patogenéticos da mionecrose e regeneração na distrofia muscular de Duchenne, possibilitando inclusive o desenvolvimento de estratégias terapêuticas mais adequadas.The mdx mouse develop an X-linked recessive muscular dystrophy (locus Xp21.1 and lack dystrophin expression. Despite showing less intense myofibrosis and scarce deposition of fatty tissue, mdx mice are considered an adequate animal model for studies on the pathogenesis of Duchenne-type muscular dystrophy. Marked histological alterations in the muscular tissues associated to myonecrosis and inflammatory mononuclear cell infiltrate (lymphocytes, monocytes/macrophages suggest a participation of the immune system in this myopathy. Modulation of the extracellular matrix (ECM components in the muscular tissue during all phases (onset, myonecrosis and regeneration of disease, indicate an important role for the ECM driving inflammatory cells to the foci of lesion. Therefore mdx mice should be regarded as an important tool for studies on pathogenetic mechanisms of Duchenne-type muscular dystrophy. Such

  12. MELATONIN AND IMMUNOMODULATION IN AGED AND IMMUNODEFICIENT MICE

    Institute of Scientific and Technical Information of China (English)

    周爱民; 袁育康; 范桂香

    2003-01-01

    Objective To investigate melatonin-related mechanisms of action on immunoregulation in aged and immunodeficient mice. Methods T lymPhocytes subunit CD4+,CD8+ and CD4+/CD8+ ratio were measured by Flow Cytometer in normal, aged and Cyclophosphamide injected mice which treated with melatonin, and compared with the results of T lymphocytes subunit in the group without melatonin as control group. Results The percentage of CD4+, CD8+ T cells in the normal mice which treated with melatonin was significantly higher than that in control group (P<0.01), CD4+/CD8+ ratio was higher but had no significant difference. In the cyclophosphamide injected group which melatonin treated, the percentage of CD4+ T cells and CD4+/CD8+ ratio were higher than those in control, The difference was significant (P<0.01), while CD8+ was lower (P<0.01). In aged melatonin treated mice group, the percentage of CD4+, CD8+ T cells and CD4+/CD8+ ratio were significantly higher than those in control (P<0.01). Conclusion Melatonin could adjust the quantity and the ratio of CD4+, CD8+ T cells in aged and immunodeficient mice. it implied that melatonin could mediate helper and suppression T lymphocytes to reinforce their immunodefence.

  13. RasGrf1 deficiency delays aging in mice

    OpenAIRE

    Borrás, Consuelo; Monleón, Daniel; López-Grueso, Raul; Gambini, Juan; Orlando, Leonardo; Federico V Pallardó; Santos, Eugenio; Viña, José; Font de Mora, Jaime

    2011-01-01

    RasGRF1 is a Ras-guanine nucleotide exchange factor implicated in a variety of physiological processes including learning and memory and glucose homeostasis. To determine the role of RASGRF1 in aging, lifespan and metabolic parameters were analyzed in aged RasGrf1−/− mice. We observed that mice deficient for RasGrf1−/− display an increase in average and most importantly, in maximal lifespan (20% higher than controls). This was not due to the role of Ras in cancer because tumor-free survival w...

  14. Administration of Glucosylceramide Ameliorated the Memory Impairment in Aged Mice

    OpenAIRE

    Yeonju Lee; Sergiy Oliynyk; Jae-Chul Jung; Jeong Jun Han; Seikwan Oh

    2013-01-01

    The function and the role of glucosylceramide have not been well studied in the central nervous system. This study was aimed to investigate the possible roles of glucosylceramide in memory function in aged mice. Glucosylceramide (50 mg/kg, p.o.) showed memory enhancing activity after 3-month treatment in the aged mice (C56BL/6, 18–20 months old) through Y-maze, novel objective test, and Morris water maze test. Long-term treatment of glucosylceramide decreased the expression of iNOS and COX-2 ...

  15. 杆状病毒修饰后的脂肪干细胞移植治疗mdx鼠的实验研究%The Study of Baculovirus Modiifed Adipose-derived Stem Cells Tranplantation on mdx Mice

    Institute of Scientific and Technical Information of China (English)

    孔杰; 操基清; 陈菲; 杨娟; 张成

    2015-01-01

    目的:利用经杆状病毒基因载体系统进行micro-dystrophin基因修饰后的脂肪干细胞(ADSCs)移植治疗Duchenne型肌营养不良症模型(mdx)鼠,探讨ADSCs移植治疗DMD的安全性及可行性。方法 Mdx鼠60只,分为mdx对照组(30只)和mdx移植组(30只);正常C57小鼠为C57对照组(30只)。体外分离培养小鼠ADSCs,利用杆状病毒基因载体进行micro-dystrophin基因修饰;将基因修饰后的ADSCs经尾静脉移植到mdx鼠体内。于移植后检测mdx鼠的运动功能(采用主动牵引实验和被动转棒实验)、血清CK水平、肌肉病理改变以及肌肉micro-dystrophin表达水平。结果经micro-dystrophin基因修饰的ADSCs移植后,能够重建mdx鼠的micro-dystrophin表达,一定程度上减轻并逆转肌肉的病理损害,进而降低血清CK水平,mdx鼠整体运动功能也有一定改善。结论 ADSCs治疗mdx鼠后,可部分重建模型鼠的dystrophin表达,改善肌肉的病理损害,表明ADSCs是有希望治愈DMD的方法之一。%Aim To explore the safety and feasibility of adipose-derived stem cells (ADSCs) transplantation on Duchenne muscular dystrophy (DMD) treatment, in which gene defect on mdx mouse was repaired with recombinant baculovirus carrying micro-dystrophin. Methods Adipose stem cells of mdx mouse were isolated and cultured in vitro. Gene defect was repaired with recombinant baculovirus. The modiifed stem cells were injected DMD mouse model through tail vein. Motor function, serum CK levels, muscle pathology and muscle dystrophin expression were observed after transplantation. Results After transplantation, micro-dystrophin expression in DMD mouse model could be rebuilt, pathological damage on muscles and serum CK levels were reduced, motor function of mouse model showed improvement. Conclusion After transplantation, gene expression can be partially reconstructed, pathological damage can be improved. These results suggested that stem cell

  16. Effects of Myostatin Deletion in Aging Mice

    OpenAIRE

    Morissette, Michael R.; Stricker, Janelle C.; Rosenberg, Michael A; Buranasombati, Cattleya; Levitan, Emily B.; Mittleman, Murray A; Rosenzweig, Anthony

    2009-01-01

    Inhibitors of myostatin, a negative regulator of skeletal muscle mass, are being developed to mitigate aging-related muscle loss. Knockout mouse studies suggest myostatin also affects adiposity, glucose handling, and cardiac growth. However, the cardiac consequences of inhibiting myostatin remain unclear. Myostatin inhibition can potentiate cardiac growth in specific settings (Morissette et al. 2006), a concern since cardiac hypertrophy is associated with adverse clinical outcomes. Therefore ...

  17. Pulmonary effects of inhaled diesel exhaust in aged mice

    International Nuclear Information System (INIS)

    Pulmonary morbidity and mortality resulting from exposure to fine particulate matter (PM) increases with age. The present studies analyzed potential mechanisms underlying increased susceptibility of the elderly to PM using diesel exhaust (DE) as a model. Mice (2 m and 18 m) were exposed to DE (0, 300, and 1000 μg/m3) for 3 h once (single) or 3 h/day for 3 days (repeated). Bronchoalveolar lavage fluid (BAL), serum and lung tissue were collected 0 and 24 h later. Exposure to DE resulted in structural alterations in the lungs of older but not younger mice, including patchy thickening of the alveolar septa and inflammatory cell localization in alveolar spaces. These effects were most pronounced 24 h after a single exposure to the higher dose of DE. Significant increases in BAL nitrogen oxides were also noted in older mice, as well as expression of lipocalin 24p3, an oxidative stress marker in the lung with no effects in younger mice. Following DE inhalation, expression of Tumor Necrosis Factor alpha (TNFα) was upregulated in lungs of both younger and older mice; however, this was attenuated in older animals. Whereas exposure to DE resulted in increases in lung Interleukin-6 (IL-6) expression in both older and younger mice, IL-8 increased only in older animals. In younger mice, constitutive expression of manganese superoxide dismutase (MnSOD) decreased after DE exposure, while in older mice, constitutive MnSOD was not detectable and DE had no effect on expression of this antioxidant. Taken together, these results suggest that altered generation of inflammatory mediators and MnSOD may contribute to increased susceptibility of older mice to inhaled DE.

  18. Marginal level dystrophin expression improves clinical outcome in a strain of dystrophin/utrophin double knockout mice.

    Directory of Open Access Journals (Sweden)

    Dejia Li

    Full Text Available Inactivation of all utrophin isoforms in dystrophin-deficient mdx mice results in a strain of utrophin knockout mdx (uko/mdx mice. Uko/mdx mice display severe clinical symptoms and die prematurely as in Duchenne muscular dystrophy (DMD patients. Here we tested the hypothesis that marginal level dystrophin expression may improve the clinical outcome of uko/mdx mice. It is well established that mdx3cv (3cv mice express a near-full length dystrophin protein at ∼5% of the normal level. We crossed utrophin-null mutation to the 3cv background. The resulting uko/3cv mice expressed the same level of dystrophin as 3cv mice but utrophin expression was completely eliminated. Surprisingly, uko/3cv mice showed a much milder phenotype. Compared to uko/mdx mice, uko/3cv mice had significantly higher body weight and stronger specific muscle force. Most importantly, uko/3cv outlived uko/mdx mice by several folds. Our results suggest that a threshold level dystrophin expression may provide vital clinical support in a severely affected DMD mouse model. This finding may hold clinical implications in developing novel DMD therapies.

  19. Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model

    OpenAIRE

    Rodino-Klapac, Louise R.; Janssen, Paul M. L.; Shontz, Kimberly M.; Canan, Benjamin; Montgomery, Chrystal L.; Griffin, Danielle; Heller, Kristin; Schmelzer, Leah; Handy, Chalonda; Clark, K. Reed; Sahenk, Zarife; Mendell, Jerry R.; Kaspar, Brian K.

    2013-01-01

    Pharmacologic strategies have provided modest improvement in the devastating muscle-wasting disease, Duchenne muscular dystrophy (DMD). Pre-clinical gene therapy studies have shown promise in the mdx mouse model; however, studies conducted after disease onset fall short of fully correcting muscle strength or protecting against contraction-induced injury. Here we examine the treatment effect on muscle physiology in aged dystrophic mice with significant disease pathology by combining two promis...

  20. Administration of Glucosylceramide Ameliorated the Memory Impairment in Aged Mice

    Directory of Open Access Journals (Sweden)

    Yeonju Lee

    2013-01-01

    Full Text Available The function and the role of glucosylceramide have not been well studied in the central nervous system. This study was aimed to investigate the possible roles of glucosylceramide in memory function in aged mice. Glucosylceramide (50 mg/kg, p.o. showed memory enhancing activity after 3-month treatment in the aged mice (C56BL/6, 18–20 months old through Y-maze, novel objective test, and Morris water maze test. Long-term treatment of glucosylceramide decreased the expression of iNOS and COX-2 in the brain of aged mice. The LPS-induced mRNA level of iNOS, COX-2, IL-1β, and TNF-α was reduced by the acute treatment with glucosylceramide in adult mice. These results suggest that glucosylceramide plays an important role in anti-inflammatory and memory enhancement, and it could be a potential new therapeutic agent for the treatment of neurodegenerative diseases such as Alzheimer’s disease.

  1. A Mathematical Model of Skeletal Muscle Disease and Immune Response in the mdx Mouse

    Directory of Open Access Journals (Sweden)

    Abdul Salam Jarrah

    2014-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.

  2. Administration of red ginseng ameliorates memory decline in aged mice

    OpenAIRE

    Lee, Yeonju; Oh, Seikwan

    2015-01-01

    Background It has been known that ginseng can be applied as a potential nutraceutical for memory impairment; however, experiments with animals of old age are few. Methods To determine the memory enhancing effect of red ginseng, C57BL/6 mice (21 mo old) were given experimental diet pellets containing 0.12% red ginseng extract (approximately 200 mg/kg/d) for 3 mo. Young and old mice (4 mo and 21 mo old, respectively) were used as the control group. The effect of red ginseng, which ameliorated m...

  3. Proteomic study on gender differences in aging kidney of mice

    Directory of Open Access Journals (Sweden)

    Cristobal Susana

    2009-04-01

    Full Text Available Abstract Background This study aims to analyze sex differences in mice aging kidney. We applied a proteomic technique based on subfractionation, and liquid chromatography coupled with 2-DE. Samples from male and female CD1-Swiss outbred mice from 28 weeks, 52 weeks, and 76 weeks were analysed by 2-DE, and selected proteins were identified by matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS. Results This proteomic analysis detected age-related changes in protein expression in 55 protein-spots, corresponding to 22 spots in males and 33 spots in females. We found a protein expression signature (PES of aging composed by 8 spots, common for both genders. The identified proteins indicated increases in oxidative and proteolytic proteins and decreases in glycolytic proteins, and antioxidant enzymes. Conclusion Our results provide insights into the gender differences associated to the decline of kidney function in aging. Thus, we show that proteomics can provide valuable information on age-related changes in expression levels of proteins and related modifications. This pilot study is still far from providing candidates for aging-biomarkers. However, we suggest that the analysis of these proteins could suggest mechanisms of cellular aging in kidney, and improve the kidney selection for transplantation.

  4. Early activation defects in T lymphocytes from aged mice.

    Science.gov (United States)

    Miller, R A; Garcia, G; Kirk, C J; Witkowski, J M

    1997-12-01

    Aging affects both calcium signals and protein kinase cascades in mouse T lymphocytes. The decline in calcium signal development largely represents differences between naive and memory T cells; the latter are resistant to increases in calcium concentration, and are more common in aged mice. Aging leads to declines in phosphorylation of a wide range of substrates in T cells stimulated by either anti-CD3 antibodies or by substances, such as phorbol myristate acetate (PMA) or ionomycin, that act at intracellular sites, but some phosphoproteins respond only in old T cells, and others respond regardless of age. Tyrosine phosphorylation of the CD3 zeta chain declines with age, both in resting T cells and after activation, but the proportion of Zap-70 that is bound to CD3 zeta increases in T cells from old mice. Zap-70 function and phosphorylation of CD3 zeta-associated Zap-70 change only slightly after stimulation of T cells by anti-CD3 and anti-CD4, and are at similar levels in activated old and young T cells. Nonetheless, induction of Raf-1, MEK, and ERK kinase activity declines with age in CD4 T cells. The effect of aging on T-cell activation is not simply an overall decline in signal intensity, but a set of qualitative changes that differ among subsets and depend at least partly on the nature of the stimulus. PMID:9476667

  5. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice.

    Science.gov (United States)

    Zhang, Hongbo; Ryu, Dongryeol; Wu, Yibo; Gariani, Karim; Wang, Xu; Luan, Peiling; D'Amico, Davide; Ropelle, Eduardo R; Lutolf, Matthias P; Aebersold, Ruedi; Schoonjans, Kristina; Menzies, Keir J; Auwerx, Johan

    2016-06-17

    Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD(+)) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmd(mdx)/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD(+) may reprogram dysfunctional SCs and improve life span in mammals. PMID:27127236

  6. Effects of Sleep Deprivation and Aging on Long-Term and Remote Memory in Mice

    Science.gov (United States)

    Vecsey, Christopher G.; Park, Alan J.; Khatib, Nora; Abel, Ted

    2015-01-01

    Sleep deprivation (SD) following hippocampus-dependent learning in young mice impairs memory when tested the following day. Here, we examined the effects of SD on remote memory in both young and aged mice. In young mice, we found that memory is still impaired 1 mo after training. SD also impaired memory in aged mice 1 d after training, but, by a…

  7. Functional recovery in aging mice after experimental stroke

    OpenAIRE

    Manwani, Bharti; Liu, Fudong; Xu, Yan; Persky, Rebecca; Li, Jun; McCullough, Louise D.

    2011-01-01

    Aging is a non modifiable risk factor for stroke. Since not all strokes can be prevented, a major emerging area of research is the development of effective strategies to enhance functional recovery after stroke. However, in the vast majority of pre-clinical stroke studies, the behavioral tests used to assess functional recovery have only been validated for use in young animals, or are designed for rats. Mice are increasingly utilized in stroke models but well validated behavioral tests design...

  8. 100-fold but not 50-fold dystrophin overexpression aggravates electrocardiographic defects in the mdx model of Duchenne muscular dystrophy

    OpenAIRE

    Yue, Yongping; Wasala, Nalinda B.; Bostick, Brian; Duan, Dongsheng

    2016-01-01

    Dystrophin gene replacement holds the promise of treating Duchenne muscular dystrophy. Supraphysiological expression is a concern for all gene therapy studies. In the case of Duchenne muscular dystrophy, Chamberlain and colleagues found that 50-fold overexpression did not cause deleterious side effect in skeletal muscle. To determine whether excessive dystrophin expression in the heart is safe, we studied two lines of transgenic mdx mice that selectively expressed a therapeutic minidystrophin...

  9. Accumulation of point mutations in mitochondrial DNA of aging mice

    Energy Technology Data Exchange (ETDEWEB)

    Khaidakov, Magomed; Heflich, Robert H.; Manjanatha, Mugimane G.; Myers, Meagan B.; Aidoo, Anane

    2003-05-15

    Mitochondrial DNA (mtDNA) exists in a highly genotoxic environment created by exposure to reactive oxygen species, somewhat deficient DNA repair, and the relatively low fidelity of polymerase gamma. Given the severity of the environment, it was anticipated that mutation accumulation in the mtDNA of aging animals should exceed that of nuclear genes by several orders of magnitude. We have analyzed fragments amplified from the D-loop region of mtDNA from 2 to 22-month-old mice. The amplified 432 bp fragments were cloned into plasmid vectors, and plasmid DNAs from individual clones were purified and sequenced. None of 110 fragments from young mice contained a mutation, while 9 of 87 clones originating from old animals contained base substitutions (chi square = 11.9, P<0.001). The estimated mutation frequency in mtDNA from old mice was 11.6{+-}2.7 or 25.4{+-}7.8 per 10{sup 5} nucleotides (depending on assumptions of clonality), which exceeds existing estimates for mutation frequencies for nuclear genes by approximately 1000-fold. Our data suggest that at 22 months of age, which roughly corresponds to 3/4 of the mouse natural life span, most mtDNA molecules carry multiple point mutations.

  10. Age Sensitivity of Behavioral Tests and Brain Substrates of Normal Aging in Mice

    Directory of Open Access Journals (Sweden)

    John A. Kennard

    2011-05-01

    Full Text Available Knowledge of age sensitivity, the capacity of a behavioral test to reliably detect age-related changes, has utility in the design of experiments to elucidate processes of normal aging. We review the application of these tests in studies of normal aging and compare and contrast the age sensitivity of the Barnes maze, eyeblink classical conditioning, fear conditioning, Morris water maze and rotorod. These tests have all been implemented to assess normal age-related changes in learning and memory in rodents, which generalize in many cases to age-related changes in learning and memory in all mammals, including humans. Behavioral assessments are a valuable means to measure functional outcomes of neuroscientific studies of aging. Highlighted in this review are the attributes and limitations of these measures in mice in the context of age sensitivity and processes of brain aging. Attributes of these tests include reliability and validity as assessments of learning and memory, well-defined neural substrates, and sensitivity to neural and pharmacological manipulations and disruptions. These tests engage the hippocampus and/or the cerebellum, two structures centrally involved in learning and memory that undergo functional and anatomical changes in normal aging. A test that is less well represented in studies of normal aging, the context pre-exposure facilitation effect (CPFE in fear conditioning, is described as a method to increase sensitivity of contextual fear conditioning to changes in the hippocampus. Recommendations for increasing the age sensitivity of all measures of normal aging in mice are included, as well as a discussion of the potential of the under-studied CPFE to advance understanding of subtle hippocampus-mediated phenomena.

  11. Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

    Science.gov (United States)

    Kaczorowski, Catherine C.; Disterhoft, John F.

    2009-01-01

    Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

  12. Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice.

    Science.gov (United States)

    Shin, Jin A; Jeong, Sae Im; Kim, Minsuk; Yoon, Joo Chun; Kim, Hee-Sun; Park, Eun-Mi

    2015-11-01

    Visceral adipose tissue is accumulated with aging. An increase in visceral fat accompanied by low-grade inflammation is associated with several adult-onset diseases. However, the effects of visceral adipose tissue inflammation on the normal and ischemic brains of aged are not clearly defined. To examine the role of visceral adipose tissue inflammation, we evaluated inflammatory cytokines in the serum, visceral adipose tissue, and brain as well as blood-brain barrier (BBB) permeability in aged male mice (20 months) underwent sham or visceral fat removal surgery compared with the young mice (2.5 months). Additionally, ischemic brain injury was compared in young and aged mice with sham and visceral fat removal surgery. Interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels in examined organs were increased in aged mice compared with the young mice, and these levels were reduced in the mice with visceral fat removal. Increased BBB permeability with reduced expression of tight junction proteins in aged sham mice were also decreased in mice with visceral fat removal. After focal ischemic injury, aged mice with visceral fat removal showed a reduction in infarct volumes, BBB permeability, and levels of proinflammatory cytokines in the ischemic brain compared with sham mice, although the neurological outcomes were not significantly improved. In addition, further upregulated visceral adipose tissue inflammation in response to ischemic brain injury was attenuated in mice with visceral fat removal. These results suggest that visceral adipose tissue inflammation is associated with age-related changes in the brain and contributes to the ischemic brain damage in the aged mice. We suggest that visceral adiposity should be considered as a factor affecting brain health and ischemic brain damage in the aged population. PMID:26184082

  13. Dynamics of chromosomal aberrations in male mice of various strains during aging.

    Science.gov (United States)

    Rozenfel'd, S V; Togo, E F; Mikheev, V S; Popovich, I G; Zabezhinskii, M A; Anisimov, V N

    2001-05-01

    We studied the incidence of chromosome aberrations in bone marrow cells and primary spermatocytes in various mouse strains. Experiments were performed on SAMP mice (accelerated aging), control SAMR mice, and long-living CBA and SHR mice. Experiments revealed a positive correlation between the age and the incidence of mutations in their somatic cells and gametes. PMID:11550060

  14. Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice.

    Directory of Open Access Journals (Sweden)

    Zhe Liang

    Full Text Available BACKGROUND: Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8-10 week Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis. METHODS: Aged (20-24 months Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival. RESULTS: In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005. Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice. CONCLUSIONS: Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.

  15. Qing'E formula alleviates the aging process in D-galactose-induced aging mice

    Science.gov (United States)

    ZHONG, LIN; HUANG, FEI; SHI, HAILIAN; WU, HUI; ZHANG, BEIBEI; WU, XIAOJUN; WEI, XIAOHUI; WANG, ZHENGTAO

    2016-01-01

    Qing'E formula (QEF) is a clinically used prescription with four ingredients, Eucommiae Cortex, Psoraleae Fructus, Juglandis Semen and Garlic Rhizoma, from the Song dynasty (10th century CE). The present study aimed to investigate the anti-aging effect and mechanisms of QEF on D-galactose-induced aging mice. A mouse subacute aging model was established by subcutaneous injection of D-galactose at the neck consecutively for 8 weeks. Motor activity and memory impairment of the mice were evaluated by the rotarod test and passive avoidance test, respectively. Serum and liver parameters were analyzed with biochemical kits. Hippocampal mRNA and protein expression levels were examined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. QEF administration significantly ameliorated the impaired motor and memory of aging mice. In the serum, QEF reduced blood urea nitrogen, creatinine, nitric oxide (NO) and malondialdehyde (MDA) levels, and inhibited alanine aminotransferase and aspartate aminotransferase activities. In the liver, QEF increased the glutathione level, enhanced total antioxidant capacity and catalase activity, deceased NO and MDA production, and reduced NO synthase activity. In the hippocampus, QEF elevated gene expression levels of Klotho, sirtuin 1 (SIRT1), forkhead box transcription factor O3, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), insulin-like growth factor-1 and peroxiredoxin-3. QEF increased protein expression levels of Klotho and SIRT1, and decreased that of PGC-1α in the hippocampus. In conclusion, QEF attenuated the aging process in D-galactose-treated mice, which may be mediated through enhancing the antioxidants in the body, protecting renal and hepatic health, and balancing hippocampal expression levels of the longevity-related genes. PMID:27347412

  16. Accumulation of point mutations in mitochondrial DNA of aging mice

    International Nuclear Information System (INIS)

    Mitochondrial DNA (mtDNA) exists in a highly genotoxic environment created by exposure to reactive oxygen species, somewhat deficient DNA repair, and the relatively low fidelity of polymerase gamma. Given the severity of the environment, it was anticipated that mutation accumulation in the mtDNA of aging animals should exceed that of nuclear genes by several orders of magnitude. We have analyzed fragments amplified from the D-loop region of mtDNA from 2 to 22-month-old mice. The amplified 432 bp fragments were cloned into plasmid vectors, and plasmid DNAs from individual clones were purified and sequenced. None of 110 fragments from young mice contained a mutation, while 9 of 87 clones originating from old animals contained base substitutions (chi square = 11.9, P5 nucleotides (depending on assumptions of clonality), which exceeds existing estimates for mutation frequencies for nuclear genes by approximately 1000-fold. Our data suggest that at 22 months of age, which roughly corresponds to 3/4 of the mouse natural life span, most mtDNA molecules carry multiple point mutations

  17. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

    Science.gov (United States)

    Kesby, James P; Kim, Jane J; Scadeng, Miriam; Woods, Gina; Kado, Deborah M; Olefsky, Jerrold M; Jeste, Dilip V; Achim, Cristian L; Semenova, Svetlana

    2015-01-01

    Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions. PMID:26448649

  18. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

    Directory of Open Access Journals (Sweden)

    James P Kesby

    Full Text Available Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old and aged (15 months old mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.

  19. Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline.

    Science.gov (United States)

    Shi, Qiaoqiao; Colodner, Kenneth J; Matousek, Sarah B; Merry, Katherine; Hong, Soyon; Kenison, Jessica E; Frost, Jeffrey L; Le, Kevin X; Li, Shaomin; Dodart, Jean-Cosme; Caldarone, Barbara J; Stevens, Beth; Lemere, Cynthia A

    2015-09-23

    The complement system is part of the innate immune response responsible for removing pathogens and cellular debris, in addition to helping to refine CNS neuronal connections via microglia-mediated pruning of inappropriate synapses during brain development. However, less is known about the role of complement during normal aging. Here, we studied the role of the central complement component, C3, in synaptic health and aging. We examined behavior as well as electrophysiological, synaptic, and neuronal changes in the brains of C3-deficient male mice (C3 KO) compared with age-, strain-, and gender-matched C57BL/6J (wild-type, WT) control mice at postnatal day 30, 4 months, and 16 months of age. We found the following: (1) region-specific and age-dependent synapse loss in aged WT mice that was not observed in C3 KO mice; (2) age-dependent neuron loss in hippocampal CA3 (but not in CA1) that followed synapse loss in aged WT mice, neither of which were observed in aged C3 KO mice; and (3) significantly enhanced LTP and cognition and less anxiety in aged C3 KO mice compared with aged WT mice. Importantly, CA3 synaptic puncta were similar between WT and C3 KO mice at P30. Together, our results suggest a novel and prominent role for complement protein C3 in mediating aged-related and region-specific changes in synaptic function and plasticity in the aging brain. Significance statement: The complement cascade, part of the innate immune response to remove pathogens, also plays a role in synaptic refinement during brain development by the removal of weak synapses. We investigated whether complement C3, a central component, affects synapse loss during aging. Wild-type (WT) and C3 knock-out (C3 KO) mice were examined at different ages. The mice were similar at 1 month of age. However, with aging, WT mice lost synapses in specific brain regions, especially in hippocampus, an area important for memory, whereas C3 KO mice were protected. Aged C3 KO mice also performed better on

  20. Effects of sleep deprivation and aging on long-term and remote memory in mice

    OpenAIRE

    Vecsey, Christopher G.; Park, Alan J.; Khatib, Nora; Abel, Ted

    2015-01-01

    Sleep deprivation (SD) following hippocampus-dependent learning in young mice impairs memory when tested the following day. Here, we examined the effects of SD on remote memory in both young and aged mice. In young mice, we found that memory is still impaired 1 mo after training. SD also impaired memory in aged mice 1 d after training, but, by a month after training, sleep-deprived and control aged animals performed similarly, primarily due to remote memory decay in the control aged animals. ...

  1. Effects of chronic estrogen treatment on modulating age-related bone loss in female mice.

    Science.gov (United States)

    Syed, Farhan A; Mödder, Ulrike Il; Roforth, Matthew; Hensen, Ira; Fraser, Daniel G; Peterson, James M; Oursler, Merry Jo; Khosla, Sundeep

    2010-11-01

    While female mice do not have the equivalent of a menopause, they do undergo reproductive senescence. Thus, to dissociate the effects of aging versus estrogen deficiency on age-related bone loss, we sham-operated, ovariectomized, or ovariectomized and estrogen-replaced female C57/BL6 mice at 6 months of age and followed them to age 18 to 22 months. Lumbar spines and femurs were excised for analysis, and bone marrow hematopoietic lineage negative (lin-) cells (enriched for osteoprogenitor cells) were isolated for gene expression studies. Six-month-old intact control mice were euthanized to define baseline parameters. Compared with young mice, aged/sham-operated mice had a 42% reduction in lumbar spine bone volume/total volume (BV/TV), and maintaining constant estrogen levels over life in ovariectomized/estrogen-treated mice did not prevent age-related trabecular bone loss at this site. By contrast, lifelong estrogen treatment of ovariectomized mice completely prevented the age-related reduction in cortical volumetric bone mineral density (vBMD) and thickness at the tibial diaphysis present in the aged/sham-operated mice. As compared with cells from young mice, lin- cells from aged/sham-operated mice expressed significantly higher mRNA levels for osteoblast differentiation and proliferation marker genes. These data thus demonstrate that, in mice, age-related loss of cortical bone in the appendicular skeleton, but not loss of trabecular bone in the spine, can be prevented by maintaining constant estrogen levels over life. The observed increase in osteoblastic differentiation and proliferation marker gene expression in progenitor bone marrow cells from aged versus young mice may represent a compensatory mechanism in response to ongoing bone loss. PMID:20499336

  2. Increased Adipocyte Area in Injured Muscle With Aging and Impaired Remodeling in Female Mice.

    Science.gov (United States)

    Fearing, Caitlin M; Melton, David W; Lei, Xiufen; Hancock, Heather; Wang, Hanzhou; Sarwar, Zaheer U; Porter, Laurel; McHale, Matthew; McManus, Linda M; Shireman, Paula K

    2016-08-01

    We demonstrated that young male and female mice similarly regenerated injured skeletal muscle; however, female mice transiently increased adipocyte area within regenerated muscle in a sex hormone-dependent manner. We extended these observations to investigate the effect of aging and sex on sarcopenia and muscle regeneration. Cardiotoxin injury to the tibialis anterior muscle of young, middle, and old-aged C57Bl/6J male and female mice was used to measure regenerated myofiber cross-sectional area (CSA), adipocyte area, residual necrosis, and inflammatory cell recruitment. Baseline (uninjured) myofiber CSA was decreased in old mice of both sexes compared to young and middle-aged mice. Regenerated CSA was similar in male mice in all age groups until baseline CSA was attained but decreased in middle and old age female mice compared to young females. Furthermore, adipocyte area within regenerated muscle was transiently increased in young females compared to young males and these sex-dependent increases persisted in middle and old age female mice and were associated with increased Pparg Young female mice had more pro-inflammatory monocytes/macrophages in regenerating muscle than young male mice and increased Sca-1(+)CD45(-)cells. In conclusion, sex and age influence pro-inflammatory cell recruitment, muscle regeneration, and adipocyte area following skeletal muscle injury. PMID:26273023

  3. Effect of aging and radiation in mice of different genotypes

    International Nuclear Information System (INIS)

    Data are presented on the life span of nine inbred strains and five hybrid strains of mice based on 400 mice of each sex for inbred and 200 mice of each sex for hybrid. Some of these mice were exposed when 120 days old to 250 R or 450 R of x radiation delivered at a dose rate of 60 R/min. Data on strain, sample size, and mean survival times are presented in tables

  4. Genetic analysis of intracapillary glomerular lipoprotein deposits in aging mice.

    Directory of Open Access Journals (Sweden)

    Gerda A Noordmans

    Full Text Available BACKGROUND: Renal aging is characterized by functional and structural changes like decreased glomerular filtration rate, and glomerular, tubular and interstitial damage. To gain insight in pathways involved in renal aging, we studied aged mouse strains and used genetic analysis to identify genes associated with aging phenotypes. METHODS: Upon morphological screening in kidneys from 20-month-old mice from 26 inbred strains we noted intracapillary PAS-positive deposits. The severity of these deposits was quantified by scoring of a total of 50 glomeruli per section (grade 0-4. Electron microscopy and immunohistochemical staining for apoE, apoB, apoA-IV and perilipin-2 was performed to further characterize the lesions. To identify loci associated with these PAS-positive intracapillary glomerular deposits, we performed haplotype association mapping. RESULTS: Six out of 26 mouse strains showed glomerular PAS-positive deposits. The severity of these deposits varied: NOD(0.97, NZW(0.41, NON(0.30, B10(0.21, C3 H(0.9 and C57BR(0.7. The intracapillary deposits were strongly positive for apoE and weakly positive for apoB and apoA-IV. Haplotype association mapping showed a strong association with a 30-Kb haplotype block on Chr 1 within the Esrrg gene. We investigated 1 Mb on each site of this region, which includes the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3. CONCLUSIONS: By analyzing 26 aged mouse strains we found that some strains developed an intracapillary PAS and apoE-positive lesion and identified a small haplotype block on Chr 1 within the Esrrg gene to be associated with these lipoprotein deposits. The region spanning this haplotype block contains the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3, which are all highly expressed in the kidney. Esrrg might be involved in the evolvement of these glomerular deposits by influencing lipid metabolism and possibly immune reponses.

  5. The PDE4 Inhibitor HT-0712 Improves Hippocampus-Dependent Memory in Aged Mice

    OpenAIRE

    Peters, Marco; Bletsch, Matthew; Stanley, Jennifer; Wheeler, Damian; Scott, Roderick; Tully, Tim

    2014-01-01

    Aging is associated with declines in memory and cognitive function. Here, we evaluate the effects of HT-0712 on memory formation and on cAMP response element-binding protein (CREB)-regulated genes in aged mice. HT-0712 enhanced long-term memory formation in normal young mice at brain concentrations similar to those found to increase CRE-mediated gene expression in hippocampal neurons. Aged mice showed significantly poorer contextual and trace conditioning compared with young–adult mice. In ag...

  6. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    OpenAIRE

    Li Li; Meng Xu; Bo Shen; Man Li; Qian Gao; Shou-gang Wei

    2016-01-01

    D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected ...

  7. Mice age - Does the age of the mother predict offspring behaviour?

    Science.gov (United States)

    Lerch, Sandra; Brandwein, Christiane; Dormann, Christof; Gass, Peter; Chourbaji, Sabine

    2015-08-01

    Increasing paternal age is known to be associated with a great variety of psychiatric disorders such as schizophrenia or autism. Hence the factor "age" may be taken as strategic tool to analyse specific scientific hypotheses. Additionally, this finding also needs to be addressed in rather pragmatically performed breeding protocols of model organisms, since otherwise artefacts may challenge the validity of the results. Our study was performed to investigate influences of advanced age of mouse dams (30 vs. 16weeks) on maternal- and offspring behaviour. Adult offspring of both sexes was analysed in a test battery comprising paradigms for exploration, anxiety and depressive-like behaviours. Final blood sampling was conducted for stressphysiological analysis. Interestingly, advanced age of the mothers was associated with increased nest-building quality while maternal activity was unaffected. Moreover "maternal (mice) age" (MA) affected emotionality in the offspring, which became apparent in the dark-light box and the social recognition paradigm. These findings not only emphasize MA to model a potent risk factor with regard to emotional stability, but also underscore the vast necessity to include information about breeding protocols into the methods section of any animal study. PMID:25914174

  8. Rate of lens lesion development and the age of mice at time of irradiation

    International Nuclear Information System (INIS)

    The rate of lens lesion development has been studied in mice irradiated at different age ranging from one day up to one year old mice. The time needed for the first appearance of lens lesion was shortest in groups of mice irradiated at the age of one, two and three days of life, and longest in groups of mice irradiated at the age of 5 days, 1 week and 2 weeks of life. The time needed for the first appearance of lens lesion for mice irradiated between the third week and one year of life was constant. It was longer than for mice irradiated during the first three days of life and shorter than for mice irradiated at 5 up to 14 days of life. In all but one irradiated groups the age at which the first lens lesion occurred differed significantly from the age at which the first senile changes occurred in the lens of control mice. The one exception was the group of mice irradiated at the age of one year. (author)

  9. A new immuno- dystrophin-deficient model, the NSG-mdx4Cv mouse, provides evidence for functional improvement following allogeneic satellite cell transplantation

    OpenAIRE

    Arpke, Robert W.; Darabi, Radbod; Mader, Tara L.; Zhang, Yu; Toyama, Akira; Lonetree, Cara-lin; Nash, Nardina; Lowe, Dawn A.; Perlingeiro, Rita C. R.; Kyba, Michael

    2013-01-01

    Transplantation of a myogenic cell population into an immunodeficient recipient is an excellent way of assessing the in vivo muscle-generating capacity of that cell population. To facilitate both allogeneic and xenogeneic transplantations of muscle-forming cells in mice we have developed a novel immunodeficient muscular dystrophy model, the NSG-mdx4Cv mouse. The IL2Rg mutation, which is linked to the Dmd gene on the X chromosome, simultaneously depletes NK cells and suppresses thymic lymphoma...

  10. Altered Hippocampal Transcript Profile Accompanies an Age-Related Spatial Memory Deficit in Mice

    OpenAIRE

    Verbitsky, Miguel; Yonan, Amanda L.; Malleret, Gaël; Kandel, Eric R.; Gilliam, T. Conrad; Pavlidis, Paul

    2004-01-01

    We have carried out a global survey of age-related changes in mRNA levels in the C57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged mice displayed a mild but specific deficit in spatial memory in the Morris water maze. By using Affymetrix GeneChip microarrays, we found a distinc...

  11. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer

    OpenAIRE

    Bernardes de Jesus, Bruno; Vera, Elsa; Schneeberger, Kerstin; Tejera, Agueda M.; Ayuso, Eduard; Bosch, Fatima; Blasco, Maria A.

    2012-01-01

    A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness,...

  12. Effect on fertility of aging female mice exposed to different doses of X-rays

    International Nuclear Information System (INIS)

    The reproductive performance of aging female mice of CFW/pzh strain was observed after irradiation with doses from 8 to 256 cGy. The reproductive capacity decreased statistically after irradiation of 26 weeks old mice with doses higher than 8 cGy. For mice irradiated at 40 weeks of age the same effect was observed only after irradiation with doses from 32 to 128 cGy. Comparison of these results with the effects of neonatal irradiation indicates that in the case of reproduction the sensitivity of the ovaries of 26 and 40 weeks old mice is higher than in that of newborns. 7 refs., 1 fig., 2 tabs. (author)

  13. Effects of Environmental Enrichment on Spatial Memory and Neurochemistry in Middle-Aged Mice

    OpenAIRE

    Frick, Karyn M.; Stearns, Nancy A.; Pan, Jing-Yu; Berger-Sweeney, Joanne

    2003-01-01

    The present study compared the effects of environmental enrichment on spatial memory, glutamic acid decarboxylase (GAD) activity, and synaptophysin levels in middle-aged male and female mice. Prior to testing, a subset of 18-month-old male and female C57BL/6 mice was housed with two to three toys and a running wheel in the home cage for up to 29 d. Adult mice (7 mo) of both sexes and the remaining middle-aged mice were group (social) housed, but not exposed to enrichin...

  14. Augmented Senile Plaque Load in Aged Female β-Amyloid Precursor Protein-Transgenic Mice

    OpenAIRE

    Callahan, Michael J.; Lipinski, William J.; Bian, Feng; Durham, Robert A.; Pack, Amy; Walker, Lary C.

    2001-01-01

    Transgenic mice (Tg2576) overexpressing human β-amyloid precursor protein with the Swedish mutation (APP695SWE) develop Alzheimer’s disease-like amyloid β protein (Aβ) deposits by 8 to 10 months of age. These mice show elevated levels of Aβ40 and Aβ42, as well as an age-related increase in diffuse and compact senile plaques in the brain. Senile plaque load was quantitated in the hippocampus and neocortex of 8- to 19-month-old male and female Tg2576 mice. In all mice, plaque burden increased m...

  15. Altered Hippocampal Transcript Profile Accompanies an Age-Related Spatial Memory Deficit in Mice

    Science.gov (United States)

    Verbitsky, Miguel; Yonan, Amanda L.; Malleret, Gael; Kandel, Eric R.; Gilliam, T. Conrad; Pavlidis, Paul

    2004-01-01

    We have carried out a global survey of age-related changes in mRNA levels in the 57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged…

  16. Female CREBαδ- deficient mice show earlier age-related cognitive deficits than males

    OpenAIRE

    Hebda-Bauer, Elaine K.; Luo, Jie; Watson, Stanley J.; Akil, Huda

    2007-01-01

    Age-related changes in the hippocampus increase vulnerability to impaired learning and memory. Our goal is to understand how a genetic vulnerability to cognitive impairment can be modified by aging and sex. Mice with a mutation in the cAMP response element binding (CREB) protein gene (CREBαδ- deficient mice) have a mild cognitive impairment and show test condition-dependent learning and memory deficits. We tested 3 ages of CREBαδ- deficient and wild-type (WT) mice in 2 Morris water maze (MWM)...

  17. Impaired burrowing is the most prominent behavioral deficit of aging htau mice.

    Science.gov (United States)

    Geiszler, Philippine Camilla; Barron, Matthew Richard; Pardon, Marie-Christine

    2016-08-01

    htau mice are deficient of murine tau but express all six human tau isoforms, leading to gradual tau misprocessing and aggregation in brain areas relevant to Alzheimer's disease. While histopathological changes in htau mice have been researched in the past, we focused here on functional consequences of human tau accumulation. htau mice and their background controls - murine tau knock-out (mtau(-/-)) and C57Bl/6J mice - underwent a comprehensive trial battery to investigate species-specific behavior, locomotor activity, emotional responses, exploratory traits, spatial and recognition memory as well as acquisition, retention and extinction of contextual fear at two, four, six, nine and twelve months of age. In htau mice, tau pathology was already present at two months of age, whereas deficits in food burrowing and spatial working memory were first noted at four months of age. At later stages the presence of human tau on a mtau(-/-) background appeared to guard cognitive performance; as mtau(-/-) but not htau mice differed from C57Bl/6J mice in the food burrowing, spontaneous alternation and object discrimination tasks. Aging mtau(-/-) mice also exhibited increased body mass and locomotor activity. These data highlight that reduced food-burrowing performance was the most robust aspect of the htau phenotype with aging. htau and mtau(-/-) deficits in food burrowing pointed at the necessity of intact tau systems for daily life activities. While some htau and mtau(-/-) deficits overlap, age differences between the two genotypes may reflect distinct functional effects and compared to C57Bl/6J mice, the htau phenotype appeared stronger than the mtau(-/-) phenotype at young ages but milder with aging. PMID:27167086

  18. Dysfunctional Muscle and Liver Glycogen Metabolism in mdx Dystrophic Mice

    OpenAIRE

    David I Stapleton; Xianzhong Lau; Marcelo Flores; Jennifer Trieu; Stefan M Gehrig; Annabel Chee; Timur Naim; Gordon S Lynch; René Koopman

    2014-01-01

    Background Duchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD pati...

  19. Heregulin ameliorates the dystrophic phenotype in mdx mice

    OpenAIRE

    Krag, Thomas O. B.; Bogdanovich, Sasha; Jensen, Claus J.; Fischer, M Dominik; Hansen-Schwartz, Jacob; Javazon, Elisabeth H.; Flake, Alan W.; Edvinsson, Lars; Khurana, Tejvir S.

    2004-01-01

    Duchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by absence of dystrophin. Utrophin is a chromosome 6-encoded dystrophin-related protein (DRP), sharing functional motifs with dystrophin. Utrophin's ability to compensate for dystrophin during development and when transgenically overexpressed has provided an important impetus for identifying activators of utrophin expression. The utrophin promoter A is transcriptionally regulated in part by heregulin-mediated, extrace...

  20. Heregulin ameliorates the dystrophic phenotype in mdx mice

    DEFF Research Database (Denmark)

    Krag, Thomas O B; Bogdanovich, Sasha; Jensen, Claus J;

    2004-01-01

    Duchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by absence of dystrophin. Utrophin is a chromosome 6-encoded dystrophin-related protein (DRP), sharing functional motifs with dystrophin. Utrophin's ability to compensate for dystrophin during development and when transge...... up-regulation offers a pharmacological therapeutic modality and obviates many of the toxicity and delivery issues associated with viral vector-based gene therapy for DMD....

  1. Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice

    Science.gov (United States)

    Verma, Rajkumar; Venna, Venugopal R.; Liu, Fudong; Chauhan, Anjali; Koellhoffer, Edward; Patel, Anita; Ricker, Austin; Maas, Kendra; Graf, Joerg; McCullough, Louise D.

    2016-01-01

    Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of gut-derived bacteria following stroke. Furthermore, sickness parameters and components of innate and adaptive immunity were examined. We found that while stroke induced gut permeability and bacterial translocation in both young and aged mice, only young mice were able to resolve infection. Bacterial species seeding peripheral organs also differed between young (Escherichia) and aged (Enterobacter) mice. Consequently, aged mice developed a septic response marked by persistent and exacerbated hypothermia, weight loss, and immune dysfunction compared to young mice following stroke. PMID:27115295

  2. Joint dysfunction and functional decline in middle age myostatin null mice.

    Science.gov (United States)

    Guo, Wen; Miller, Andrew D; Pencina, Karol; Wong, Siu; Lee, Amanda; Yee, Michael; Toraldo, Gianluca; Jasuja, Ravi; Bhasin, Shalender

    2016-02-01

    Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss. However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated. We report herein that male myostatin null mice (mstn(-/-)), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3-6months) to middle age (12-15months) than age-matched wt mice, measured as gripping strength and treadmill endurance. Mstn(-/-) mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration. Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon-bone insertion in mstn(-/-) mice than wt mice, even at the neonatal age. At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn(-/-) mice than wt controls. These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway. PMID:26549246

  3. RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice

    OpenAIRE

    Thomas, Ravindar R.; Khan, Shaharyar M.; Smigrodzki, Rafal M.; Onyango, Isaac G.; Dennis, Jameel; Khan, Omer M.; Portell, Francisco R.; Bennett, James P

    2012-01-01

    Mitochondrial function declines with age in postmitotic tissues such as brain, heart and skeletal muscle. Despite weekly exercise, aged mice showed substantial losses of mtDNA gene copy numbers and reductions in mtDNA gene transcription and mitobiogenesis signaling in brain and heart. We treated these mice with weekly intravenous injections of recombinant human mitochondrial transcription factor A (rhTFAM). RhTFAM treatment for one month increased mitochondrial respiration in brain, heart and...

  4. Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice.

    Science.gov (United States)

    García, Mayra; Misplon, Julia A; Price, Graeme E; Lo, Chia-Yun; Epstein, Suzanne L

    2016-01-01

    Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP+M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11-17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life. PMID:27055234

  5. Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice

    Science.gov (United States)

    García, Mayra; Misplon, Julia A.; Price, Graeme E.; Lo, Chia-Yun; Epstein, Suzanne L.

    2016-01-01

    Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP+M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11–17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life. PMID:27055234

  6. Reduced IGF-1 Signaling Delays Age-associated Proteotoxicity in Mice

    OpenAIRE

    Cohen, Ehud; Paulsson, Johan F.; Blinder, Pablo; Burstyn-Cohen, Tal; Du, Deguo; Estepa, Gabriela; Adame, Anthony; Pham, Hang M.; Holzenberger, Martin; Kelly, Jeffery W.; Masliah, Eliezer; Dillin, Andrew

    2009-01-01

    The Insulin/IGF signaling pathway (IIS) is a prominent regulator of aging of worms, flies, mice and likely humans. Delayed aging by IIS reduction protects the nematode, C. elegans, from toxicity associated with the aggregation of the Alzheimer's disease linked human peptide, Aβ. We reduced IGF signaling in Alzheimer's model mice and discovered that these animals are protected from the Alzheimer's-like disease symptoms including reduced behavioral impairment, neruoinflammation, neuronal and sy...

  7. An adjuvanted respiratory syncytial virus fusion protein induces protection in aged BALB/c mice

    Directory of Open Access Journals (Sweden)

    Cherukuri Anu

    2012-10-01

    Full Text Available Abstract Background Respiratory Syncytial Virus (RSV causes significant disease in the elderly, in part, because immunosenescence impairs protective immune responses to infection in this population. Despite previous and current efforts, there is no RSV vaccine currently licensed in infants or elderly adults. Adjuvanted RSV subunit vaccines have the potential to boost waning immune responses and reduce the burden of RSV disease in the elderly population. Results We used an aged BALB/c mouse model to evaluate immune responses to RSV Fusion (F protein in the absence and presence of an alum adjuvant. We demonstrate that aged BALB/c mice immunized with alum-adjuvanted RSV F protein had significantly reduced lung viral titers at day 4 following challenge with wild-type (wt RSV. Serum neutralizing antibody titers measured on day 27 correlated with protection in both young and aged vaccinated mice, although the magnitude of antibody titers was lower in aged mice. Unlike young mice, in aged mice, alum-adjuvanted RSV F did not induce lung TH2-type cytokines or eosinophil infiltration compared to non-adjuvanted F protein following wt RSV challenge. Conclusion Our studies demonstrate that neutralizing anti-RSV antibody titers correlate with protection in both young and aged BALB/c mice vaccinated with RSV F protein vaccines. The F + alum formulation mediated greater protection compared to the non-adjuvanted F protein in both young and aged mice. However, while alum can boost F-specific antibody responses in aged mice, it does not completely overcome the reduced ability of a senescent immune system to respond to the RSV F antigen. Thus, our data suggest that a stronger adjuvant may be required for the prevention of RSV disease in immunosenescent populations, to achieve the appropriate balance of protective neutralizing antibodies and effective TH1-type cytokine response along with minimal lung immunopathology.

  8. Influence of dose and age of radiation exposure on attributable risk in mice

    International Nuclear Information System (INIS)

    The present study was aimed to clarify influence of the dose and age of radiation exposure on attributable risk, relative cumulative hazard and expression pattern of the lethal diseases. The attributable risk, relative cumulative hazard and excess cumulative hazard were estimated with the age-specific mortalities. Experimental data using female B6C3F1 mice were made subject of analysis. In this experiment mice were irradiated at day 14, 17 or 18 prenatal age or day 0, 7, 35, 105, 240 or 365 postnatal age with doses ranging from 0.95 to 5.7 Gy of 137Cs γ-rays and were allowed to live out their entire life spans under a specific pathogen free condition. Among mice irradiated at day 0 postnatal period the attributable risk and relative cumulative hazard were 38 % and 1.61, respectively; whereas, shortening of the mean life span was 7 %. Shape of dose-response relationship for the attributable risk was downward concave and that for the relative cumulative hazard was upward concave. The relative cumulative hazards in mice irradiated during neonatal or juvenile period were apparently higher than that irradiated during adulthood. Latent period for expression of radiation-induced lethal diseases in mice irradiated during the prenatal or early postnatal period was longer than that in mice exposed during adult period. Susceptibility of mice in the late fetal period to induction of late-occurring lethal diseases was lower than neonatal mice and was almost similar to young adult mice. The relative cumulative hazard did not increase with statistically significant difference when mice were irradiated at day 14 prenatal age with 0.95 Gy. (author)

  9. Microsoft® SQL Server® 2008 MDX Step by Step

    CERN Document Server

    Smith, Bryan; Consulting, Hitachi

    2009-01-01

    Teach yourself the Multidimensional Expressions (MDX) query language-one step at a time. With this practical, learn-by-doing tutorial, you'll build the core techniques for using MDX with Analysis Services to deliver high-performance business intelligence solutions. Discover how to: Construct and execute MDX queriesWork with tuples, sets, and expressionsBuild complex sets to retrieve the exact data users needPerform aggregation functions and navigate data hierarchiesAssemble time-based business metricsCustomize an Analysis Services cube through the MDX scriptImplement dynamic security to cont

  10. Ginseng berry extract supplementation improves age-related decline of insulin signaling in mice.

    Science.gov (United States)

    Seo, Eunhui; Kim, Sunmi; Lee, Sang Jun; Oh, Byung-Chul; Jun, Hee-Sook

    2015-04-01

    The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old) were maintained on a regular diet (CON) or a regular diet supplemented with 0.05% ginseng berry extract (GBD) for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016) and insulin resistance scores (HOMA-IR) (p = 0.012), suggesting that GBD improved insulin sensitivity. Pancreatic islet hypertrophy was also ameliorated in GBD-fed mice (p = 0.007). Protein levels of tyrosine phosphorylated insulin receptor substrate (IRS)-1 (p = 0.047), and protein kinase B (AKT) (p = 0.037), were up-regulated in the muscle of insulin-injected GBD-fed mice compared with CON-fed mice. The expressions of forkhead box protein O1 (FOXO1) (p = 0.036) and peroxisome proliferator-activated receptor gamma (PPARγ) (p = 0.032), which are known as aging- and insulin resistance-related genes, were also increased in the muscle of GBD-fed mice. We conclude that ginseng berry extract consumption might increase activation of IRS-1 and AKT, contributing to the improvement of insulin sensitivity in aged mice. PMID:25912041

  11. Ginseng Berry Extract Supplementation Improves Age-Related Decline of Insulin Signaling in Mice

    Directory of Open Access Journals (Sweden)

    Eunhui Seo

    2015-04-01

    Full Text Available The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old were maintained on a regular diet (CON or a regular diet supplemented with 0.05% ginseng berry extract (GBD for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016 and insulin resistance scores (HOMA-IR (p = 0.012, suggesting that GBD improved insulin sensitivity. Pancreatic islet hypertrophy was also ameliorated in GBD-fed mice (p = 0.007. Protein levels of tyrosine phosphorylated insulin receptor substrate (IRS-1 (p = 0.047, and protein kinase B (AKT (p = 0.037, were up-regulated in the muscle of insulin-injected GBD-fed mice compared with CON-fed mice. The expressions of forkhead box protein O1 (FOXO1 (p = 0.036 and peroxisome proliferator-activated receptor gamma (PPARγ (p = 0.032, which are known as aging- and insulin resistance-related genes, were also increased in the muscle of GBD-fed mice. We conclude that ginseng berry extract consumption might increase activation of IRS-1 and AKT, contributing to the improvement of insulin sensitivity in aged mice.

  12. Minimal impact of age and housing temperature on the metabolic phenotype of Acc2-/- mice.

    Science.gov (United States)

    Brandon, Amanda E; Stuart, Ella; Leslie, Simon J; Hoehn, Kyle L; James, David E; Kraegen, Edward W; Turner, Nigel; Cooney, Gregory J

    2016-03-01

    An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12-16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42-54 weeks of age, male WT and Acc2(-/-) mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2(-/-) mice, aged Acc2(-/-) mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2(-/-) mice respectively, PFAO in mice, but this has little impact on body composition or insulin action. PMID:26668208

  13. Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice

    Science.gov (United States)

    Aso, Kazuyoshi; Tsuruhara, Akitoshi; Takagaki, Kentaro; Oki, Katsuyuki; Ota, Megumi; Nose, Yasuhiro; Tanemura, Hideki; Urushihata, Naoki; Sasanuma, Jinichi; Sano, Masayuki; Hirano, Atsuyuki; Aso, Rio; McGhee, Jerry R.; Fujihashi, Kohtaro

    2016-01-01

    It has been shown that adipose-derived mesenchymal stem cells (AMSCs) can differentiate into adipocytes, chondrocytes and osteoblasts. Several clinical trials have shown the ability of AMSCs to regenerate these differentiated cell types. Age-associated dysregulation of the gastrointestinal (GI) immune system has been well documented. Our previous studies showed that impaired mucosal immunity in the GI tract occurs earlier during agingthan is seen in the systemic compartment. In this study, we examined the potential of AMSCs to restore the GI mucosal immune system in aged mice. Aged (>18 mo old) mice were adoptively transferred with AMSCs. Two weeks later, mice were orally immunized with ovalbumin (OVA) plus cholera toxin (CT) three times at weekly intervals. Seven days after the final immunization, when fecal extract samples and plasma were subjected to OVA- and CT-B-specific ELISA, elevated levels of mucosal secretory IgA (SIgA) and plasma IgG antibody (Ab) responses were noted in aged mouse recipients. Similar results were also seen aged mice which received AMSCs at one year of age. When cytokine production was examined, OVA-stimulated Peyer’s patch CD4+ T cells produced increased levels of IL-4. Further, CD4+ T cells from the lamina propria revealed elevated levels of IL-4 and IFN-γ production. In contrast, aged mice without AMSC transfer showed essentially no OVA- or CT-B-specific mucosal SIgA or plasma IgG Ab or cytokine responses. Of importance, fecal extracts from AMSC transferred aged mice showed neutralization activity to CT intoxication. These results suggest that AMSCs can restore impaired mucosal immunity in the GI tract of aged mice. PMID:26840058

  14. Estradiol to aged female or male mice improves learning in inhibitory avoidance and water maze tasks

    OpenAIRE

    Frye, Cheryl A.; Rhodes, Madeline E; Dudek, Bruce

    2005-01-01

    Although 17β-Estradiol (E2) improves cognitive performance of aged female mice, its mnemonic effects when administered post-training to aged male mice have not been examined. E2 (10 µg, SC) or oil vehicle was administered to intact, 24-month-old female or male congenic (primarily C57BL/6 background) mice immediately after training in the inhibitory avoidance or water maze tasks. Following behavioral testing, effects of 1 or 24 h of E2 exposure on hippocampal levels of E2 and brain-derived neu...

  15. 100-fold but not 50-fold dystrophin overexpression aggravates electrocardiographic defects in the mdx model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Yue, Yongping; Wasala, Nalinda B; Bostick, Brian; Duan, Dongsheng

    2016-01-01

    Dystrophin gene replacement holds the promise of treating Duchenne muscular dystrophy. Supraphysiological expression is a concern for all gene therapy studies. In the case of Duchenne muscular dystrophy, Chamberlain and colleagues found that 50-fold overexpression did not cause deleterious side effect in skeletal muscle. To determine whether excessive dystrophin expression in the heart is safe, we studied two lines of transgenic mdx mice that selectively expressed a therapeutic minidystrophin gene in the heart at 50-fold and 100-fold of the normal levels. In the line with 50-fold overexpression, minidystrophin showed sarcolemmal localization and electrocardiogram abnormalities were corrected. However, in the line with 100-fold overexpression, we not only detected sarcolemmal minidystrophin expression but also observed accumulation of minidystrophin vesicles in the sarcoplasm. Excessive minidystrophin expression did not correct tachycardia, a characteristic feature of Duchenne muscular dystrophy. Importantly, several electrocardiogram parameters (QT interval, QRS duration and the cardiomyopathy index) became worse than that of mdx mice. Our data suggests that the mouse heart can tolerate 50-fold minidystrophin overexpression, but 100-fold overexpression leads to cardiac toxicity. PMID:27419194

  16. 100-fold but not 50-fold dystrophin overexpression aggravates electrocardiographic defects in the mdx model of Duchenne muscular dystrophy

    Science.gov (United States)

    Yue, Yongping; Wasala, Nalinda B; Bostick, Brian; Duan, Dongsheng

    2016-01-01

    Dystrophin gene replacement holds the promise of treating Duchenne muscular dystrophy. Supraphysiological expression is a concern for all gene therapy studies. In the case of Duchenne muscular dystrophy, Chamberlain and colleagues found that 50-fold overexpression did not cause deleterious side effect in skeletal muscle. To determine whether excessive dystrophin expression in the heart is safe, we studied two lines of transgenic mdx mice that selectively expressed a therapeutic minidystrophin gene in the heart at 50-fold and 100-fold of the normal levels. In the line with 50-fold overexpression, minidystrophin showed sarcolemmal localization and electrocardiogram abnormalities were corrected. However, in the line with 100-fold overexpression, we not only detected sarcolemmal minidystrophin expression but also observed accumulation of minidystrophin vesicles in the sarcoplasm. Excessive minidystrophin expression did not correct tachycardia, a characteristic feature of Duchenne muscular dystrophy. Importantly, several electrocardiogram parameters (QT interval, QRS duration and the cardiomyopathy index) became worse than that of mdx mice. Our data suggests that the mouse heart can tolerate 50-fold minidystrophin overexpression, but 100-fold overexpression leads to cardiac toxicity. PMID:27419194

  17. Age-Related Deterioration of Rod Vision in Mice

    OpenAIRE

    Kolesnikov, Alexander V.; Fan, Jie; Crouch, Rosalie K.; Kefalov, Vladimir J.

    2010-01-01

    Even in healthy individuals, aging leads to deterioration in visual acuity, contrast sensitivity, visual field, and dark adaptation. Little is known about the neural mechanisms that drive the age-related changes of the retina and more specifically of photoreceptors. According to one hypothesis, the age-related deterioration in rod function is due to the limited availability of 11-cis-retinal for rod pigment formation. To determine how aging affects rod photoreceptors and to test the retinoid ...

  18. β - Alanine protects mice from memory deficits induced by ageing, scopolamine, diazepam and ethanol

    Directory of Open Access Journals (Sweden)

    Dhingra D

    2006-01-01

    Full Text Available The present study was undertaken to investigate the effects of β-alanine (a glycine agonist, on learning and memory in mice. β-alanine (5, 10, 20 and 40 mg/kg i.p. was administered for 6 successive days, to young (3 months old and aged-mice (16 months old. The learning and memory parameters were assessed, using elevated plus-maze and passive-avoidance apparatus. The effect of β-alanine (20 mg/kg for 6 days on locomotor function of young and aged mice, was studied using photoactometer, to rule out the increase in locomotor performance of mice. β-alanine at both the doses (10 and 20 mg/kg, significantly improved learning and memory of young- and aged- mice. β-alanine also reversed scopolamine (0.4 mg/kg i.p., ethanol (1.0 g/kg i.p. and diazepam (1.0 mg/kg i.p. -induced amnesia in young mice. There was no significant effect of β-alanine on the locomotor activity of both young and aged mice. The probable underlying mechanism of the memory-enhancing effect of β-alanine appears to be related to its antioxidant, anti-amyloid and procholinergic activities.

  19. Functional substitution by TAT-utrophin in dystrophin-deficient mice.

    Directory of Open Access Journals (Sweden)

    Kevin J Sonnemann

    2009-05-01

    Full Text Available BACKGROUND: The loss of dystrophin compromises muscle cell membrane stability and causes Duchenne muscular dystrophy and/or various forms of cardiomyopathy. Increased expression of the dystrophin homolog utrophin by gene delivery or pharmacologic up-regulation has been demonstrated to restore membrane integrity and improve the phenotype in the dystrophin-deficient mdx mouse. However, the lack of a viable therapy in humans predicates the need to explore alternative methods to combat dystrophin deficiency. We investigated whether systemic administration of recombinant full-length utrophin (Utr or DeltaR4-21 "micro" utrophin (muUtr protein modified with the cell-penetrating TAT protein transduction domain could attenuate the phenotype of mdx mice. METHODS AND FINDINGS: Recombinant TAT-Utr and TAT-muUtr proteins were expressed using the baculovirus system and purified using FLAG-affinity chromatography. Age-matched mdx mice received six twice-weekly intraperitoneal injections of either recombinant protein or PBS. Three days after the final injection, mice were analyzed for several phenotypic parameters of dystrophin deficiency. Injected TAT-muUtr transduced all tissues examined, integrated with members of the dystrophin complex, reduced serum levels of creatine kinase (11,290+/-920 U versus 5,950+/-1,120 U; PBS versus TAT, the prevalence of muscle degeneration/regeneration (54%+/-5% versus 37%+/-4% of centrally nucleated fibers; PBS versus TAT, the susceptibility to eccentric contraction-induced force drop (72%+/-5% versus 40%+/-8% drop; PBS versus TAT, and increased specific force production (9.7+/-1.1 N/cm(2 versus 12.8+/-0.9 N/cm(2; PBS versus TAT. CONCLUSIONS: These results are, to our knowledge, the first to establish the efficacy and feasibility of TAT-utrophin-based constructs as a novel direct protein-replacement therapy for the treatment of skeletal and cardiac muscle diseases caused by loss of dystrophin.

  20. Global view of transcriptome in the brains of aged NR2B transgenic mice*****

    Institute of Scientific and Technical Information of China (English)

    Chunxia Li; Men Su; Huimin Wang; Yinghe Hu

    2013-01-01

    NR2B subunits are involved in regulating aging, in particular, age-related learning and memory deficits. We examined 19-month-old NR2B transgenic mice and their littermate controls. First, we detected expression of the NR2B subunit gene, Grin2b, in the neocortex of transgenic mice using real-time PCR. Next, we used microarrays to examine differences in neocortical gene expression. Pathway and signal-net analyses identified multiple pathways altered in the transgenic mice, in-cluding the P53, Jak-STAT, Wnt, and Notch pathways, as wel as regulation of the actin cytoskeleton and neuroactive ligand-receptor interactions. Further signal-net analysis highlighted the P53 and insulin-like growth factor pathways as key regulatory pathways. Our results provide new insight into understanding the molecular mechanisms of NR2B regulated age-related memory storage, normal organismal aging and age-related disease.

  1. Complement factor H deficiency results in decreased neuroretinal expression of Cd59a in aged mice

    DEFF Research Database (Denmark)

    Faber, Carsten; Williams, Jennifer; Juel, Helene Bæk; Greenwood, John; Nissen, Mogens Holst; Moss, Stephen E.

    2012-01-01

    changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. Methods. Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh−/− C57BL/6J mice was analyzed by...... microarrays. Expression of a wide range of complement genes was compared with expression in liver. Results. An age-associated increased expression of complement, particularly C1q, C3, and factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the...... neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Hepatic expression of Cd59a increased with age regardless of Cfh genotype. Conclusions. While the connection between CFH deficiency and failure to upregulate CD59a remains unknown, these...

  2. Running rescues a fear-based contextual discrimination deficit in aged mice

    OpenAIRE

    Wu, Melody V; Luna, Victor M.; Hen, René

    2015-01-01

    Normal aging and exercise exert extensive, often opposing, effects on the dentate gyrus (DG) of the hippocampus altering volume, synaptic function, and behaviors. The DG is especially important for behaviors requiring pattern separation—a cognitive process that enables animals to differentiate between highly similar contextual experiences. To determine how age and exercise modulate pattern separation in an aversive setting, young, aged, and aged mice provided with a running wheel were assayed...

  3. Characteristics of spinal microglia in aged and obese mice: potential contributions to impaired sensory behavior

    OpenAIRE

    Lee, Seunghwan; Wu, YaSi; Shi, Xiang Qun; Zhang, Ji

    2015-01-01

    Background Both aging and obesity have been recognized widely as health conditions that profoundly affect individuals, families and the society. Aged and obese people often report altered pain responses while underlying mechanisms have not been fully elucidated. We aim to understand whether spinal microglia could potentially contribute to altered sensory behavior in aged and obese population. Results In this study, we monitored pain behavior in adult (6 months) and aged (17 months) mice fed w...

  4. Treadmill Exercise Attenuates Retinal Oxidative Stress in Naturally-Aged Mice: An Immunohistochemical Study

    OpenAIRE

    Chan-Sik Kim; Sok Park; Yoonseok Chun; Wook Song; Hee-Jae Kim; Junghyun Kim

    2015-01-01

    In the retina, a number of degenerative diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration, may occur as a result of aging. Oxidative damage is believed to contribute to the pathogenesis of aging as well as to age-related retinal disease. Although physiological exercise has been shown to reduce oxidative stress in rats and mice, it is not known whether it has a similar effect in retinal tissues. The aim of this study was to evaluate retinal oxidative str...

  5. Short-term Treatment of Daumone Improves Hepatic Inflammation in Aged Mice

    OpenAIRE

    Park, Jong Hee; Ha, Hunjoo

    2015-01-01

    Chronic inflammation has been proposed as one of the main molecular mechanisms of aging and age-related diseases. Although evidence in humans is limited, short-term calorie restriction (CR) has been shown to have anti-inflammatory effects in aged experimental animals. We reported on the long-term treatment of daumone, a synthetic pheromone secreted by Caenorhabditis elegans in an energy deficient environment, extends the life-span and attenuates liver injury in aged mice. The present study ex...

  6. Comparison of mice with accelerated aging caused by distinct mechanisms.

    Science.gov (United States)

    Gurkar, Aditi U; Niedernhofer, Laura J

    2015-08-01

    Aging is the primary risk factor for numerous chronic, debilitating diseases. These diseases impact quality of life of the elderly and consume a large portion of health care costs. The cost of age-related diseases will only increase as the world's population continues to live longer. Thus it would be advantageous to consider aging itself as a therapeutic target, potentially stemming multiple age-related diseases simultaneously. While logical, this is extremely challenging as the molecular mechanisms that drive aging are still unknown. Furthermore, clinical trials to treat aging are impractical. Even in preclinical models, testing interventions to extend healthspan in old age are lengthy and therefore costly. One approach to expedite aging studies is to take advantage of mouse strains that are engineered to age rapidly. These strains are genetically and phenotypically quite diverse. This review aims to offer a comparison of several of these strains to highlight their relative strengths and weaknesses as models of mammalian and more specifically human aging. Additionally, careful identification of commonalities among the strains may lead to the identification of fundamental pathways of aging. PMID:25617508

  7. Age-Related Hearing Loss in Mn-SOD Heterozygous Knockout Mice

    Directory of Open Access Journals (Sweden)

    Makoto Kinoshita

    2013-01-01

    Full Text Available Age-related hearing loss (AHL reduces the quality of life for many elderly individuals. Manganese superoxide dismutase (Mn-SOD, one of the antioxidant enzymes acting within the mitochondria, plays a crucial role in scavenging reactive oxygen species (ROS. To determine whether reduction in Mn-SOD accelerates AHL, we evaluated auditory function in Mn-SOD heterozygous knockout (HET mice and their littermate wild-type (WT C57BL/6 mice by means of auditory brainstem response (ABR. Mean ABR thresholds were significantly increased at 16 months when compared to those at 4 months in both WT and HET mice, but they did not significantly differ between them at either age. The extent of hair cell loss, spiral ganglion cell density, and thickness of the stria vascularis also did not differ between WT and HET mice at either age. At 16 months, immunoreactivity of 8-hydroxydeoxyguanosine was significantly greater in the SGC and SV in HET mice compared to WT mice, but that of 4-hydroxynonenal did not differ between them. These findings suggest that, although decrease of Mn-SOD by half may increase oxidative stress in the cochlea to some extent, it may not be sufficient to accelerate age-related cochlear damage under physiological aging process.

  8. Mitochondrial DNA deletion and aging induced by low dose rate of radiation in mice

    International Nuclear Information System (INIS)

    Mitochondrial DNA (mtDNA) is a closed circular DNA molecule and more than 100 copies are present in a cell. Deletion mutation of mtDNA accumulates with aging and can be a suitable marker for estimating biological effects on radiation-induced mutation in mice. The mice life span study in the Institute for Environmental Sciences suggests that low dose rate of radiation might accelerate aging in mice prolongly irradiated by 137Cs γ-rays (20 mGy/day for 400 days). To know the relationships between low dose rate irradiation, aging and mutation, we observed deletion mutations of mtDNA from mice irradiated by 137Cs γ-rays (20 mGy/day) for different dates. The real-time fluorescence PCR method was sensitive enough to determine the relative amount of deletion in several tissues. Age-dependent accumulations of deletion mutations were observed in aged mice (250-700 days). However, a significant increase of deletion mutation related to accumulated dose was not detected in 137Cs γ-ray irradiated mice for 4-12 Gy. These data suggest that the effect of the low dose rate irradiation on mtDNA is within a background level. (author)

  9. Altered left ventricular performance in aging physically active mice with an ankle sprain injury.

    Science.gov (United States)

    Turner, Michael J; Guderian, Sophie; Wikstrom, Erik A; Huot, Joshua R; Peck, Bailey D; Arthur, Susan T; Marino, Joseph S; Hubbard-Turner, Tricia

    2016-02-01

    We assessed the impact of differing physical activity levels throughout the lifespan, using a musculoskeletal injury model, on the age-related changes in left ventricular (LV) parameters in active mice. Forty male mice (CBA/J) were randomly placed into one of three running wheel groups (transected CFL group, transected ATFL/CFL group, SHAM group) or a SHAM Sedentary group (SHAMSED). Before surgery and every 6 weeks after surgery, LV parameters were measured under 2.5 % isoflurane inhalation. Group effects for daily distance run was significantly greater for the SHAM and lesser for the ATLF/CFL mice (p = 0.013) with distance run decreasing with age for all mice (p < 0.0001). Beginning at 6 months of age, interaction (group × age) was noted with LV posterior wall thickness-to-radius ratios (h/r) where h/r increased with age in the ATFL/CFL and SHAMSED mice while the SHAM and CFL mice exhibited decreased h/r with age (p = 0.0002). Passive filling velocity (E wave) was significantly greater in the SHAM mice and lowest for the ATFL/CFL and SHAMSED mice (p < 0.0001) beginning at 9 months of age. Active filling velocity (A wave) was not different between groups (p = 0.10). Passive-to-active filling velocity ratio (E/A ratio) was different between groups (p < 0.0001), with higher ratios for the SHAM mice and lower ratios for the ATFL/CFL and SHAMSED mice in response to physical activity beginning at 9 months of age. Passive-to-active filling velocity ratio decreased with age (p < 0.0001). Regular physical activity throughout the lifespan improved LV structure, passive filling velocity, and E/A ratio by 6 to 9 months of age and attenuated any negative alterations throughout the second half of life. The diastolic filling differences were found to be significantly related to the amount of activity performed by 9 months and at the end of the lifespan. PMID:26803818

  10. Effects of Aging on Spermatogenesis, Sperm Maturation and Fertility in Mice

    Institute of Scientific and Technical Information of China (English)

    Qiu-ju CHEN; Wei-jie ZHU; Jing LI

    2006-01-01

    Objective To investigate effects of aging on spermatogenesis in testis, sperm maturation in epididymis, and fertility in mice.Methods Testicular specimens, caput epididymal sperm and cauda epididymal sperm were obtained from Kuming mice (18-month aged group, n=15; 6-month young group as control, n=15). The testicular histological examinations and quantitative evaluations on spermatogenesis were performed. Sperm parameters including sperm density, sperm viability, sperm motility, and normal morphological rate were assessed. The fertilization rate and embryo development were measured by in vitro fertilization and embryo culture.Results The histological changes of testes in aged mice were mainly seminiferous tubule atrophy and hypospermatogenesis. In aged testes, a significant decline was found in the numbers of round spermatids and elongated spermatids per Sertoli cell (P<0.01). Sperm density, sperm motility and normal morphological rate in caput epididymis and cauda epididymis in aged mice significantly decreased (P<0. 05). The fertilization rate and embryo development of aged group were lower than those in the control(P< 0.01).Conclusions Spermatogenesis and sperm functions could be maintained in the aging male. However, aging affects spermatogenesis and sperm maturation, which leads to lower the quality of sperm, including sperm fertilizing capacity. The development of embryo from aging sperm would have more abnormalities.

  11. Defects in mitochondrial ATP synthesis in dystrophin-deficient mdx skeletal muscles may be caused by complex I insufficiency.

    Directory of Open Access Journals (Sweden)

    Emma Rybalka

    Full Text Available Duchenne Muscular Dystrophy is a chronic, progressive and ultimately fatal skeletal muscle wasting disease characterised by sarcolemmal fragility and intracellular Ca2+ dysregulation secondary to the absence of dystrophin. Mounting literature also suggests that the dysfunction of key energy systems within the muscle may contribute to pathological muscle wasting by reducing ATP availability to Ca2+ regulation and fibre regeneration. No study to date has biochemically quantified and contrasted mitochondrial ATP production capacity by dystrophic mitochondria isolated from their pathophysiological environment such to determine whether mitochondria are indeed capable of meeting this heightened cellular ATP demand, or examined the effects of an increasing extramitochondrial Ca2+ environment. Using isolated mitochondria from the diaphragm and tibialis anterior of 12 week-old dystrophin-deficient mdx and healthy control mice (C57BL10/ScSn we have demonstrated severely depressed Complex I-mediated mitochondrial ATP production rate in mdx mitochondria that occurs irrespective of the macronutrient-derivative substrate combination fed into the Kreb's cycle, and, which is partially, but significantly, ameliorated by inhibition of Complex I with rotenone and stimulation of Complex II-mediated ATP-production with succinate. There was no difference in the MAPR response of mdx mitochondria to increasing extramitochondrial Ca2+ load in comparison to controls, and 400 nM extramitochondrial Ca2+ was generally shown to be inhibitory to MAPR in both groups. Our data suggests that DMD pathology is exacerbated by a Complex I deficiency, which may contribute in part to the severe reductions in ATP production previously observed in dystrophic skeletal muscle.

  12. Factor analysis of attentional set-shifting performance in young and aged mice

    Directory of Open Access Journals (Sweden)

    Geyer Mark A

    2011-08-01

    Full Text Available Abstract Background Executive dysfunction may play a major role in cognitive decline with aging because frontal lobe structures are particularly vulnerable to advancing age. Lesion studies in rats and mice have suggested that intradimensional shifts (IDSs, extradimensional shifts (EDSs, and reversal learning are mediated by the anterior cingulate cortex, the medial prefrontal cortex, and the orbitofrontal cortex, respectively. We hypothesized that the latent structure of cognitive performance would reflect functional localization in the brain and would be altered by aging. Methods Young (4 months, n = 16 and aged (23 months, n = 18 C57BL/6N mice performed an attentional set-shifting task (ASST that evaluates simple discrimination (SD, compound discrimination (CD, IDS, EDS, and reversal learning. The performance data were subjected to an exploratory factor analysis to extract the latent structures of ASST performance in young and aged mice. Results The factor analysis extracted two- and three-factor models. In the two-factor model, the factor associated with SD and CD was clearly separated from the factor associated with the rest of the ASST stages in the young mice only. In the three-factor model, the SD and CD loaded on distinct factors. The three-factor model also showed a separation of factors associated with IDS, EDS, and CD reversal. However, the other reversal learning variables, ID reversal and ED reversal, had somewhat inconsistent factor loadings. Conclusions The separation of performance factors in aged mice was less clear than in young mice, which suggests that aged mice utilize neuronal networks more broadly for specific cognitive functions. The result that the factors associated with SD and CD were separated in the three-factor model may suggest that the introduction of an irrelevant or distracting dimension results in the use of a new/orthogonal strategy for better discrimination.

  13. Types and rate of cataract development in mice irradiated at different ages

    International Nuclear Information System (INIS)

    The effect of age on the development of radiation cataract has been investigated in an inbred A strain of mice and, as a result, the patterns of age dependence and senile mice cataract development were obtained. In general, the lenses of mice 1 to 3 days old were the most sensitive to radiation; the maximum resistance was noted in 5-day-old mice, and from this age up to 3 to 7 weeks of life there was a period of increasing sensitivity. In older animals the lens sensitivity tends to level off. The early stages of cataract occurred in all irradiated groups at a younger age than in the control group, but the late stages occurred in irradiated groups at the same age as the senile cataract occurred in the control group. Two types of cataract were observed. One was typical for young irradiated mice 1 to 5 days of age and the other was typical for all remaining irradiated groups and for a control group. Also, an attempt was made to correlate the obtained results with the cell kinetics in normal lens epithelium

  14. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.

    Directory of Open Access Journals (Sweden)

    Jung Yoon Park

    Full Text Available Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W, display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

  15. The mouse as a model for understanding chronic diseases of aging: the histopathologic basis of aging in inbred mice

    Directory of Open Access Journals (Sweden)

    David Harrison

    2011-06-01

    Full Text Available Inbred mice provide a unique tool to study aging populations because of the genetic homogeneity within an inbred strain, their short life span, and the tools for analysis which are available. A large-scale longitudinal and cross-sectional aging study was conducted on 30 inbred strains to determine, using histopathology, the type and diversity of diseases mice develop as they age. These data provide tools that when linked with modern in silico genetic mapping tools, can begin to unravel the complex genetics of many of the common chronic diseases associated with aging in humans and other mammals. In addition, novel disease models were discovered in some strains, such as rhabdomyosarcoma in old A/J mice, to diseases affecting many but not all strains including pseudoxanthoma elasticum, pulmonary adenoma, alopecia areata, and many others. This extensive data set is now available online and provides a useful tool to help better understand strain-specific background diseases that can complicate interpretation of genetically engineered mice and other manipulatable mouse studies that utilize these strains.

  16. Longitudinal Attentional Engagement Rescues Mice from Age-Related Cognitive Declines and Cognitive Inflexibility

    Science.gov (United States)

    Matzel, Louis D.; Light, Kenneth R.; Wass, Christopher; Colas-Zelin, Danielle; Denman-Brice, Alexander; Waddel, Adam C.; Kolata, Stefan

    2011-01-01

    Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm…

  17. p21 both attenuates and drives senescence and aging in BubR1 progeroid mice.

    NARCIS (Netherlands)

    Baker, D.J.; Weaver, R.L.; Deursen, J.M.A. van

    2013-01-01

    BubR1 insufficiency occurs with natural aging and induces progeroid phenotypes in both mice and children with mosaic variegated aneuploidy syndrome. In response to BubR1 insufficiency, skeletal muscle, fat, and lens tissue engage p19(Arf) to attenuate senescence and age-related deterioration. Here,

  18. CD36 expression contributes to age induced cardiomyopathy in mice

    Science.gov (United States)

    Cardiac remodeling and impaired cardiac performance in the elderly significantly increase the risk of developing heart disease. Although vascular abnormalities associated with aging contribute to the age-related decline in cardiac function, myocardium-specific events may also be involved. We show th...

  19. CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice.

    Science.gov (United States)

    Ramirez, Alejandro; Co, Mary; Mathew, Anuja

    2016-01-01

    Several studies have shown a reduced efficacy of influenza vaccines in the elderly compared to young adults. In this study, we evaluated the immunogenicity and protective efficacy of a commercially available inactivated influenza vaccine (Fluzone®) in young adult and aged mice. C57/BL6 mice were administered a single or double immunization of Fluzone® with or without CpG and challenged intranasally with H1N1 A/California/09 virus. A double immunization of Fluzone® adjuvanted with CpG elicited the highest level of protection in young adult mice which was associated with increases in influenza specific IgG, elevated HAI titres, reduced viral titres and lung inflammation. In contrast, the vaccine schedule which provided fully protective immunity in young adult mice conferred limited protection in aged mice. Antigen presenting cells from aged mice were found to be less responsive to in vitro stimulation by Fluzone and CpG which may partially explain this result. Our data are supportive of studies that have shown limited effectiveness of influenza vaccines in the elderly and provide important information relevant to the design of more immunogenic vaccines in this age group. PMID:26934728

  20. Age-dependent changes in diastolic Ca2+ and Na+ concentrations in dystrophic cardiomyopathy: Role of Ca2+ entry and IP3

    International Nuclear Information System (INIS)

    Highlights: • Age-dependent increase in [Ca2+]d and [Na+]d in mdx cardiomyocytes. • Gadolinium significantly reduced both [Ca2+]d and [Na+]d at all ages. • IP3-pathway inhibition reduced cations concentrations in dystrophic cardiomyocytes. - Abstract: Duchenne muscular dystrophy (DMD) is a lethal X-inherited disease caused by dystrophin deficiency. Besides the relatively well characterized skeletal muscle degenerative processes, DMD is also associated with a dilated cardiomyopathy that leads to progressive heart failure at the end of the second decade. The aim of the present study was to characterize the diastolic Ca2+ concentration ([Ca2+]d) and diastolic Na+ concentration ([Na+]d) abnormalities in cardiomyocytes isolated from 3-, 6-, 9-, and 12-month old mdx mice using ion-selective microelectrodes. In addition, the contributions of gadolinium (Gd3+)-sensitive Ca2+ entry and inositol triphosphate (IP3) signaling pathways in abnormal [Ca2+]d and [Na+]d were investigated. Our results showed an age-dependent increase in both [Ca2+]d and [Na+]d in dystrophic cardiomyocytes compared to those isolated from age-matched wt mice. Gd3+ treatment significantly reduced both [Ca2+]d and [Na+]d at all ages. In addition, blockade of the IP3-pathway with either U-73122 or xestospongin C significantly reduced ion concentrations in dystrophic cardiomyocytes. Co-treatment with U-73122 and Gd3+ normalized both [Ca2+]d and [Na+]d at all ages in dystrophic cardiomyocytes. These data showed that loss of dystrophin in mdx cardiomyocytes produced an age-dependent intracellular Ca2+ and Na+ overload mediated at least in part by enhanced Ca2+ entry through Gd3+ sensitive transient receptor potential channels (TRPC), and by IP3 receptors

  1. Age and isolation influence steroids release and chemical signaling in male mice.

    Science.gov (United States)

    Mucignat-Caretta, Carla; Cavaggioni, Andrea; Redaelli, Marco; Da Dalt, Laura; Zagotto, Giuseppe; Gabai, Gianfranco

    2014-05-01

    Social interactions in mice involve olfactory signals, which convey information about the emitter. In turn, the mouse social and physiological status may modify the release of chemical cues. In this study, the influences of age and social isolation on the endocrine response and the release of chemical signals were investigated in male CD1 mice, allocated into four groups: Young Isolated (from weaning till 60days; N=6), Adult Isolated (till 180days; N=6), Young Grouped (6 mice/cage; till 60days; N=18), Adult Grouped (6 mice/cage; till 180days; N=18). Mice were transferred in a clean cage to observe the micturition pattern and then sacrificed. Body and organs weights, serum testosterone, dehydroepiandrosterone, corticosterone and the ratio Major Urinary Protein/creatinine were measured. Urinary volatile molecules potentially involved in pheromonal communication were identified. Androgen secretion was greater in isolated mice (P<0.05), suggesting a greater reactivity of the Hypothalamic-Pituitary-Gonadal axis. Grouped mice presented a higher degree of adrenal activity, and young mice showed a higher serum corticosterone (P<0.05) suggesting a greater stimulation of the Hypothalamic-Pituitary-Adrenal axis. The micturition pattern typical of dominant male, consisting in voiding numerous droplets, was observed in Young Isolated mice only, which showed a higher protein/creatinine ratio (P<0.05). Urinary 2-s-butyl-thiazoline was higher in both Young and Adult Isolated mice (P<0.005). Young Isolated mice showed the most prominent difference in both micturition pattern and potentially active substance emission, while long term isolation resulted in a less extreme phenotype; therefore social isolation had a higher impact on young mice hormone and pheromone release. PMID:24525008

  2. The synthetic thyroid hormone, levothyroxine, protects cholinergic neurons in the hippocampus of naturally aged mice

    Institute of Scientific and Technical Information of China (English)

    Ailing Fu; Rumei Zhou; Xingran Xu

    2014-01-01

    The thyroid hormones, triiodothyronine and thyroxine, play important roles in cognitive func-tion during the mammalian lifespan. However, thyroid hormones have not yet been used as a therapeutic agent for normal age-related cognitive deficits. In this study, CD-1 mice (aged 24 months) were intraperitoneally injected with levothyroxine (L-T4;1.6μg/kg per day) for 3 consecutive months. Our findings revealed a significant improvement in hippocampal cyto-skeletal rearrangement of actin and an increase in serum hormone levels of L-T4-treated aged mice. Furthermore, the survival rate of these mice was dramatically increased from 60%to 93.3%. The Morris water maze task indicated that L-T4 restored impaired spatial memory in aged mice. Furthermore, level of choline acetyltransferase, acetylcholine, and superoxide dismutase were in-creased in these mice, thus suggesting that a possible mechanism by which L-T4 reversed cognitive impairment was caused by increased activity of these markers. Overall, supplement of low-dosage L-T4 may be a potential therapeutic strategy for normal age-related cognitive deifcits.

  3. Premature skin aging features rescued by inhibition of NADPH oxidase activity in XPC-deficient mice.

    Science.gov (United States)

    Hosseini, Mohsen; Mahfouf, Walid; Serrano-Sanchez, Martin; Raad, Houssam; Harfouche, Ghida; Bonneu, Marc; Claverol, Stephane; Mazurier, Frederic; Rossignol, Rodrigue; Taieb, Alain; Rezvani, Hamid Reza

    2015-04-01

    Xeroderma pigmentosum type C (XP-C) is characterized mostly by a predisposition to skin cancers and accelerated photoaging, but little is known about premature skin aging in this disease. By comparing young and old mice, we found that the level of progerin and p16(INK4a) expression, β-galactosidase activity, and reactive oxygen species, which increase with age, were higher in young Xpc(-/-) mice than in young Xpc(+/+) ones. The expression level of mitochondrial complexes and mitochondrial functions in the skin of young Xpc(-/-) was as low as in control aged Xpc(+/+)animals. Furthermore, the metabolic profile in young Xpc(-/-) mice resembled that found in aged Xpc(+/+) mice. Furthermore, premature skin aging features in young Xpc(-/-) mice were mostly rescued by inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) activity by using a NOX1 peptide inhibitor, suggesting that the continuous oxidative stress due to overactivation of NOX1 has a causative role in the underlying pathophysiology. PMID:25437426

  4. Ageing and the humoral immune response in mice

    International Nuclear Information System (INIS)

    The study presented in this thesis is concerned with changes in the humoral immune system as a function of age in different inbred mouse strains. Their capacity to develop humoral immune responses to experimentally given thymus-dependent and thymus-independent antigens under various conditions is compared. Furthermore, experiments employing thymus transplantation and thymic humoral factors which are directed at the restoration of the diminished T cell functions in old age are reported. (Auth.)

  5. Sex effects of Interleukin-6 deficiency on neuroinflammation in aged C57Bl/6 mice

    OpenAIRE

    Miller, VM; Lawrence, DA; Coccaro, GA; Mondal, TK; Andrews, K; Dreiem, A; Seegal, RF

    2010-01-01

    High levels of Interleukin-6 (IL-6) are associated with an increased risk of dementia in the elderly and can increase neuroinflammation in mice. Dementia is more frequent in females, and IL-6 is regulated by estrogen, suggesting elevated IL-6 levels may contribute to neuroinflammation and dementia particularly in women. Therefore we hypothesized that IL-6 deficient (−/−) female mice would have lower aging-related neuroinflammation than wild type (WT). We quantified neuroinflammatory markers w...

  6. Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice.

    Directory of Open Access Journals (Sweden)

    Caitlin S Latimer

    Full Text Available Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for six weeks. Exercise decreased hippocampal astrocyte and myelin markers of aging but increased VEGF, a marker of angiogenesis. Brain vascular casts revealed exercise-induced structural modifications associated with improved endothelial function in the periphery. Our results suggest that age-related astrocyte hypertrophy/reactivity and myelin dysregulation are aggravated by a sedentary lifestyle and accompanying reductions in vascular function. However, these effects appear reversible with exercise initiated at mid-age. As this period of the lifespan coincides with the appearance of multiple markers of brain aging, including initial signs of cognitive decline, it may represent a window of opportunity for intervention as the brain appears to still possess significant vascular plasticity. These results may also have particular implications for aging females who are more susceptible than males to certain risk factors which contribute to vascular aging.

  7. Ginseng Berry Extract Supplementation Improves Age-Related Decline of Insulin Signaling in Mice

    OpenAIRE

    Eunhui Seo; Sunmi Kim; Sang Jun Lee; Byung-Chul Oh; Hee-Sook Jun

    2015-01-01

    The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old) were maintained on a regular diet (CON) or a regular diet supplemented with 0.05% ginseng berry extract (GBD) for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016) and insulin resistance scores (HOMA-IR) (p = 0.012), suggesting that GBD improved insulin sensitivity. Pancreatic isl...

  8. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    Institute of Scientific and Technical Information of China (English)

    Li Li; Meng Xu; Bo Shen; Man Li; Qian Gao; Shou-gang Wei

    2016-01-01

    D-galactose has been widely used in aging research because of its efifcacy in inducing senescence and accelerating aging in animal models. The present study investigated the beneifts of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-ga-lactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apop-tosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice.

  9. Polysaccharide Extracted from Laminaria japonica Delays Intrinsic Skin Aging in Mice

    Science.gov (United States)

    Hu, Longyuan; Tan, Jia; Yang, Xiaomei; Tan, Haitao; Xu, Xiaozhen; You, Manhang; Qin, Wu; Huang, Liangzhao; Li, Siqi; Mo, Manqiu; Wei, Huifen; Li, Jing; Tan, Jiyong

    2016-01-01

    This study aimed to determine the effect of topically applied Laminaria polysaccharide (LP) on skin aging. We applied ointment containing LP (10, 25, and 50 μg/g) or vitamin E (10 μg/g) to the dorsal skin of aging mice for 12 months and young control mice for 4 weeks. Electron microscopy analysis of skin samples revealed that LP increased dermal thickness and skin collagen content. Tissue inhibitor of metalloprotease- (TIMP-) 1 expression was upregulated while that of matrix metalloproteinase- (MMP-) 1 was downregulated in skin tissue of LP-treated as compared to untreated aging mice. Additionally, phosphorylation of c-Jun N-terminal kinase (JNK) and p38 was higher in aging skin than in young skin, while LP treatment suppressed phospho-JNK expression. LP application also enhanced the expression of antioxidative enzymes in skin tissue, causing a decrease in malondialdehyde levels and increases in superoxide dismutase, catalase, and glutathione peroxidase levels relative to those in untreated aging mice. These results indicate that LP inhibits MMP-1 expression by preventing oxidative stress and JNK phosphorylation, thereby delaying skin collagen breakdown during aging. PMID:27143987

  10. Beta-lapachone, a modulator of NAD metabolism, prevents health declines in aged mice.

    Directory of Open Access Journals (Sweden)

    Jeong-sook Lee

    Full Text Available NADH-quinone oxidoreductase 1 (NQO1 modulates cellular NAD(+/NADH ratio which has been associated with the aging and anti-aging mechanisms of calorie restriction (CR. Here, we demonstrate that the facilitation of NQO1 activity by feeding β-lapachone (βL, an exogenous NQO1 co-substrate, prevented age-dependent decline of motor and cognitive function in aged mice. βL-fed mice did not alter their food-intake or locomotor activity but did increase their energy expenditure as measured by oxygen consumption and heat generation. Mitochondrial structure and numbers were disorganized and decreased in the muscles of control diet group but those defects were less severe in βL-fed aged mice. Furthermore, for a subset of genes associated with energy metabolism, mice fed the βL-diet showed similar changes in gene expression to the CR group (fed 70% of the control diet. These results support the potentiation of NQO1 activity by a βL diet and could be an option for preventing age-related decline of muscle and brain functions.

  11. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice.

    Science.gov (United States)

    Li, Li; Xu, Meng; Shen, Bo; Li, Man; Gao, Qian; Wei, Shou-Gang

    2016-05-01

    D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apoptosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice. PMID:27335566

  12. Changes with age in swimming performance of X-irradiated mice

    International Nuclear Information System (INIS)

    The time required to swim 250 cm was determined once weekly for the entire life of fifteen pairs of male dd/K mice. The irradiated group was exposed to a single 224 rad of X-rays at 20 weeks of age. Median survival time (ST50) for the control was 88.9 weeks and that for the irradiated group was 77.4 weeks, and both regression lines relating to death rate and age were parallel. The swimming ability of control mice began to decrease when the mice were 40 weeks of age, after which there was a gradual reduction with age at 0.00646/day. In the irradiated group, the swimming ability decreased from seven weeks after irradiation. The time of 50% reduction of swimming speed (TRS50) for the control was 78.9 weeks and that for the irradiated group was 66.3 weeks, and the slopes of the regression lines relating reduction rate and age were similar. Differences between ST50 and TRS50 were 10 weeks in the control and 11 weeks in the irradiated group, respectively. These results indicate that there is no basic difference in the reduction in swimming ability between control and irradiated mice. The X-irradiation may simply mean that the reduction in the swimming ability is displaced to an earlier time with no alteration in the rate of reduction, and that the earlier appearance in the irradiated group is related to premature aging as induced by irradiation. (author)

  13. Galectin-1 Protein Therapy Prevents Pathology and Improves Muscle Function in the mdx Mouse Model of Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Van Ry, Pam M; Wuebbles, Ryan D; Key, Megan; Burkin, Dean J

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by mutations in the dystrophin gene, leading to the loss of a critical component of the sarcolemmal dystrophin glycoprotein complex. Galectin-1 is a small 14 kDa protein normally found in skeletal muscle and has been shown to be a modifier of immune response, muscle repair, and apoptosis. Galectin-1 levels are elevated in the muscle of mouse and dog models of DMD. Together, these findings led us to hypothesize that Galectin-1 may serve as a modifier of disease progression in DMD. To test this hypothesis, recombinant mouse Galectin-1 was produced and used to treat myogenic cells and the mdx mouse model of DMD. Here we show that intramuscular and intraperitoneal injections of Galectin-1 into mdx mice prevented pathology and improved muscle function in skeletal muscle. These improvements were a result of enhanced sarcolemmal stability mediated by elevated utrophin and α7β1 integrin protein levels. Together our results demonstrate for the first time that Galectin-1 may serve as an exciting new protein therapeutic for the treatment of DMD. PMID:26050991

  14. Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

    Institute of Scientific and Technical Information of China (English)

    Hongkai Wang; Chengren Li; Hanzhi Wang; Feng Mei; Zhi Liu; Hai-Ying Shen; Lan Xiao

    2013-01-01

    Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined.Recently,accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis.We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia.In the present study,three different age cohorts of mice,i.e.juvenile (3 weeks),young-adult (6 weeks) and middle-aged (8months),were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination.Then,age-related vulnerability to CPZ-induced demyelination,behavioral outcomes,and myelination-related molecular biological changes were assessed.We demonstrated:(1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum,a region closely associated with the pathophysiology of schizophrenia; (2)the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein,more loss of CC-1-positive mature oligodendrocytes,and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice.Together,our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit,providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

  15. Nitrite Treatment Rescues Cardiac Dysfunction in Aged Mice Treated with Conjugated Linoleic Acid

    OpenAIRE

    Piell, Kellianne M.; Kelm, Natia Qipshidze; Caroway, Megan P.; Aman, Masarath; Cole, Marsha P.

    2014-01-01

    Conjugated linoleic acid (cLA) is a commercially available weight loss supplement that is not currently regulated by the FDA. Numerous studies suggest that cLA mediates protection in diseases including cancer, diabetes, atherosclerosis, immune function, and obesity. Based upon these reports, it was hypothesized that supplementation of cLA would improve heart function in aged wild-type (WT) mice. At 10 months of age, mice were treated with cLA, nitrite, or the combination of the two. Echocardi...

  16. Age-dependent effects of UCP2 deficiency on experimental acute pancreatitis in mice.

    Directory of Open Access Journals (Sweden)

    Sarah Müller

    Full Text Available Reactive oxygen species (ROS have been implicated in the pathogenesis of acute pancreatitis (AP for many years but experimental evidence is still limited. Uncoupling protein 2 (UCP2-deficient mice are an accepted model of age-related oxidative stress. Here, we have analysed how UCP2 deficiency affects the severity of experimental AP in young and older mice (3 and 12 months old, respectively triggered by up to 7 injections of the secretagogue cerulein (50 μg/kg body weight at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of alpha-amylase, intrapancreatic trypsin activation and levels of myeloperoxidase (MPO in lung and pancreatic tissue. Furthermore, in vitro studies with pancreatic acini were performed. At an age of 3 months, UCP2-/- mice and wild-type (WT C57BL/6 mice were virtually indistinguishable with respect to disease severity. In contrast, 12 months old UCP2-/- mice developed a more severe pancreatic damage than WT mice at late time points after the induction of AP (24 h and 7 days, respectively, suggesting retarded regeneration. Furthermore, a higher peak level of alpha-amylase activity and gradually increased MPO levels in pancreatic and lung tissue were observed in UCP2-/- mice. Interestingly, intrapancreatic trypsin activities (in vivo studies and intraacinar trypsin and elastase activation in response to cerulein treatment (in vitro studies were not enhanced but even diminished in the knockout strain. Finally, UCP2-/- mice displayed a diminished ratio of reduced and oxidized glutathione in serum but no increased ROS levels in pancreatic acini. Together, our data indicate an aggravating effect of UCP2 deficiency on the severity of experimental AP in older but not in young mice. We suggest that increased severity of AP in 12 months old UCP2-/- is caused by an imbalanced inflammatory response but is unrelated to acinar cell functions.

  17. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

    OpenAIRE

    Sara Chiappalupi; Giovanni De Luca; Francesca Mancuso; Luca Madaro; Francesca Fallarino; Carmine Nicoletti; Mario Calvitti; Iva Arato; Giulia Falabella; Laura Salvadori; Antonio Di Meo; Antonello Bufalari; Stefano Giovagnoli; Riccardo Calafiore; Rosario Donato

    2015-01-01

    We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data ...

  18. Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp −/− mice[S

    OpenAIRE

    Newberry, Elizabeth P.; Kennedy, Susan M; Xie, Yan; Luo, Jianyang; Crooke, Rosanne M.; Graham, Mark J.; Fu, Jin; Piomelli, Daniele; Davidson, Nicholas O.

    2012-01-01

    The tissue-specific sources and regulated production of physiological signals that modulate food intake are incompletely understood. Previous work showed that L-Fabp−/− mice are protected against obesity and hepatic steatosis induced by a high-fat diet, findings at odds with an apparent obesity phenotype in a distinct line of aged L-Fabp−/− mice. Here we show that the lean phenotype in L-Fabp−/− mice is recapitulated in aged, chow-fed mice and correlates with alterations in hepatic, but not i...

  19. Mathematical modeling of left ventricular dimensional changes in mice during aging

    Directory of Open Access Journals (Sweden)

    Yang Tianyi

    2012-12-01

    Full Text Available Abstract Cardiac aging is characterized by diastolic dysfunction of the left ventricle (LV, which is due in part to increased LV wall stiffness. In the diastolic phase, myocytes are relaxed and extracellular matrix (ECM is a critical determinant to the changes of LV wall stiffness. To evaluate the effects of ECM composition on cardiac aging, we developed a mathematical model to predict LV dimension and wall stiffness changes in aging mice by integrating mechanical laws and our experimental results. We measured LV dimension, wall thickness, LV mass, and collagen content for wild type (WT C57/BL6J mice of ages ranging from 7.3 months to those of 34.0 months. The model was established using the thick wall theory and stretch-induced tissue growth to an isotropic and homogeneous elastic composite with mixed constituents. The initial conditions of the simulation were set based on the data from the young mice. Matlab simulations of this mathematical model demonstrated that the model captured the major features of LV remodeling with age and closely approximated experimental results. Specifically, the temporal progression of the LV interior and exterior dimensions demonstrated the same trend and order-of-magnitude change as our experimental results. In conclusion, we present here a validated mathematical model of cardiac aging that applies the thick-wall theory and stretch-induced tissue growth to LV remodeling with age.

  20. Grip strength is potentially an early indicator of age-related decline in mice.

    Science.gov (United States)

    Ge, Xuan; Cho, Anthony; Ciol, Marcia A; Pettan-Brewer, Christina; Snyder, Jessica; Rabinovitch, Peter; Ladiges, Warren

    2016-01-01

    The hand grip test has been correlated with mobility and physical performance in older people and has been shown to be a long-term predictor of mortality. Implementation of new strategies for enhancing healthy aging and maintaining independent living are dependent on predictable preclinical studies. The mouse is used extensively as a model in these types of studies, and the paw grip strength test is similar to the hand grip test for people in that it assesses the ability to grip a device with the paw, is non-invasive and easy to perform, and provides reproducible information. However, little has been reported on how grip strength declines with increasing age in mice. This report shows that grip strength was decreased in C57BL/6 (B6) NIA and C57BL/6×BALB/c F1 (CB6F1) NIA male mice at 12 months of age compared to 8-month-old mice, and continued a robust decline to 20 months and then 28 months of age, when the study was terminated. The decline was not related to lean muscle mass, but extensive age-related carpal and digital exostosis could help explain the decreased grip strength times with increasing age. In conclusion, the grip strength test could be useful in mouse preclinical studies to help make translational predictions on treatment strategies to enhance healthy aging. PMID:27613499

  1. Age-Dependent Defects of Regulatory B Cells in Wiskott-Aldrich Syndrome Gene Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Tadafumi Yokoyama

    Full Text Available The Wiskott-Aldrich syndrome (WAS is a rare X-linked primary immunodeficiency characterized by recurrent infections, thrombocytopenia, eczema, and high incidence of malignancy and autoimmunity. The cellular mechanisms underlying autoimmune complications in WAS have been extensively studied; however, they remain incompletely defined. We investigated the characteristics of IL-10-producing CD19+CD1dhighCD5+ B cells (CD1dhighCD5+ Breg obtained from Was gene knockout (WKO mice and found that their numbers were significantly lower in these mice compared to wild type (WT controls. Moreover, we found a significant age-dependent reduction of the percentage of IL-10-expressing cells in WKO CD1dhighCD5+ Breg cells as compared to age-matched WT control mice. CD1dhighCD5+ Breg cells from older WKO mice did not suppress the in vitro production of inflammatory cytokines from activated CD4+ T cells. Interestingly, CD1dhighCD5+ Breg cells from older WKO mice displayed a basal activated phenotype which may prevent normal cellular responses, among which is the expression of IL-10. These defects may contribute to the susceptibility to autoimmunity with age in patients with WAS.

  2. Professional Microsoft SQL Server Analysis Services 2008 with MDX

    CERN Document Server

    Harinath, Sivakumar; Meenakshisundaram, Sethu

    2009-01-01

    When used with the MDX query language, SQL Server Analysis Services allows developers to build full-scale database applications to support such business functions as budgeting, forecasting, and market analysis.; Shows readers how to build data warehouses and multi-dimensional databases, query databases, and use Analysis Services and other components of SQL Server to provide end-to-end solutions; Revised, updated, and enhanced, the book discusses new features such as improved integration with Office and Excel 2007; query performance enhancements; improvements to aggregation designer, dimension

  3. The Cardioprotective Effect of Vitamin E (Alpha-Tocopherol Is Strongly Related to Age and Gender in Mice.

    Directory of Open Access Journals (Sweden)

    Xiao-Xia Hu

    Full Text Available Vitamin E (VitE only prevented cardiovascular diseases in some patients and the mechanisms remain unknown. VitE levels can be affected by aging and gender. We hypothesize that age and gender can influence VitE's cardioprotective effect. Mice were divided into 4 groups according to age and gender, and each group of mice were divided into a control group and a VitE group. The mice were administered water or VitE for 21 days; Afterward, the cardiac function and myocardial infarct size and cardiomyocyte apoptosis were measured after myocardial ischemia reperfusion(MI/R. VitE may significantly improved cardiac function in young male mice and aged female mice by enhancing ERK1/2 activity and reducing JNK activity. Enhanced expression of HSP90 and Bcl-2 were also seen in young male mice. No changes in cardiac function and cardiac proteins were detected in aged male mice and VitE was even liked to exert a reverse effect in cardiac function in young mice by enhancing JNK activity and reducing Bcl-2 expression. Those effects were in accordance with the changes of myocardial infarction size and cardiomyocyte apoptosis in each group of mice. VitE may reduce MI/R injury by inhibiting cardiomyocyte apoptosis in young male mice and aged female mice but not in aged male mice. VitE was possibly harmful for young female mice, shown as increased cardiomyocyte apoptosis after MI/R. Thus, we speculated that the efficacy of VitE in cardiac protection was associated with age and gender.

  4. The Cardioprotective Effect of Vitamin E (Alpha-Tocopherol) Is Strongly Related to Age and Gender in Mice

    Science.gov (United States)

    Li, Yan; Lin, Ze-Bang; Liu, Xiang; Wang, Jing-Feng; Chen, Yang-Xin; Wang, Zhi-Ping; Zhang, Xi; Ou, Zhi-Jun; Ou, Jing-Song

    2015-01-01

    Vitamin E (VitE) only prevented cardiovascular diseases in some patients and the mechanisms remain unknown. VitE levels can be affected by aging and gender. We hypothesize that age and gender can influence VitE’s cardioprotective effect. Mice were divided into 4 groups according to age and gender, and each group of mice were divided into a control group and a VitE group. The mice were administered water or VitE for 21 days; Afterward, the cardiac function and myocardial infarct size and cardiomyocyte apoptosis were measured after myocardial ischemia reperfusion(MI/R). VitE may significantly improved cardiac function in young male mice and aged female mice by enhancing ERK1/2 activity and reducing JNK activity. Enhanced expression of HSP90 and Bcl-2 were also seen in young male mice. No changes in cardiac function and cardiac proteins were detected in aged male mice and VitE was even liked to exert a reverse effect in cardiac function in young mice by enhancing JNK activity and reducing Bcl-2 expression. Those effects were in accordance with the changes of myocardial infarction size and cardiomyocyte apoptosis in each group of mice. VitE may reduce MI/R injury by inhibiting cardiomyocyte apoptosis in young male mice and aged female mice but not in aged male mice. VitE was possibly harmful for young female mice, shown as increased cardiomyocyte apoptosis after MI/R. Thus, we speculated that the efficacy of VitE in cardiac protection was associated with age and gender. PMID:26331272

  5. Diabetes exacerbates amyloid and neurovascular pathology in aging-accelerated mice

    OpenAIRE

    Currais, Antonio; Prior, Marguerite; Lo, David; Jolivalt, Corinne; Schubert, David; Maher, Pamela

    2012-01-01

    Mounting evidence supports a link between diabetes, cognitive dysfunction and aging. However, the physiological mechanisms by which diabetes impacts brain function and cognition are not fully understood. To determine how diabetes contributes to cognitive dysfunction and age-associated pathology, we used streptozotocin to induce type 1 diabetes (T1D) in senescence-accelerated prone 8 (SAMP8) and senescence-resistant 1 (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted in...

  6. Content of stromal precursor cells in heterotopic transplants of bone marrow in CBA mice of various ages.

    Science.gov (United States)

    Gorskaya, Yu F; Kuralesova, A I; Shuklina, E Yu; Nesterenko, V G

    2002-02-01

    Efficiency of colony formation of stromal precursor cells in cultured bone marrow transplants from old (24 month) CBA mice implanted to young (2-month-old) mice almost 3-fold surpassed that in cultured transplants implanted to old recipients. The content of nucleated cells in bone marrow transplants from senescence accelerated mice SAMP increased more than 2-fold, if SAMR mice with normal aging rate were used as the recipients instead of SAMP mice. Bone marrow taken from old and young CBA mice endured the same number of transplantations if the recipient mice were of the same age (5 month). It was concluded that stromal tissue considerably changes with age and is under strict control of the body. PMID:12432868

  7. ADAM12 overexpression does not improve outcome in mice with laminin alpha2-deficient muscular dystrophy

    DEFF Research Database (Denmark)

    Guo, Ling T; Shelton, G Diane; Wewer, Ulla M;

    2005-01-01

    We have recently shown that overexpression of ADAM12 results in increased muscle regeneration and significantly reduced pathology in mdx, dystrophin deficient mice. In the present study, we tested the effect of overexpressing ADAM12 in dy(W) laminin-deficient mice. dy mice have a very severe clin...

  8. Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice.

    Science.gov (United States)

    Jeong, Sae Im; Shin, Jin A; Cho, Sunghee; Kim, Hye Won; Lee, Ji Yoon; Kang, Jihee Lee; Park, Eun-Mi

    2016-08-01

    Resveratrol is known to improve metabolic dysfunction associated with obesity. Visceral obesity is a sign of aging and is considered a risk factor for ischemic stroke. In this study, we investigated the effects of resveratrol on inflammation in visceral adipose tissue and the brain and its effects on ischemic brain injury in aged female mice. Mice treated with resveratrol (0.1 mg/kg, p.o.) for 10 days showed reduced levels of interleukin-1β and tumor necrosis factor-α, as well as a reduction in the size of adipocytes in visceral adipose tissue. Resveratrol also reduced interleukin-1β and tumor necrosis factor-α protein levels and immunoglobulin G extravasation in the brain. Mice treated with resveratrol demonstrated smaller infarct size, improved neurological function, and blunted peripheral inflammation at 3 days postischemic stroke. These results showed that resveratrol counteracted inflammation in visceral adipose tissue and in the brain and reduced stroke-induced brain injury and peripheral inflammation in aged female mice. Therefore, resveratrol administration can be a valuable strategy for the prevention of age-associated and disease-provoked inflammation in postmenopausal women. PMID:27318135

  9. Effect of Mitochondrial Transplantation from Cumulus Granular Cells to the Early Embryos of Aged Mice

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Objective To assess the role of mitochondria in the early embryonic development of ageing mice.Methods Mitochondria isolated from cumulus granular cells of aged mice were microinjected into oocytes or zygotes of aged mice. In the setting of oocyte injection, mitochondria were transferred via intracytoplasmic sperm injection (ICSI+MIT), and ICSI without mitochondrial transfer. In the setting of zygote injection, mitochondria were directly microinjected into fertilized oocytes (MIT), and those injected with buffer alone (mock injection) or not injected (uninjected) served as controls.Results Although the rates of oocyte cleavage between ICSI and ICSI+MIT groups were not statistically different (P>0.05), the rate of blastocyst in the ICSI+MIT group was significantly higher than that in ICSI group (P<0.05). Although both the cleavage and blastocyst rates of mock injection group were significantly lower than those of uninjected group (P<0.05), likely due to mechanical damages of the cells by microinjection, the decrease of these rates was prevented by mitochondrial transfer. After mitochondrial transfer, the rates of both cleavage and blastocyst were significantly improved over the mock-injection group (P<0.05).Conclusion Mitochondrial transplantation can improve the developmental potential of early embryos of aged mice.

  10. Characteristics of bone marrow-derived endothelial progenitor cells in aged mice

    International Nuclear Information System (INIS)

    Evidence for dysfunction of endothelial repair in aged mice was sought by studying the pattern of induced differentiation, quantity, and function of bone marrow-derived endothelial progenitor cells (EPCs) in aged mice. The CD117-positive stem cell population was separated from bone marrow by magnetic activated cell-sorting system (MACS), and EPCs were defined by demonstrating the expression of CD117+CD34+Flk-1+ by flow cytometry. After 7 days of culture, the number of clones formed was counted, and proliferation and migration of EPCs were analyzed by MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and modified Boyden chamber assay. The results demonstrated that compared to the control group, the quantity of bone marrow-derived CD117+ stem cells and EPCs, as well as the proliferation, migration, the number of clones formed, and phagocytotic function of EPCs were significantly reduced in aged mice. There were no significant differences in the morphology and induced differentiation pattern of EPCs between the aged mouse group and the control group. Authors suggest that the dysfunction of EPCs may serve as a surrogate parameter of vascular function in old mice

  11. Middle age has a significant impact on gene expression during skin wound healing in male mice.

    Science.gov (United States)

    Yanai, Hagai; Lumenta, David Benjamin; Vierlinger, Klemens; Hofner, Manuela; Kitzinger, Hugo-Benito; Kamolz, Lars-Peter; Nöhammer, Christa; Chilosi, Marco; Fraifeld, Vadim E

    2016-08-01

    The vast majority of research on the impact of age on skin wound healing (WH) compares old animals to young ones. The middle age is often ignored in biogerontological research despite the fact that many functions that decline in an age-dependent manner have starting points in mid-life. With this in mind, we examined gene expression patterns during skin WH in late middle-aged versus young adult male mice, using the head and back punch models. The rationale behind this study was that the impact of age would first be detectable at the transcriptional level. We pinpointed several pathways which were over-activated in the middle-aged mice, both in the intact skin and during WH. Among them were various metabolic, immune-inflammatory and growth-promoting pathways. These transcriptional changes were much more pronounced in the head than in the back. In summary, the middle age has a significant impact on gene expression in intact and healing skin. It seems that the head punch model is more sensitive to the effect of age than the back model, and we suggest that it should be more widely applied in aging research on wound healing. PMID:27241672

  12. High Sensitivity of Aged Mice to Deoxynivalenol (Vomitoxin)-Induced Anorexia Corresponds to Elevated Proinflammatory Cytokine and Satiety Hormone Responses

    Science.gov (United States)

    Clark, Erica S.; Flannery, Brenna M.; Gardner, Elizabeth M.; Pestka, James J.

    2015-01-01

    Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes. PMID:26492270

  13. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    International Nuclear Information System (INIS)

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting 3H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities

  14. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    Energy Technology Data Exchange (ETDEWEB)

    Burton, C.K.; Ho, I.K.; Hoskins, B.

    1986-03-01

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting /sup 3/H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities.

  15. Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type.

    Science.gov (United States)

    Kane, Alice E; Mitchell, Sarah J; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G; de Cabo, Rafael; Hilmer, Sarah N

    2016-01-01

    Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID:26615879

  16. Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis

    Science.gov (United States)

    Westvik, Tormod S; Fitzgerald, Tamara N; Muto, Akihito; Maloney, Stephen P; Pimiento, Jose M; Fancher, Tiffany T; Magri, Dania; Westvik, Hilde H; Nishibe, Toshiya; Velazquez, Omaida C; Dardik, Alan

    2009-01-01

    Objective(s) Older patients are thought to tolerate acute ischemia more poorly than younger patients. Since aging may depress both angiogenesis and arteriogenesis, we determined the effects of age on both angiogenesis and arteriogenesis, in a model of severe acute limb ischemia. Methods Young adult (3 month) and aged (18 month) C57BL/6 mice underwent right common iliac artery and vein ligation and transection. Data were collected on days 0, 7, and 14. Perfusion was measured with laser Doppler and compared to the contralateral limb. Functional deficits were evaluated with the Tarlov scale. Capillary density and endothelial progenitor cell (EPC) number were determined by direct counting lectin-positive/alpha-actin-negative cells and VEGFR2/CXCR4 dually-positive cells, respectively; angiography was performed to directly assess arteriogenesis. Results Young adult and aged mice had a similar degree of decreased perfusion after iliac ligation (young, n=15: 20.4±1.9%, vs. old, n=20: 19.6±1.3%; p=.72, ANOVA); however, young mice recovered faster and to a greater degree than aged mice (day 7, 35±6% vs. 17±4%, p=.046; day 14, 60±5% vs. 27±7%, p=.0014). Aged mice had worse functional recovery by day 14 compared to young mice (2.3±.3 vs. 4.3±.4; p=.0021). Aged mice had increased capillary density (day 7, 12.9±4.4 vs. 2.8±0.3 capillaries/hpf; p=.02) and increased number of EPC incorporated into the ischemic muscle (day 7, 8.1±0.9 vs. 2.5±1.9 cells; p=0.007) compared to young mice, but diminished numbers of collateral vessels to the ischemic limb (1 vs. 9; p=0.01), as seen on angiography. Conclusions After severe hindlimb ischemia, aged animals become ischemic to a similar degree as young animals, but aged animals have significantly impaired arteriogenesis and functional recovery compared to younger animals. These results suggest that strategies to stimulate arteriogenesis may complement those that increase angiogenesis, and may result in improved relief of ischemia

  17. Membrane Sealant Poloxamer P188 Protects Against Isoproterenol Induced Cardiomyopathy in Dystrophin Deficient Mice

    Directory of Open Access Journals (Sweden)

    Sali Arpana

    2011-05-01

    Full Text Available Abstract Background Cardiomyopathy in Duchenne muscular dystrophy (DMD is an increasing cause of death in patients. The absence of dystrophin leads to loss of membrane integrity, cell death and fibrosis in cardiac muscle. Treatment of cardiomyocyte membrane instability could help prevent cardiomyopathy. Methods Three month old female mdx mice were exposed to the β1 receptor agonist isoproterenol subcutaneously and treated with the non-ionic tri-block copolymer Poloxamer P188 (P188 (460 mg/kg/dose i.p. daily. Cardiac function was assessed using high frequency echocardiography. Tissue was evaluated with Evans Blue Dye (EBD and picrosirius red staining. Results BL10 control mice tolerated 30 mg/kg/day of isoproterenol for 4 weeks while death occurred in mdx mice at 30, 15, 10, 5 and 1 mg/kg/day within 24 hours. Mdx mice tolerated a low dose of 0.5 mg/kg/day. Isoproterenol exposed mdx mice showed significantly increased heart rates (p Conclusions This model suggests that chronic intermittent intraperitoneal P188 treatment can prevent isoproterenol induced cardiomyopathy in dystrophin deficient mdx mice.

  18. Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice

    Science.gov (United States)

    Xu, Zhipeng; Dong, Yuanlin; Wang, Hui; Culley, Deborah J.; Marcantonio, Edward R.; Crosby, Gregory; Tanzi, Rudolph E.; Zhang, Yiying; Xie, Zhongcong

    2014-01-01

    Post-operative cognitive dysfunction (POCD) is associated with increased cost of care, morbidity, and mortality. However, its pathogenesis remains largely to be determined. Specifically, it is unknown why elderly patients are more likely to develop POCD and whether POCD is dependent on general anesthesia. We therefore set out to investigate the effects of peripheral surgery on the cognition and Alzheimer-related neuropathology in mice with different ages. Abdominal surgery under local anesthesia was established in the mice. The surgery induced post-operative elevation in brain β-amyloid (Aβ) levels and cognitive impairment in the 18 month-old wild-type and 9 month-old Alzheimer's disease transgenic mice, but not the 9 month-old wild-type mice. The Aβ accumulation likely resulted from elevation of beta-site amyloid precursor protein cleaving enzyme and phosphorylated eukaryotic translation initiation factor 2α. γ-Secretase inhibitor compound E ameliorated the surgery-induced brain Aβ accumulation and cognitive impairment in the 18 month-old mice. These data suggested that the peripheral surgery was able to induce cognitive impairment independent of general anesthesia, and that the combination of peripheral surgery with aging- or Alzheimer gene mutation-associated Aβ accumulation was needed for the POCD to occur. These findings would likely promote more research to investigate the pathogenesis of POCD.

  19. Influence of age and caloric restriction on liver glycolytic enzyme activities and metabolite concentrations in mice.

    Science.gov (United States)

    Hagopian, Kevork; Ramsey, Jon J; Weindruch, Richard

    2003-03-01

    The influence of caloric restriction (CR) from 2 months of age on the activities of liver glycolytic enzymes and metabolite levels was studied in young and old mice. Livers were sampled 48 h after the last scheduled feeding time. Old mice on CR showed significant decreases in the activities of all the enzymes studied, except for aldolase, triosephosphate isomerase and phosphoglycerate mutase, which were unchanged. The metabolites glucose, glucose-6-phosphate, fructose-6-phosphate, pyruvate and lactate were lower while fructose-1,6-bisphosphate, glyceraldehyde-3-phosphate, dihydroxyacetone phosphate, 3-phosphoglycerate and phosphoenolpyruvate were increased in old CR. Young mice on CR also showed reduced enzyme activities, except for aldolase, triosephosphate isomerase and enolase which were unchanged when compared with young controls. The metabolites glucose, glucose-6-phosphate, fructose-6-phosphate and pyruvate were decreased when compared with young controls, while phosphoenolpyruvate was increased. Ketone bodies increased (65%) in old, but not young, CR mice while fructose-2,6-bisphosphate decreased in both young (22%) and old CR (28%) mice. The results indicate that decreased hepatic glucose levels in CR mice are associated with decreased enzyme activities but not a uniform decrease in metabolite levels. Increased ketone body levels indicate increased utilization of non-carbohydrate fuels while decreased fructose-2,6-bisphosphate level suggests its importance in the control of glycolysis in CR. PMID:12581789

  20. Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice.

    Science.gov (United States)

    Cummins, Nathan W; Weaver, Eric A; May, Shannon M; Croatt, Anthony J; Foreman, Oded; Kennedy, Richard B; Poland, Gregory A; Barry, Michael A; Nath, Karl A; Badley, Andrew D

    2012-07-01

    Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genome-wide association study evaluated the expression of single-nucleotide polymorphisms (SNPs) in the HO-1 gene and the response to influenza vaccination in healthy humans. HO-1-deficient mice had decreased survival after influenza infection compared to WT mice (median survival 5.5 vs. 6.5 d, P=0.016). HO-1-deficient mice had impaired production of antibody following influenza vaccination compared to WT mice (mean antibody titer 869 vs. 1698, P=0.02). One SNP in HO-1 and one SNP in the constitutively expressed isoform HO-2 were independently associated with decreased antibody production after influenza vaccination in healthy human volunteers (P=0.017 and 0.014, respectively). HO-1 deficient mice were paired with sex- and age-matched WT controls. HO-1 affects the immune response to both influenza infection and vaccination, suggesting that therapeutic induction of HO-1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness. PMID:22490782

  1. Glutathione restores the mechanism of synaptic plasticity in aged mice to that of the adult.

    Directory of Open Access Journals (Sweden)

    Julie M Robillard

    Full Text Available Glutathione (GSH, the major endogenous antioxidant produced by cells, can modulate the activity of N-methyl-D-aspartate receptors (NMDARs through its reducing functions. During aging, an increase in oxidative stress leads to decreased levels of GSH in the brain. Concurrently, aging is characterized by calcium dysregulation, thought to underlie impairments in hippocampal NMDAR-dependent long-term potentiation (LTP, a form of synaptic plasticity thought to represent a cellular model for memory. Here we show that orally supplementing aged mice with N-acetylcysteine, a precursor for the formation of glutathione, reverses the L-type calcium channel-dependent LTP seen in aged animals to NMDAR-dependent LTP. In addition, introducing glutathione in the intrapipette solution during whole-cell recordings restores LTP obtained in whole-cell conditions in the aged hippocampus. We conclude that aging leads to a reduced redox potential in hippocampal neurons, triggering impairments in LTP.

  2. Transcriptome composition of the preoptic area in mid-age and escitalopram treatment in male mice.

    Science.gov (United States)

    Moriya, Shogo; Soga, Tomoko; Wong, Dutt Way; Parhar, Ishwar S

    2016-05-27

    The decrease in serotonergic neurotransmission during aging can increase the risk of neuropsychiatric diseases such as depression in elderly population and decline the reproductive system. Therefore, it is important to understand the age-associated molecular mechanisms of brain aging. In this study, the effect of aging and chronic escitalopram (antidepressant) treatment to admit mice was investigated by comparing transcriptomes in the preoptic area (POA) which is a key nucleus for reproduction. In the mid-aged brain, the immune system-related genes were increased and hormone response-related genes were decreased. In the escitalopram treated brains, transcription-, granule cell proliferation- and vasoconstriction-related genes were increased and olfactory receptors were decreased. Since homeostasis and neuroprotection-related genes were altered in both of mid-age and escitalopram treatment, these genes could be important for serotonin related physiologies in the POA. PMID:27113202

  3. Gender-Divergent Profile of Bile Acid Homeostasis during Aging of Mice

    OpenAIRE

    Fu, Zidong Donna; Csanaky, Iván L.; Klaassen, Curtis D.

    2012-01-01

    Aging is a physiological process with a progressive decline of adaptation and functional capacity of the body. Bile acids (BAs) have been recognized as signaling molecules regulating the homeostasis of glucose, lipid, and energy. The current study characterizes the age-related changes of individual BA concentrations by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in serum and liver of male and female C57BL/6 mice from 3 to 27 months of age. Total BA concentrat...

  4. L-DOPA Reverses Motor Deficits Associated with Normal Aging in Mice

    OpenAIRE

    Allen, Erika; Carlson, Kirsten M.; Zigmond, Michael J.; Cavanaugh, Jane E.

    2010-01-01

    We wished to determine whether L-DOPA, a common treatment for the motor deficits in Parkinson's disease, could also reverse the motor deficits that occur during aging. We assessed motor performance in young (2-3 months) and old (20-21 months) male C57BL/6 mice using the challenge beam and cylinder tests. Prior to testing, mice were treated with L-DOPA or vehicle. Following testing, striatal tissue was analyzed for phenotypic markers of dopamine neurons: dopamine, dopamine transporter, and tyr...

  5. Liver Fatty Acid Binding Protein Gene Ablation Enhances Age-Dependent Weight Gain in Male Mice

    OpenAIRE

    Martin, Gregory G.; Atshaves, Barbara P.; McIntosh, Avery L.; Payne, H. Ross; Mackie, John T.; Kier, Ann B.; Schroeder, Friedhelm

    2008-01-01

    Although studies performed in vitro and with transfected cells in culture suggest a role for liver fatty acid binding protein (L-FABP) in regulating fatty acid oxidation and fat deposition, the physiological significance of this possibility is not completely clear. To begin to address this question, the effect of L-FABP gene ablation on phenotype of standard rodent chow-fed male mice was examined with increasing age up to 18 mo. While young (2-3 mo) L-FABP null mice displayed no visually obvi...

  6. Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis.

    Science.gov (United States)

    Kivinen, Niko; Felszeghy, Szabolcs; Kinnunen, Aino I; Setälä, Niko; Aikio, Mari; Kinnunen, Kati; Sironen, Reijo; Pihlajaniemi, Taina; Kauppinen, Anu; Kaarniranta, Kai

    2016-08-01

    Collagen XVIII has the structural properties of both collagen and proteoglycan. It has been found at the basement membrane/stromal interface where it is thought to mediate their attachment. Endostatin, a proteolytic fragment from collagen XVIII C-terminal end has been reported to possess anti-angiogenic properties. Age-related vision loss in collagen XVIII mutant mice has been accompanied with a pathological accumulation of deposits under the retinal pigment epithelium (RPE). We have recently demonstrated that impaired proteasomal and autophagy clearance are associated with the pathogenesis of age-related macular degeneration. This study examined the staining levels of proteasomal and autophagy markers in the RPE of different ages of the Col18a1 (-/-) mice. Eyes from 3, 6-7, 10-13 and 18 months old mice were enucleated and embedded in paraffin according to the routine protocol. Sequential 5 μm-thick parasagittal samples were immunostained for proteasome and autophagy markers ubiquitin (ub), SQSTM1/p62 and beclin-1. The levels of immunopositivity in the RPE cells were evaluated by confocal microscopy. Collagen XVIII knock-out mice had undergone age-related RPE degeneration accompanied by an accumulation of drusen-like deposits. Ub protein conjugate staining was prominent in both RPE cytoplasm and extracellular space whereas SQSTM1/p62 and beclin-1 stainings were clearly present in the basal part of RPE cell cytoplasm in the Col18a1 (-/-) mice. SQSTM1/p62 displayed mild extracellular space staining. Disturbed proteostasis regulated by collagen XVIII might be responsible for the RPE degeneration, increased protein aggregation, ultimately leading to choroidal neovascularization. PMID:27125427

  7. Inhibition of Advanced Glycation End Products (AGEs Accumulation by Pyridoxamine Modulates Glomerular and Mesangial Cell Estrogen Receptor α Expression in Aged Female Mice.

    Directory of Open Access Journals (Sweden)

    Simone Pereira-Simon

    Full Text Available Age-related increases in oxidant stress (OS play a role in regulation of estrogen receptor (ER expression in the kidneys. In this study, we establish that in vivo 17β-estradiol (E2 replacement can no longer upregulate glomerular ER expression by 21 months of age in female mice (anestrous. We hypothesized that advanced glycation end product (AGE accumulation, an important source of oxidant stress, contributes to these glomerular ER expression alterations. We treated 19-month old ovariectomized female mice with pyridoxamine (Pyr, a potent AGE inhibitor, in the presence or absence of E2 replacement. Glomerular ERα mRNA expression was upregulated in mice treated with both Pyr and E2 replacement and TGFβ mRNA expression decreased compared to controls. Histological sections of kidneys demonstrated decreased type IV collagen deposition in mice receiving Pyr and E2 compared to placebo control mice. In addition, anti-AGE defenses Sirtuin1 (SIRT1 and advanced glycation receptor 1 (AGER1 were also upregulated in glomeruli following treatment with Pyr and E2. Mesangial cells isolated from all groups of mice demonstrated similar ERα, SIRT1, and AGER1 expression changes to those of whole glomeruli. To demonstrate that AGE accumulation contributes to the observed age-related changes in the glomeruli of aged female mice, we treated mesangial cells from young female mice with AGE-BSA and found similar downregulation of ERα, SIRT1, and AGER1 expression. These results suggest that inhibition of intracellular AGE accumulation with pyridoxamine may protect glomeruli against age-related oxidant stress by preventing an increase of TGFβ production and by regulation of the estrogen receptor.

  8. Proteomic Profiling of the Dystrophin-Deficient MDX Heart Reveals Drastically Altered Levels of Key Metabolic and Contractile Proteins

    Directory of Open Access Journals (Sweden)

    Caroline Lewis

    2010-01-01

    Full Text Available Although Duchenne muscular dystrophy is primarily classified as a neuromuscular disease, cardiac complications play an important role in the course of this X-linked inherited disorder. The pathobiochemical steps causing a progressive decline in the dystrophic heart are not well understood. We therefore carried out a fluorescence difference in-gel electrophoretic analysis of 9-month-old dystrophin-deficient versus age-matched normal heart, using the established MDX mouse model of muscular dystrophy-related cardiomyopathy. Out of 2,509 detectable protein spots, 79 2D-spots showed a drastic differential expression pattern, with the concentration of 3 proteins being increased, including nucleoside diphosphate kinase and lamin-A/C, and of 26 protein species being decreased, including ATP synthase, fatty acid binding-protein, isocitrate dehydrogenase, NADH dehydrogenase, porin, peroxiredoxin, adenylate kinase, tropomyosin, actin, and myosin light chains. Hence, the lack of cardiac dystrophin appears to trigger a generally perturbed protein expression pattern in the MDX heart, affecting especially energy metabolism and contractile proteins.

  9. β2-Adrenergic receptor ablation modulates hepatic lipid accumulation and glucose tolerance in aging mice.

    Science.gov (United States)

    Shi, Yun; Shu, Zhen-Ju; Xue, Xiaoling; Yeh, Chih-Ko; Katz, Michael S; Kamat, Amrita

    2016-06-01

    Catecholamines acting through β-adrenergic receptors (β1-, β2-, β3-AR subtypes) modulate important biological responses in various tissues. Our previous studies suggest a role for increased hepatic β-AR-mediated signaling during aging as a mediator of hepatic steatosis, liver glucose output, and insulin resistance in rodents. In the current study, we have utilized β2-AR knockout (KO) and wildtype (WT) control mice to define further the role of β2-AR signaling during aging on lipid and glucose metabolism. Our results demonstrate for the first time that age-related increases in hepatic triglyceride accumulation and body weight are attenuated upon β2-AR ablation. Although no differences in plasma triglyceride, non-esterified fatty acids or insulin levels were detected between old WT and KO animals, an age-associated increase in hepatic expression of lipid homeostasis regulator Cidea was significantly reduced in old KO mice. Interestingly, we also observed a shift from reduced glucose tolerance in young adult KO animals to significantly improved glucose tolerance in old KO when compared to age-matched WT mice. These results provide evidence for an important role played by β2-ARs in the regulation of lipid and glucose metabolism during aging. The effect of β2-AR ablation on caloric intake during aging is currently not known and requires investigation. Future studies are also warranted to delineate the β2-AR-mediated mechanisms involved in the control of lipid and glucose homeostasis, especially in the context of a growing aging population. PMID:26952573

  10. Dietary polyphenol supplementation prevents alterations of spatial navigation in middle-aged mice

    Directory of Open Access Journals (Sweden)

    Julien eBensalem

    2016-02-01

    Full Text Available Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB (from the Neurophenols Consortium with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal CaMKII mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of NGF mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline.

  11. Comparison of catalase immunoreactivity in the hippocampus between young, adult and aged mice and rats.

    Science.gov (United States)

    Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Lee, Tae-Kyeong; Cho, Jeong Hwi; Kim, In Hye; Park, Joon Ha; Lee, Jae-Chul; Tae, Hyun-Jin; Lee, Choong-Hyun; Won, Moo-Ho; Lee, Yun Lyul; Choi, Soo Young; Hong, Seongkweon

    2016-07-01

    Catalase (CAT) is an important antioxidant enzyme and is crucial in modulating synaptic plasticity in the brain. In this study, CAT expression as well as neuronal distribution was compared in the hippocampus among young, adult and aged mice and rats. Male ICR mice and Sprague Dawley rats were used at postnatal month (PM) 1, PM 6 and PM 24 as the young, adult and aged groups, respectively (n=14/group). CAT expression was examined by immunohistochemistry and western blot analysis. In addition, neuronal distribution was examined by NeuN immunohistochemistry. In the present study, the mean number of NeuN‑immunoreactive neurons was marginally decreased in mouse and rat hippocampi during aging, although this change was not identified to be significantly different. However, CAT immunoreactivity was significantly increased in pyramidal and granule neurons in the adult mouse and rat hippocampi and was significantly decreased in the aged mouse and rat hippocampi compared with that in the young animals. CAT protein levels in the hippocampus were also lowest in the aged mouse and rat hippocampus. These results indicate that CAT expression is significantly decreased in the hippocampi of aged animals and decreased CAT expression may be closely associated with aging. PMID:27221506

  12. C-Terminal-Truncated Microdystrophin Recruits Dystrobrevin and Syntrophin to the Dystrophin-Associated Glycoprotein Complex and Reduces Muscular Dystrophy in Symptomatic Utrophin/Dystrophin Double-Knockout Mice

    OpenAIRE

    Yue, Yongping; LIU, MINGJU; Duan, Dongsheng

    2006-01-01

    C-terminal-truncated (ΔC) microdystrophin is being developed for Duchenne muscular dystrophy gene therapy. Encouraging results have been achieved in the mdx mouse model. Unfortunately, mdx mice do not display the same phenotype as human patients. Evaluating ΔC microdystrophin in a symptomatic model will be of significant relevance to human trials. Utrophin/dystrophin double-knockout (u-dko) mice were developed to model severe dystrophic changes in human patients. In this study we evaluated th...

  13. Experimental febrile seizures induce age-dependent structural plasticity and improve memory in mice.

    Science.gov (United States)

    Tao, K; Ichikawa, J; Matsuki, N; Ikegaya, Y; Koyama, R

    2016-03-24

    Population-based studies have demonstrated that children with a history of febrile seizure (FS) perform better than age-matched controls at hippocampus-dependent memory tasks. Here, we report that FSs induce two distinct structural reorganizations in the hippocampus and bidirectionally modify future learning abilities in an age-dependent manner. Compared with age-matched controls, adult mice that had experienced experimental FSs induced by hyperthermia (HT) on postnatal day 14 (P14-HT) performed better in a cognitive task that requires dentate granule cells (DGCs). The enhanced memory performance correlated with an FS-induced persistent increase in the density of large mossy fiber terminals (LMTs) of the DGCs. The memory enhancement was not observed in mice that had experienced HT-induced seizures at P11 which exhibited abnormally located DGCs in addition to the increased LMT density. The ectopic DGCs of the P11-HT mice were abolished by the diuretic bumetanide, and this pharmacological treatment unveiled the masked memory enhancement. Thus, this work provides a novel basis for age-dependent structural plasticity in which FSs influence future brain function. PMID:26794590

  14. Restoration of the immune functions in aged mice by supplementation with a new herbal composition, HemoHIM.

    Science.gov (United States)

    Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee; Yee, Sung-Tae

    2008-01-01

    The effect of a new herbal composition, HemoHIM, on immune functions was examined in aged mice, in which various immune responses had been impaired. The composition HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Supplementation to the aged mice with HemoHIM restored the proliferative response and cytokine production of splenocytes with a response to ConA. Also, HemoHIM recovered the NK cell activity which had been impaired in the aged mice. Meanwhile aging is known to reduce the Th1-like function, but not the Th2-like function, resulting in a Th1/Th2 imbalance. HemoHIM restored the Th1/Th2 balance in the aged mice through enhanced IFN-gamma and IgG2a production, and conversely a reduced IL-4 and IgG1 production. It was found that one factor for the Th1/Th2 imbalance in the aged mice was a lower production of IL-12p70. However, HemoHIM restored the IL-12p70 production in the aged mice. These results suggested that HemoHIM was effective for the restoration of impaired immune functions of the aged mice and therefore could be a good recommendation for immune restoration in elderly humans. PMID:17705143

  15. From chaos to split-ups--SHG microscopy reveals a specific remodelling mechanism in ageing dystrophic muscle.

    Science.gov (United States)

    Buttgereit, Andreas; Weber, Cornelia; Garbe, Christoph S; Friedrich, Oliver

    2013-02-01

    Duchenne muscular dystrophy (DMD) is a common inherited muscle disease showing chronic inflammation and progressive muscle weakness. Absent dystrophin renders sarcolemma more Ca(2+) -permeable, disturbs signalling and triggers inflammation. Sustained degeneration/regeneration cycles render muscle cytoarchitecture susceptible to remodelling. Quantitative morphometry was introduced in living cells using second-harmonic generation (SHG) microscopy of myosin. As the time course of cellular remodelling is not known, we used SHG microscopy in mdx muscle fibres over a wide age range for three-dimensional (3D) rendering and detection of verniers and cosine angle sums (CASs). Wild-type (wt) and transgenic mini-dystrophin mice (MinD) were also studied. Vernier densities (VDs) declined in wt and MinD fibres until adulthood, while in mdx fibres, VDs remained significantly elevated during the life span. CAS values were close to unity in adult wt and MinD fibres, in agreement with tight regular myofibril orientation, while always smaller in mdx fibres. Using SHG 3D morphometry, we identified two types of altered ultrastructure: branched fibres and a novel, previously undetected 'chaotic' fibre type, both of which can be classified by distinct CAS and VD combinations. We present a novel model of tissue remodelling in dystrophic progression with age that involves the transition from normal to chaotic to branched fibres. Our model predicts a ~50% contribution of altered cytoarchitecture to progressive force loss with age. We also provide an improved automated image algorithm that is suitable for future ageing studies in human myopathies. PMID:23132094

  16. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

    Science.gov (United States)

    Chiappalupi, Sara; Luca, Giovanni; Mancuso, Francesca; Madaro, Luca; Fallarino, Francesca; Nicoletti, Carmine; Calvitti, Mario; Arato, Iva; Falabella, Giulia; Salvadori, Laura; Di Meo, Antonio; Bufalari, Antonello; Giovagnoli, Stefano; Calafiore, Riccardo; Donato, Rosario; Sorci, Guglielmo

    2015-01-01

    We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12-month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week-old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1]. PMID:26759818

  17. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

    Directory of Open Access Journals (Sweden)

    Sara Chiappalupi

    2015-12-01

    Full Text Available We report data about the effects of intraperitoneal (i.p. injection of specific pathogen-free (SPF porcine Sertoli cells (SeC encapsulated into clinical grade alginate-based microcapsules (SeC-MC on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD, an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12-month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week-old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1].

  18. Reactive Oxygen Species Limit the Ability of Bone Marrow Stromal Cells to Support Hematopoietic Reconstitution in Aging Mice

    Science.gov (United States)

    Khatri, Rahul; Krishnan, Shyam; Roy, Sushmita; Chattopadhyay, Saborni; Kumar, Vikash

    2016-01-01

    Aging of organ and abnormal tissue regeneration are recurrent problems in physiological and pathophysiological conditions. This is most crucial in case of high-turnover tissues, like bone marrow (BM). Using reciprocal transplantation experiments in mouse, we have shown that self-renewal potential of hematopoietic stem and progenitor cells (HSPCs) and BM cellularity are markedly influenced with the age of the recipient mice rather than donor mice. Moreover, accumulation of excessive reactive oxygen species (ROS) in BM stromal cells compared to HSPC compartment, in time-dependent manner, suggests that oxidative stress is involved in suppression of BM cellularity by affecting microenvironment in aged mice. Treatment of these mice with a polyphenolic antioxidant curcumin is found to partially quench ROS, thereby rescues stromal cells from oxidative stress-dependent cellular injury. This rejuvenation of stromal cells significantly improves hematopoietic reconstitution in 18-month-old mice compared to age control mice. In conclusion, this study implicates the role of ROS in perturbation of stromal cell function upon aging, which in turn affects BM's reconstitution ability in aged mice. Thus, a rejuvenation therapy using curcumin, before HSPC transplantation, is found to be an efficient strategy for successful marrow reconstitution in older mice. PMID:27140293

  19. Effect of Cistanche Desertica Polysaccharides on Learning and Memory Functions and Ultrastructure of Cerebral Neurons in Experimental Aging Mice

    Institute of Scientific and Technical Information of China (English)

    孙云; 邓杨梅; 王德俊; 沈春锋; 刘晓梅; 张洪泉

    2001-01-01

    To observe the effects of Cistanche desertica polysaccharides (CDP) on the learning and memory functions and cerebral ultrastructure in experimental aging mice. Methods: CDP was administrated intragastrically 50 or 100 mg/kg per day for 64 successive days to experimental aging model mice induced by D-galactose, then the learning and memory functions of mice were estimated by step-down test and Y-maze test; organelles of brain tissue and cerebral ultrastructure were observed by transmission electron microscope and physical strength was determined by swimming test. Results: CDP could obviously enhance the learning and memory functions (P<0.01) and prolong the swimming time (P<0.05), decrease the number of lipofuscin and slow down the degeneration of mitochondria in neurons(P<0.05), and improve the degeneration of cerebral ultra-structure in aging mice. Conclusion: CDP could improve the impaired physiological function and alleviate cerebral morphological change in experimental aging mice.

  20. Aged mice have increased inflammatory monocyte concentration and altered expression of cell-surface functional receptors

    Indian Academy of Sciences (India)

    Kelley Strohacker; Whitney L Breslin; Katie C Carpenter; Brian K McFarlin

    2012-03-01

    The expression of monocyte cell-surface receptors represents one index of immune dysfunction, which is common with aging. Although mouse models of aging are prevalent, monocyte subset assessment is rare. Our purpose was to compare cell receptor expression on classic (CD115+/Gr-1high) and non-classic (CD115+/Gr-1low) monocytes from 80- or 20-week-old CD-1 mice. Three-colour flow cytometry was used to determine the concentration of monocyte subsets and their respective cell-surface expression of TLR2, TLR4, CD80, CD86, MHC II and CD54. These receptors were selected because they have been previously associated with altered monocyte function. Data were analysed with independent -tests; significance was set at < 0.05. Old mice had a greater concentration of both classic (258%, =0.003) and non-classic (70%, =0.026) monocytes. The classic : non-classic monocyte ratio doubled in old as compared with that in young mice (=0.006), indicating a pro-inflammatory shift. TLR4 ($\\downarrow$27%, =0.001) and CD80 ($\\downarrow$37%, =0.004) were decreased on classic monocytes from old as compared with those from young mice. TLR2 ($\\uparrow$24%, =0.002) and MHCII ($\\downarrow$21%, =0.026) were altered on non-classic monocytes from old as compared with those from young mice. The increased classic : non-classic monocyte ratio combined with changes in the cell-surface receptor expression on both monocyte subsets is indicative of immune dysfunction, which may increase age-associated disease risk.

  1. Aging in mice reduces the ability to sustain sleep/wake states.

    Directory of Open Access Journals (Sweden)

    Mathieu E Wimmer

    Full Text Available One of the most significant problems facing older individuals is difficulty staying asleep at night and awake during the day. Understanding the mechanisms by which the regulation of sleep/wake goes awry with age is a critical step in identifying novel therapeutic strategies to improve quality of life for the elderly. We measured wake, non-rapid eye movement (NREM and rapid-eye movement (REM sleep in young (2-4 months-old and aged (22-24 months-old C57BL6/NIA mice. We used both conventional measures (i.e., bout number and bout duration and an innovative spike-and-slab statistical approach to characterize age-related fragmentation of sleep/wake. The short (spike and long (slab components of the spike-and-slab mixture model capture the distribution of bouts for each behavioral state in mice. Using this novel analytical approach, we found that aged animals are less able to sustain long episodes of wakefulness or NREM sleep. Additionally, spectral analysis of EEG recordings revealed that aging slows theta peak frequency, a correlate of arousal. These combined analyses provide a window into the mechanisms underlying the destabilization of long periods of sleep and wake and reduced vigilance that develop with aging.

  2. Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice

    OpenAIRE

    Wang, Shuying; Davis, Brian M.; Zwick, Melissa; Waxman, Stephen G.; Albers, Kathryn M.

    2005-01-01

    Sensory neurons in aging mammals undergo changes in anatomy, physiology and gene expression that correlate with reduced sensory perception. In this study we compared young and aged mice to identify proteins that might contribute to this loss of sensation. We first show using behavioral testing that thermal sensitivity in aged male and female mice is reduced. Expression of sodium channel (Nav1.8 and Nav1.9) and transient receptor potential vanilloid (TRPV) channels in DRG and peripheral nerves...

  3. Expression of complement system components during aging and amyloid deposition in APP transgenic mice

    Directory of Open Access Journals (Sweden)

    Wiederhold Karl-Heinz

    2009-11-01

    Full Text Available Abstract Background A causal role of the complement system in Alzheimer's disease pathogenesis has been postulated based on the identification of different activated components up to the membrane attack complex at amyloid plaques in brain. However, histological studies of amyloid plaque bearing APP transgenic mice provided only evidence for an activation of the early parts of the complement cascade. To better understand the contribution of normal aging and amyloid deposition to the increase in complement activation we performed a detailed characterization of the expression of the major mouse complement components. Methods APP23 mice expressing human APP751 with the Swedish double mutation as well as C57BL/6 mice were used at different ages. mRNA was quantified by Realtime PCR and the age- as well as amyloid induced changes determined. The protein levels of complement C1q and C3 were analysed by Western blotting. Histology was done to test for amyloid plaque association and activation of the complement cascade. Results High mRNA levels were detected for C1q and some inhibitory complement components. The expression of most activating components starting at C3 was low. Expression of C1q, C3, C4, C5 and factor B mRNA increased with age in control C57BL/6 mice. C1q and C3 mRNA showed a substantial additional elevation during amyloid formation in APP23 mice. This increase was confirmed on the protein level using Western blotting, whereas immunohistology indicated a recruitment of complement to amyloid plaques up to the C3 convertase. Conclusion Early but not late components of the mouse complement system show an age-dependent increase in expression. The response to amyloid deposition is comparatively smaller. The low expression of C3 and C5 and failure to upregulate C5 and downstream components differs from human AD brain and likely contributes to the lack of full complement activation in APP transgenic mice.

  4. Beneficial effects of cornel iridoid glycoside on behavioral impairment and senescence status in SAMP8 mice at different ages.

    Science.gov (United States)

    Ma, Denglei; Zhu, Yanqiu; Li, Yanzheng; Yang, Cuicui; Zhang, Li; Li, Yali; Li, Lin; Zhang, Lan

    2016-10-01

    The aim of the present study was to investigate the effects of cornel iridoid glycoside (CIG) on behavioral changes and senescent status in senescence-accelerated mouse-prone 8 (SAMP8) mice at different ages (6, 10, and 14 months old). The learning and memory ability, the motor function and the aging conditions of SAMP8 mice were evaluated after CIG treatment in this study. Results showed that intragastrical administration of CIG (100 and 200mg/kg) for two months obviously improved the impaired cognitive ability of SAMP8 mice at the age of 6 months and 10 months, respectively. The treatment with CIG significantly increased the motor function of SAMP8 mice at 10 months and 14 months of age, respectively. CIG also evidently decreased the high grading score of senescence and increased the low surviving rate of SAMP8 mice at the age of 14 months. In addition, CIG treatment inhibited tau hyperphosphorylation in the hippocampus and striatum of SAMP8 mice at different ages. Together, these results indicate that CIG represent a potentially useful treatment for ameliorating the impaired cognitive ability, the motor dysfunction, aging conditions and hyperphosphorylation of tau in aging and age-related neurodegenerative diseases, such as Alzheimer's disease. PMID:27283974

  5. Dietary wolfberry supplementation enhances the protective effect of flu vaccine against influenza challenge in aged mice.

    Science.gov (United States)

    Du, Xiaogang; Wang, Junpeng; Niu, Xinli; Smith, Donald; Wu, Dayong; Meydani, Simin Nikbin

    2014-02-01

    Current vaccines for influenza do not fully protect the aged against influenza infection. Although wolfberry (goji berry) has been shown to improve immune response, including enhanced antibody production, after vaccination in the aged, it is not known if this effect would translate to better protection after influenza infection, nor is its underlying mechanism well understood. To address these issues, we conducted a study using a 2 × 2 design in which aged male mice (20-22 mo) were fed a control or a 5% wolfberry diet for 30 d, then immunized with an influenza vaccine or saline (control) on days 31 and 52 of the dietary intervention, and finally challenged with influenza A/Puerto Rico/8/34 virus. Mice fed wolfberry had higher influenza antibody titers and improved symptoms (less postinfection weight loss) compared with the mice treated by vaccine alone. Furthermore, an in vitro mechanistic study showed that wolfberry supplementation enhanced maturation and activity of antigen-presenting dendritic cells (DCs) in aged mice, as indicated by phenotypic change in expression of DC activation markers major histocompatibility complex class II, cluster of differentiation (CD) 40, CD80, and CD86, and functional change in DC production of cytokines interleukin-12 and tumor necrosis factor-α as well as DC endocytosis. Also, adoptive transfer of wolfberry-treated bone marrow DCs (loaded with ovalbumin(323-339)-peptide) promoted antigen-specific T cell proliferation as well as interleukin-4 and interferon-γ production in CD4(+) T cells. In summary, our data indicate that dietary wolfberry enhances the efficacy of influenza vaccination, resulting in better host protection to prevent subsequent influenza infection; this effect may be partly attributed to improved DC function. PMID:24336457

  6. Early Signs of Pathological Cognitive Aging in Mice Lacking High-Affinity Nicotinic Receptors

    OpenAIRE

    Konsolaki, Eleni; Tsakanikas, Panagiotis; Polissidis, Alexia V.; Stamatakis, Antonios; Skaliora, Irini

    2016-01-01

    In order to address pathological cognitive decline effectively, it is critical to adopt early preventive measures in individuals considered at risk. It is therefore essential to develop approaches that identify such individuals before the onset of irreversible dementia. A deficient cholinergic system has been consistently implicated as one of the main factors associated with a heightened vulnerability to the aging process. In the present study we used mice lacking high affinity nicotinic rece...

  7. Probiotic microbes sustain youthful serum testosterone levels and testicular size in aging mice.

    Directory of Open Access Journals (Sweden)

    Theofilos Poutahidis

    Full Text Available The decline of circulating testosterone levels in aging men is associated with adverse health effects. During studies of probiotic bacteria and obesity, we discovered that male mice routinely consuming purified lactic acid bacteria originally isolated from human milk had larger testicles and increased serum testosterone levels compared to their age-matched controls. Further investigation using microscopy-assisted histomorphometry of testicular tissue showed that mice consuming Lactobacillus reuteri in their drinking water had significantly increased seminiferous tubule cross-sectional profiles and increased spermatogenesis and Leydig cell numbers per testis when compared with matched diet counterparts This showed that criteria of gonadal aging were reduced after routinely consuming a purified microbe such as L. reuteri. We tested whether these features typical of sustained reproductive fitness may be due to anti-inflammatory properties of L. reuteri, and found that testicular mass and other indicators typical of old age were similarly restored to youthful levels using systemic administration of antibodies blocking pro-inflammatory cytokine interleukin-17A. This indicated that uncontrolled host inflammatory responses contributed to the testicular atrophy phenotype in aged mice. Reduced circulating testosterone levels have been implicated in many adverse effects; dietary L. reuteri or other probiotic supplementation may provide a viable natural approach to prevention of male hypogonadism, absent the controversy and side-effects of traditional therapies, and yield practical options for management of disorders typically associated with normal aging. These novel findings suggest a potential high impact for microbe therapy in public health by imparting hormonal and gonad features of reproductive fitness typical of much younger healthy individuals.

  8. Minocycline attenuates post-operative cognitive impairment in aged mice by inhibiting microglia activation.

    Science.gov (United States)

    Wang, Hui-Lin; Liu, Hua; Xue, Zhang-Gang; Liao, Qing-Wu; Fang, Hao

    2016-09-01

    Although it is known that isoflurane exposure or surgery leads to post-operative cognitive dysfunction in aged rodents, there are few clinical interventions and treatments available to prevent this disorder. Minocycline (MINO) produces neuroprotection from several neurodegenerative diseases and various experimental animal models. Therefore, we set out to investigate the effects of MINO pre-treatment on isoflurane or surgery induced cognitive impairment in aged mice by assessing the hippocampal-dependent spatial memory performance using the Morris water maze task. Hippocampal tissues were isolated from mice and evaluated by Western blot analysis, immunofluorescence procedures and protein array system. Our results elucidate that MINO down-regulated the isoflurane-induced and surgery-induced enhancement in the protein levels of pro-inflammatory cytokine tumour necrosis factor alpha, interleukin (IL)-1β, interferon-γ and microglia marker Iba-1, and up-regulated protein levels of the anti-inflammatory cytokine IL-4 and IL-10. These findings suggest that pre-treatment with MINO attenuated isoflurane or surgery induced cognitive impairment by inhibiting the overactivation of microglia in aged mice. PMID:27061744

  9. Aged mice display an altered pulmonary host response to Francisella tularensis live vaccine strain (LVS) infections

    OpenAIRE

    CA, Mares; SS, Ojeda; Q., Li; EG, Morris; JJ, Coalson; JM, Teale

    2009-01-01

    Aging is a complex phenomenon that has been shown to affect many organ systems including the innate and adaptive immune systems. The current study was designed to examine the potential effect of immunosenescence on the pulmonary immune response using a Francisella tularensis live vaccine strain (LVS) inhalation infection model. F. tularensis is a gram-negative intracellular pathogen that can cause a severe pneumonia.In this study both young (8-12 week old) and aged (20-24 month old) mice were...

  10. Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice

    Directory of Open Access Journals (Sweden)

    Francesco Tamagnini

    2015-10-01

    These data show that Aβ-overexpression in aged mice altered the capacitance, the neuronal firing and the AP waveform of CA1 pyramidal neurons. Some of these findings are consistent with previous work on younger PDAPP, they also show important differences that can be potentially ascribed to the interaction between amyloidopathy and ageing. Such a change of IE properties over time underlies that the increased incidence of seizure observed in AD patients might rely on different mechanistic pathways during progression of the disease.

  11. Kcne4 deletion sex- and age-specifically impairs cardiac repolarization in mice.

    Science.gov (United States)

    Crump, Shawn M; Hu, Zhaoyang; Kant, Ritu; Levy, Daniel I; Goldstein, Steve A N; Abbott, Geoffrey W

    2016-01-01

    Myocardial repolarization capacity varies with sex, age, and pathology; the molecular basis for this variation is incompletely understood. Here, we show that the transcript for KCNE4, a voltage-gated potassium (Kv) channel β subunit associated with human atrial fibrillation, was 8-fold more highly expressed in the male left ventricle compared with females in young adult C57BL/6 mice (P 45% (P 3-fold (P = 0.01) to match noncastrated levels. KCNE4 is thereby shown to be a DHT-regulated determinant of cardiac excitability and a molecular substrate for sex- and age-dependent cardiac arrhythmogenesis. PMID:26399785

  12. In vivo and in vitro study of the primary and secondary antibody response to a bacterial antigen in aged mice.

    OpenAIRE

    Borghesi, C.; Nicoletti, C.

    1995-01-01

    One of the most important manifestations of aging in both humans and laboratory animals is a gradual decline in immune effectiveness. However, it is not clear as to how general is this decline. We here report that aged BALB/c mice showed no decline in the magnitude of the in vivo primary antibody response to phosphorylcholine (PC), an immunodominant epitope of the Streptococcus pneumoniae R36a (Pn). Often it appeared that aged mice responded better than young syngeneic mice. In contrast, the ...

  13. Lifelong vitamin E intake retards age-associated decline of spatial learning ability in apoE-deficient mice

    OpenAIRE

    McDonald, Shelley R.; Forster, Michael J.

    2005-01-01

    The potential for lifelong vitamin E supplementation to delay age-associated cognitive decline was tested in apoE-deficient and wild-type C57BL/6 mice. Beginning at eight weeks of age, the mice were maintained on a control diet or diets supplemented with dl-α-tocopheryl acetate yielding approximate daily intakes of either 20 or 200 mg/kg body weight. When 6 or 18 months of age, cognitive functioning of the mice was assessed using swim maze and discriminated avoidance testing procedures. For t...

  14. The Cardioprotective Effect of Vitamin E (Alpha-Tocopherol) Is Strongly Related to Age and Gender in Mice

    OpenAIRE

    Hu, Xiao-Xia; Fu, Li; Li, Yan; Lin, Ze-Bang; Liu, Xiang; Wang, Jing-Feng; Chen, Yang-xin; Wang, Zhi-Ping; Zhang, Xi; Ou, Zhi-Jun; Ou, Jing-Song

    2015-01-01

    Vitamin E (VitE) only prevented cardiovascular diseases in some patients and the mechanisms remain unknown. VitE levels can be affected by aging and gender. We hypothesize that age and gender can influence VitE’s cardioprotective effect. Mice were divided into 4 groups according to age and gender, and each group of mice were divided into a control group and a VitE group. The mice were administered water or VitE for 21 days; Afterward, the cardiac function and myocardial infarct size and cardi...

  15. Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.

    Science.gov (United States)

    Mitchell, Sarah J; Madrigal-Matute, Julio; Scheibye-Knudsen, Morten; Fang, Evandro; Aon, Miguel; González-Reyes, José A; Cortassa, Sonia; Kaushik, Susmita; Gonzalez-Freire, Marta; Patel, Bindi; Wahl, Devin; Ali, Ahmed; Calvo-Rubio, Miguel; Burón, María I; Guiterrez, Vincent; Ward, Theresa M; Palacios, Hector H; Cai, Huan; Frederick, David W; Hine, Christopher; Broeskamp, Filomena; Habering, Lukas; Dawson, John; Beasley, T Mark; Wan, Junxiang; Ikeno, Yuji; Hubbard, Gene; Becker, Kevin G; Zhang, Yongqing; Bohr, Vilhelm A; Longo, Dan L; Navas, Placido; Ferrucci, Luigi; Sinclair, David A; Cohen, Pinchas; Egan, Josephine M; Mitchell, James R; Baur, Joseph A; Allison, David B; Anson, R Michael; Villalba, José M; Madeo, Frank; Cuervo, Ana Maria; Pearson, Kevin J; Ingram, Donald K; Bernier, Michel; de Cabo, Rafael

    2016-06-14

    Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions. PMID:27304509

  16. Effects of velvet antler polypeptide on sexual behavior and testosterone synthesis in aging male mice

    Science.gov (United States)

    Zang, Zhi-Jun; Tang, Hong-Feng; Tuo, Ying; Xing, Wei-Jie; Ji, Su-Yun; Gao, Yong; Deng, Chun-Hua

    2016-01-01

    Twenty-four-month-old male C57BL/6 mice with low serum testosterone levels were used as a late-onset hypogonadism (LOH) animal model for examining the effects of velvet antler polypeptide (VAP) on sexual function and testosterone synthesis. These mice received VAP for 5 consecutive weeks by daily gavage at doses of 100, 200, or 300 mg kg−1 body weight per day (n = 10 mice per dose). Control animals (n = 10) received the same weight-based volume of vehicle. Sexual behavior and testosterone levels in serum and interstitial tissue of testis were measured after the last administration of VAP. Furthermore, to investigate the mechanisms of how VAP affects sexual behavior and testosterone synthesis in vivo, the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD) in Leydig cells was also measured by immunofluorescence staining and quantitative real-time PCR. As a result, VAP produced a significant improvement in the sexual function of these aging male mice. Serum testosterone level and intratesticular testosterone (ITT) concentration also increased in the VAP-treated groups. The expression of StAR, P450scc, and 3β-HSD was also found to be enhanced in the VAP-treated groups compared with the control group. Our results suggested that VAP was effective in improving sexual function in aging male mice. The effect of velvet antler on sexual function was due to the increased expression of several rate-limiting enzymes of testosterone synthesis (StAR, P450scc, and 3β-HSD) and the following promotion of testosterone synthesis in vivo. PMID:26608944

  17. Age related retention and dose burden after injection of 224Ra and 227Th in mice

    International Nuclear Information System (INIS)

    Incorporation of 224Ra in different aged female NMRI mice was investigated. The retention in skeleton (long bones) decreased continuously with age and remained constant after an age of about 10 months (decrease of percentage uptake from 50 to 25%). Rather similar conditions were found for the retention of 227Th, but with a somewhat smaller decrease (45 to 35%). These skeletal doses are often based on the values of femur concentration. In the case of mice, however, most bone tumours occur in the lumbar vertebrae, where the retention does not vary much with age. In contrast to the skeleton the retention of 224Ra was increased with age in the spleen, reaching concentrations even higher than that in the skeleton of old animals. It was remarkable that radium was retained in the spleen in this high concentration only when it was injected directly (as 224Ra) but much less, when it was given indirectly i.e. as the daughter nuclide 223Ra of its parent 227Th. If equal skeletal doses for different aged animals are to be intended, the reduced retention in the higher age has to be taken into account. Since dosage is mostly related to body weight (for instance Bq per kilogram) the resulting skeletal dose will be too small if the body weight and skeletal weight would be proportional. Since by the growth of fat tissue the body weight normally increases more than skeletal weight (after an age of a few months), the lowered retention might be more or less corrected for by relating to body weight. 3 refs.; 3 figs

  18. The sensitivity of female NMRI mice of different ages for osteosarcoma induction with 227thorium

    International Nuclear Information System (INIS)

    The effect of age on osteosarcoma induction after incorporation of the short-lived alpha-emitter 227Th was studied in 12 month old and young (1 month and 3 month old) female NMRI mice. Injection of 1 μCi/kg 227Th in 1 month or 12 month old mice induced osteosarcomas with a similar incidence in both groups (21% and 16%, maximum corrected cumulative incidence 32% and 43%). The osteosarcoma appearance time in the older animals was shorter and there was no significant difference in the age at appearance of osteosarcomas in the two groups. After injection of 5 μCi/kg 227Th the maximum corrected cumulative osteosarcoma incidence was considerably lower in the older group (10%) than in the younger group (61%) despite the fact that there were 32 survivors in the older group at the time of appearance of the last osteosarcoma. Incorporation of 2x1 μCi/kg 227Th at the age of 12 months and 14 months or 3 months and 5 months induced osteosarcoma with a similar maximum corrected cumulative osteosarcoma incidence (62% and 68% respectively). The mean osteosarcoma appearance time after the first incorporation was shorter in the older age group than in the younger age group but osteosarcomas still appeared overall at a younger age in the younger age group. The mean osteosarcoma appearance time after the first incorporation following fractionation of the internal irradiation period, by injection of 1 μCi/kg at the age of 3 months and 12 months, was significantly longer than in either the 3-months/5-months group or the 12-months /14-months group. (orig.)

  19. Evaluation of Diagnostic Methods for Myocoptes musculinus According to Age and Treatment Status of Mice (Mus musculus)

    OpenAIRE

    Rice, Kelly A; Albacarys, Lauren K; Pate, Kelly A. Metcalf; Perkins, Cheryl; Henderson, Kenneth S; Watson, Julie

    2013-01-01

    Detecting and controlling murine fur mites continues to be challenging. Here we compared the efficacy of fur-pluck, cage PCR, and fur PCR testing of mice naturally infested with Myocoptes musculinus and make recommendations regarding the application of these diagnostic strategies in aged or treated mice. We compared all 3 diagnostic methods in groups of infested and noninfested control mice over time. For fur plucks, we used a scoring system to quantitatively compare mite infestations across ...

  20. Age influence on mice lung tissue response to [i]Aspergillus fumigatus[/i] chronic exposure

    Directory of Open Access Journals (Sweden)

    Marta Kinga Lemieszek

    2015-02-01

    Full Text Available [b]Introduction and objective[/b]. Exposure to conidia of [i]Aspergillus fumigatus[/i] was described as a causative factor of a number of the respiratory system diseases, including asthma, chronic eosinophilic pneumonia, hypersensitivity pneumonitis and bronchopulmonary aspergillosis. The study investigates the effects of the repeated exposure to [i]A. fumigatus[/i] in mice pulmonary compartment. Our work tackles two, so far insufficiently addressed, important aspects of interaction between affected organism and[i] A. fumigatus[/i]: 1 recurrent character of exposure (characteristic for pathomechanism of the abovementioned disease states and 2 impact of aging, potentially important for the differentiation response to an antigen. [b]Materials and methods[/b]. In order to dissect alterations of the immune system involved with both aging and chronic exposure to [i]A. fumigatus[/i], we used 3- and 18-month-old C57BL/6J mice exposed to repeated[i] A. fumigatus[/i] inhalations for 7 and 28 days. Changes in lung tissue were monitored by histological and biochemical evaluation. Concentration of pro- and anti-inflammatory cytokines in lung homogenates was assessed by ELISA tests. [b]Results and conclusions. [/b]Our study demonstrated that chronic inflammation in pulmonary compartment, characterized by the significant increase of proinflammatory cytokines (IL1, IL6, IL10 levels, was the dominant feature of mice response to repeated [i]A. fumigatus[/i] inhalations. The pattern of cytokines’ profile in the course of exposure was similar in both age groups, however in old mice the growth of the cytokines’ levels was more pronounced (especially in case of IL1.

  1. Reciprocal translocations in ageing mice and mice with long-term low-level 239Pu contamination

    International Nuclear Information System (INIS)

    Single intravenous injections of 185 Bq monomeric 239Pu were given to male mice, and the frequency of primary spermatocytes with reciprocal translocations, determined 724 days after treatment, was not significantly different from that of age-matched untreated controls. These old animals showed significantly higher aberration frequencies than young adults. The data therefore show that for low initial activity and very long retention time the possible cytogenetic effects of incorporated nuclide does not change the age-related pattern of increase of spontaneous chromosome aberrations. Considerations of the main variables involved in the induction of cytogenetic effects of incorporated plutonium, based on literature data, indicate that the initial injected activity, the estimated total accumulated average organ dose, and the retention time interact in a complex way; as far as can be seen at present, the effects seem to be dependent mainly on the initial activity at short times after contamination, while the retention time appears to be predominant in the case of long-term observations. (author)

  2. αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction

    Science.gov (United States)

    Greten-Harrison, Becket; Polydoro, Manuela; Morimoto-Tomita, Megumi; Diao, Ling; Williams, Andrew M.; Nie, Esther H.; Makani, Sachin; Tian, Ning; Castillo, Pablo E.; Buchman, Vladimir L.; Chandra, Sreeganga S.

    2010-01-01

    Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, α-, β-, and γ-synuclein. α-Synuclein has been the focus of intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized αβγ-synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by ∼30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease. PMID:20974939

  3. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

    Science.gov (United States)

    Bitto, Alessandro; Ito, Takashi K; Pineda, Victor V; LeTexier, Nicolas J; Huang, Heather Z; Sutlief, Elissa; Tung, Herman; Vizzini, Nicholas; Chen, Belle; Smith, Kaleb; Meza, Daniel; Yajima, Masanao; Beyer, Richard P; Kerr, Kathleen F; Davis, Daniel J; Gillespie, Catherine H; Snyder, Jessica M; Treuting, Piper M; Kaeberlein, Matt

    2016-01-01

    The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome. DOI: http://dx.doi.org/10.7554/eLife.16351.001 PMID:27549339

  4. CpG ODN Enhances Immunization Effects of Hepatitis B Vaccine in Aged Mice

    Institute of Scientific and Technical Information of China (English)

    WeibingQin; JianweiJiang; QiaoerChen; NingYang; YifengWang; XiangcaiWei; RuqiangOu

    2004-01-01

    Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides in contexts of unique sequence (CpG motifs) is active as adjuvant in induction of cellular and humoral immune responses in young mice. To date, there are only limited reports about effect of CpG ODN on immune responses against hepatitis B (HB) infection in aged mice. Our studies demonstrated there were significant increases in secreting of total anti-HB IgG, IgG1 and IgG2a, as well as of IL-12 and IFN-γ, when CpG ODNs were injected together with hepatitis B antigen in aged mice. Moreover, CpG ODN could stimulate proliferation of spleen lymphocytes in a dose-dependent manner. Taken together, the results we obtained indicate that the adding of CpG ODN into the vaccine antigen might be useful in development of more effective vaccination for inducing anti-HB virus responses in the elderly. Cellular & Molecular Immunology. 2004;1(2):148-152.

  5. CpG ODN Enhances Immunization Effects of Hepatitis B Vaccine in Aged Mice

    Institute of Scientific and Technical Information of China (English)

    Weibing Qin; Jianwei Jiang; Qiaoer Chen; Ning Yang; Yifeng Wang; Xiangcai Wei; Ruqiang Ou

    2004-01-01

    Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides in contexts of unique sequence (CpG motifs) is active as adjuvant in induction of cellular and humoral immune responses in young mice. To date, there are only limited reports about effect of CpG ODN on immune responses against hepatitis B (HB) infection in aged mice. Our studies demonstrated there were significant increases in secreting of total anti-HB IgG, IgG1 and IgG2a, as well as of IL-12 and IFN-γ, when CpG ODNs were injected together with hepatitis B antigen in aged mice. Moreover, CpG ODN could stimulate proliferation of spleen lymphocytes in a dose-dependent manner. Taken together, the results we obtained indicate that the adding of CpG ODN into the vaccine antigen might be useful in development of more effective vaccination for inducing anti-HB virus responses in the elderly.

  6. Comparative gene expression and phenotype analyses of skeletal muscle from aged wild-type and PAPP-A-deficient mice.

    Science.gov (United States)

    Conover, Cheryl A; Bale, Laurie K; Nair, K Sreekumaran

    2016-07-01

    Mice deficient in pregnancy-associated plasma protein-A (PAPP-A) have extended lifespan associated with decreased incidence and severity of degenerative diseases of age, such as cardiomyopathy and nephropathy. In this study, the effect of PAPP-A deficiency on aging skeletal muscle was investigated. Whole-genome expression profiling was performed on soleus muscles from 18-month-old wild-type (WT) and PAPP-A knock-out (KO) mice of the same sex and from the same litter ('womb-mates') to identify potential mechanisms of skeletal muscle aging and its retardation in PAPP-A deficiency. Top genes regulated in PAPP-A KO compared to WT muscle were associated with increased muscle function, increased metabolism, in particular lipid metabolism, and decreased stress. Fiber cross-sectional area was significantly increased in solei from PAPP-A KO mice. In vitro contractility experiments indicated increased specific force and decreased fatigue in solei from PAPP-A KO mice. Intrinsic mitochondrial oxidative capacity was significantly increased in skeletal muscle of aged PAPP-A KO compared to WT mice. Moreover, 18-month-old PAPP-A KO mice exhibited significantly enhanced endurance running on a treadmill. Thus, PAPP-A deficiency in mice is associated with indices of healthy skeletal muscle function with age. PMID:27086066

  7. Effect of nuclear factor κB inhibition on serotype 9 adeno-associated viral (AAV9) minidystrophin gene transfer to the mdx mouse.

    Science.gov (United States)

    Reay, Daniel P; Niizawa, Gabriela A; Watchko, Jon F; Daood, Molly; Reay, Ja'Nean C; Raggi, Eugene; Clemens, Paula R

    2012-01-01

    Gene therapy studies for Duchenne muscular dystrophy (DMD) have focused on viral vector-mediated gene transfer to provide therapeutic protein expression or treatment with drugs to limit dystrophic changes in muscle. The pathological activation of the nuclear factor (NF)-κB signaling pathway has emerged as an important cause of dystrophic muscle changes in muscular dystrophy. Furthermore, activation of NF-κB may inhibit gene transfer by promoting inflammation in response to the transgene or vector. Therefore, we hypothesized that inhibition of pathological NF-κB activation in muscle would complement the therapeutic benefits of dystrophin gene transfer in the mdx mouse model of DMD. Systemic gene transfer using serotype 9 adeno-associated viral (AAV9) vectors is promising for treatment of preclinical models of DMD because of vector tropism to cardiac and skeletal muscle. In quadriceps of C57BL/10ScSn-Dmd(mdx)/J (mdx) mice, the addition of octalysine (8K)-NF-κB essential modulator (NEMO)-binding domain (8K-NBD) peptide treatment to AAV9 minidystrophin gene delivery resulted in increased levels of recombinant dystrophin expression suggesting that 8K-NBD treatment promoted an environment in muscle tissue conducive to higher levels of expression. Indices of necrosis and regeneration were diminished with AAV9 gene delivery alone and to a greater degree with the addition of 8K-NBD treatment. In diaphragm muscle, high-level transgene expression was achieved with AAV9 minidystoophin gene delivery alone; therefore, improvements in histological and physiological indices were comparable in the two treatment groups. The data support benefit from 8K-NBD treatment to complement gene transfer therapy for DMD in muscle tissue that receives incomplete levels of transduction by gene transfer, which may be highly significant for clinical applications of muscle gene delivery. PMID:22231732

  8. Age-Dependent Neuroimmune Modulation of IGF-1R in the Traumatic Mice

    Directory of Open Access Journals (Sweden)

    Zhao Hui

    2012-05-01

    Full Text Available Abstract Background Age-dependent neuroimmune modulation following traumatic stress is accompanied by discordant upregulation of Fyn signaling in the frontal cortex, but the mechanistic details of the potential cellular behavior regarding IGF-1R/Fyn have not been established. Methods Trans-synaptic IGF-1R signaling during the traumatic stress was comparably examined in wild type, Fyn (−/− and MOR (−/− mice. Techniques included primary neuron culture, in vitro kinase activity, immunoprecipitation, Western Blot, sucrose discontinuous centrifugation. Besides that, [3 H] incorporation was used to assay lymphocyte proliferation and NK cell activity. Results We demonstrate robust upregulation of synaptic Fyn activity following traumatic stress, with higher amplitude in 2-month mice than that in 1-year counterpart. We also established that the increased Fyn signaling is accompanied by its molecular connection with IGF-1R within the synaptic zone. Detained analysis using Fyn (−/− and MOR (−/− mice reveal that IGF-1R/Fyn signaling is governed to a large extent by mu opioid receptor (MOR, and with age-dependent manner; these signaling cascades played a central role in the modulation of lymphocyte proliferation and NK cell activity. Conclusions Our data argued for a pivotal role of synaptic IGF-1R/Fyn signaling controlled by MOR downstream signaling cascades were crucial for the age-dependent neuroimmune modulation following traumatic stress. The result here might present a new quality of synaptic cellular communication governing the stress like events and have significant potential for the development of therapeutic approaches designed to minimize the heightened vulnerability during aging.

  9. n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice

    Directory of Open Access Journals (Sweden)

    Debora eCutuli

    2014-08-01

    Full Text Available As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogenesis, volume, neurodegeneration and metabolic correlates to verify n-3 PUFA neuroprotective effects in aging. To this aim 19 month-old mice were given n-3 PUFA mixture, or olive oil or no dietary supplement for 8 weeks during which hippocampal-dependent mnesic functions were tested. At the end of behavioral testing morphological and metabolic correlates were analyzed. n-3 PUFA supplemented aged mice exhibited better object recognition memory, spatial and localizatory memory, and aversive response retention, without modifications in anxiety levels in comparison to controls. These improved hippocampal cognitive functions occurred in the context of an enhanced cellular plasticity and a reduced neurodegeneration. In fact, n-3 PUFA supplementation increased hippocampal neurogenesis and dendritic arborization of newborn neurons, volume, neuronal density and microglial cell number, while it decreased apoptosis, astrocytosis and lipofuscin accumulation in the hippocampus. The increased levels of some metabolic correlates (blood Acetyl-L-Carnitine and brain n-3 PUFA concentrations found in n-3 PUFA supplemented mice also pointed towards an effective neuroprotection.On the basis of the present results n-3 PUFA supplementation appears to be a useful tool in health promotion and cognitive decline prevention during aging.

  10. Evaluation of Electrical Impedance as a Biomarker of Myostatin Inhibition in Wild Type and Muscular Dystrophy Mice.

    Directory of Open Access Journals (Sweden)

    Benjamin Sanchez

    Full Text Available Non-invasive and effort independent biomarkers are needed to better assess the effects of drug therapy on healthy muscle and that affected by muscular dystrophy (mdx. Here we evaluated the use of multi-frequency electrical impedance for this purpose with comparison to force and histological parameters.Eight wild-type (wt and 10 mdx mice were treated weekly with RAP-031 activin type IIB receptor at a dose of 10 mg kg-1 twice weekly for 16 weeks; the investigators were blinded to treatment and disease status. At the completion of treatment, impedance measurements, in situ force measurements, and histology analyses were performed.As compared to untreated animals, RAP-031 wt and mdx treated mice had greater body mass (18% and 17%, p 70 Hz, but not in the mdx animals. In contrast, maximum force normalized by muscle mass was unchanged in the wt animals and lower in the mdx animals by 21% (p < 0.01. Similarly, myofiber size was only non-significantly higher in treated versus untreated animals (8% p = 0.44 and 12% p = 0.31 for wt and mdx animals, respectively.Our findings demonstrate electrical impedance of muscle reproduce the functional and histological changes associated with myostatin pathway inhibition and do not reflect differences in muscle size or volume. This technique deserves further study in both animal and human therapeutic trials.

  11. Influence of prolonged dietary consumption of zeolites on a survival rate and intestine response in mice different age after irradiation

    International Nuclear Information System (INIS)

    Effect of long-term dietary consumption of zeolites on the structural-functional status of adherent mucous layers of digestive tract in mice of different age is studied as well as zeolites effect on the survival and mean life span in irradiation mice. Mice were exposed to whole-body acute irradiation at 4 Gy dose. RUM-17 X-ray apparatus was used for exposure. It is shown that the zeolites increase the survival and mean life span in mice following irradiation. Shivirtuin caused more expressed effect than that of pegasin

  12. Longevity and tumour incidence in mice exposed to fast neutrons at different ages

    International Nuclear Information System (INIS)

    Experiments are under way in the authors' laboratory to observe both neoplastic and non-neoplastic late effects in mice irradiated with fission neutrons and X-rays at three different ages. Analysis of data from over 2800 animals is in progress and a preliminary evaluation can be made on the survival and the pathology at spontaneous death of mice irradiated in utero and at 3 months of age. Single doses of 250kV X-rays or of attenuated fission neutrons obtained in the biological channel of the experimental fast reactor RSV TAPIRO of the Casaccia Centre were given to male BC3F1 mice of 3 months of age and to pregnant females on day 17.5 post coitum. Both male and female offspring of the latter group were followed to spontaneous death, along with appropriate untreated controls. As for the 3 month old irradiated animals their mean survival time was decreased by X-rays, the dose-effect relationship being compatible with a linear fitting. Fission neutrons proved to be more efficient than X-rays in the induction of life shortening, but the shape of the dose-effect relationship did not fit a linear model because efficiency is higher at low than at high neutron doses. Reticulum cell sarcoma (RCS) was decreased by increasing X-ray and neutron doses, the latter being more efficient. The final incidences of all other neoplasms, regardless of tumour type and site, indicate that neutrons are more efficient than X-rays in tumour induction at low and intermediate doses. As for prenatally irradiated mice, no detectable effect on mean lifespan was observed for either type of radiation. A low final frequency of RCS was seen after irradiation at all dose levels of both types of radiation. The incidence of all other tumours was practically unchanged in male mice irradiated as foetuses with X-rays, but a significant excess was found after neutron irradiation, showing a frequency peak in the range of 0.27-0.45Gy. Similar results were obtained after irradiation of foetal females. (author)

  13. Effects of Saikokaryukotsuboreito on Spermatogenesis and Fertility in Aging Male Mice

    Science.gov (United States)

    Zang, Zhi-Jun; Ji, Su-Yun; Zhang, Ya-Nan; Gao, Yong; Zhang, Bin

    2016-01-01

    Background: Aspermia caused by exogenous testosterone limit its usage in late-onset hypogonadism (LOH) patients desiring fertility. Saikokaryukotsuboreito (SKRBT) is reported to improve serum testosterone and relieve LOH-related symptoms. However, it is unclear whether SKRBT affects fertility. We aimed to examine the effects of SKRBT on spermatogenesis and fertility in aging male mice. Methods: Thirty aging male mice were randomly assigned to three groups. Mice were orally administered with phosphate-buffer solution or SKRBT (300 mg/kg, daily) or received testosterone by subcutaneous injections (10 mg/kg, every 3 days). Thirty days later, each male mouse was mated with two female mice. All animals were sacrificed at the end of 90 days. Intratesticular testosterone (ITT) levels, quality of sperm, expression of synaptonemal complex protein 3 (SYCP3), and fertility were assayed. Results: In the SKRBT-treated group, ITT, quality of sperm, and expression of SYCP3 were all improved compared with the control group (ITT: 85.50 ± 12.31 ng/g vs. 74.10 ± 11.45 ng/g, P = 0.027; sperm number: [14.94 ± 4.63] × 106 cells/ml vs. [8.79 ± 4.38] × 106 cells/ml, P = 0.002; sperm motility: 43.16 ± 9.93% vs. 33.51 ± 6.98%, P = 0.015; the number of SYCP3-positive cells/tubule: 77.50 ± 11.01 ng/ml vs. 49.30 ± 8.73 ng/ml, P 0.05, respectively). In the testosterone-treated group, ITT, quality of sperm, and expression of SYCP3 were markedly lower than the control group (ITT: 59.00 ± 8.67, P = 0.005; sperm number: [4.34 ± 2.45] × 106 cells/ml, P = 0.018; sperm motility: 19.53 ± 7.69%, P = 0.001; the number of SYCP3-positive cells/tubule: 30.00 ± 11.28, P < 0.001; the percentage of SYCP3-positive tubules/section 71.98 ± 8.88%, P = 0.001; the expression of SYCP3 protein: 0.71 ± 0.09, P < 0.001), and fertility was also suppressed (P < 0.05, respectively). Conclusion: SKRBT had no adverse effect on fertility potential in aging male mice. PMID:26996482

  14. Effect of Methylphenidate on Retention and Retrieval of Passive Avoidance Memory in Young and Aged Mice

    Directory of Open Access Journals (Sweden)

    Arzi

    2014-10-01

    Full Text Available Background Several studies showed that dopamine and norepinephrine improve retention and retrieval of memory. Methylphenidate is an enhancer of dopamine and norepinephrine in brain. Objectives In the present study, the effect of methylphenidate was evaluated on retention and retrieval of memory in young and aged mice using passive avoidance apparatus. Materials and Methods Animals were divided into groups (n = 8 as follows: test groups received electric shock plus methylphenidate (2.5, 5 and 10mg kg-1, i. P., control group received electric shock plus normal saline and blank group received only electric shock. In all groups, step-down latency for both retention and retrieval test of memory was measured. Methylphenidate was administered immediately after receiving electric shock in the retention test, but methylphenidate was administered 23.5 hours after receiving electric shock in the retrieval test. Results The mean of step-down latency on day 4 was significantly higher compared to day 2 (P < 0.05 in all young and aged groups of mice. The best response was attained with 5 mg/kg of methylphenidate. In memory retention test, the mean of step-down latency in young groups that received 2.5 and 5 mg/kg methylphenidate was significantly longer(P < 0.05 than aged groups. However, this difference was not significant in memory retrieval test. Conclusions Methylphenidate may improve memory retention and retrieval.

  15. Dietary lactoferrin alleviates age-related lacrimal gland dysfunction in mice.

    Directory of Open Access Journals (Sweden)

    Motoko Kawashima

    Full Text Available BACKGROUND: Decrease in lacrimal gland secretory function is related to age-induced dry eye disease. Lactoferrin, the main glycoprotein component of tears, has multiple functions, including anti-inflammatory effects and the promotion of cell growth. We investigated how oral administration of lactoferrin affects age-related lacrimal dysfunction. METHODS AND FINDINGS: Twelve-month-old male C57BL/6Cr Slc mice were randomly divided into a control fed group and an oral lactoferrin treatment group. Tear function was measured at a 6-month time-point. After euthanasia, the lacrimal glands were subjected to histological examination with 8-hydroxy-2'-deoxyguanosine (8-OHdG antibodies, and serum concentrations of 8-OHdG and hexanoyl-lysine adduct (HEL were evaluated. Additionally, monocyte chemotactic protein-1(MCP-1 and tumor necrosis factor-α (TNF-α gene expression levels were determined by real-time PCR. The volume of tear secretion was significantly larger in the treated group than in the control. Lactoferrin administration reduced inflammatory cell infiltration and the MCP-1 and TNF-α expression levels. Serum concentrations of 8-OHdG and HEL in the lactoferrin group were lower than those in the control group and were associated with attenuated 8-OHdG immunostaining of the lacrimal glands. CONCLUSION: Oral lactoferrin administration preserves lacrimal gland function in aged mice by attenuating oxidative damage and suppressing subsequent gland inflammation.

  16. Hyperbaric Oxygen Exposure Reduces Age-Related Decrease in Oxidative Capacity of the Tibialis Anterior Muscle in Mice

    Directory of Open Access Journals (Sweden)

    Takahiro Nishizaka

    2010-01-01

    Full Text Available The effects of exposure to hyperbaric oxygen on the oxidative capacity of the skeletal muscles in mice at different ages were investigated. We exposed 5-, 34-, 55-, and 88-week-old mice to 36% oxygen at 950 mmHg for 6 hours per day for 2 weeks. The activities of succinate dehydrogenase (SDH, which is a mitochondrial marker enzyme, of the tibialis anterior muscle in hyperbaric mice were compared with those in age-matched mice under normobaric conditions (21% oxygen at 760 mmHg. Furthermore, the SDH activities of type IIA and type IIB fibers in the muscle were determined using quantitative histochemical analysis. The SDH activity of the muscle in normobaric mice decreased with age. Similar results were observed in both type IIA and type IIB fibers in the muscle. The decrease in the SDH activity of the muscle was reduced in hyperbaric mice at 57 and 90 weeks. The decreased SDH activities of type IIA and type IIB fibers were reduced in hyperbaric mice at 90 weeks and at 57 and 90 weeks, respectively. We conclude that exposure to hyperbaric oxygen used in this study reduces the age-related decrease in the oxidative capacity of skeletal muscles.

  17. Ablation of neurogenesis attenuates recovery of motor function after focal cerebral ischemia in middle-aged mice.

    Directory of Open Access Journals (Sweden)

    Fen Sun

    Full Text Available Depletion of neurogenesis worsens functional outcome in young-adult mice after focal cerebral ischemia, but whether a similar effect occurs in older mice is unknown. Using middle-aged (12-month-old transgenic (DCX-TK((+ mice that express herpes simplex virus thymidine kinase (HSV-TK under control of the doublecortin (DCX promoter, we conditionally depleted DCX-positive cells in the subventricular zone (SVZ and hippocampus by treatment with ganciclovir (GCV for 14 days. Focal cerebral ischemia was induced by permanent occlusion of the middle cerebral artery (MCAO or occlusion of the distal segment of middle cerebral artery (dMCAO on day 14 of vehicle or GCV treatment and mice were killed 24 hr or 12 weeks later. Increased infarct volume or brain atrophy was found in GCV- compared to vehicle-treated middle-aged DCX-TK((+ mice, both 24 hr after MCAO and 12 weeks after dMCAO. More severe motor deficits were also observed in GCV-treated, middle-aged DCX-TK((+ transgenic mice at both time points. Our results indicate that ischemia-induced newborn neurons contribute to anatomical and functional outcome after experimental stroke in middle-aged mice.

  18. Deficiency in Poly(ADP-ribose Polymerase-1 (PARP-1 Accelerates Aging and Spontaneous Carcinogenesis in Mice

    Directory of Open Access Journals (Sweden)

    Vladimir N. Anisimov

    2008-04-01

    Full Text Available Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosylation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosylation and PARP-1 may also play an important role in aging. Here we show that PARP-1-/- mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP-1-/- mice. The incidence of spontaneous tumors in both PARP-1-/- and PARP-1+/+ groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP-1-/- mice than PARP-1+/+ mice (72% and 49%, resp.; P< .05. In addition, spontaneous tumors appear earlier in PARP-1-/- mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.

  19. Palladium and platinum nanoparticles attenuate aging-like skin atrophy via antioxidant activity in mice.

    Directory of Open Access Journals (Sweden)

    Shuichi Shibuya

    Full Text Available Cu-Zn superoxide dismutase (Sod1 loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd and platinum (Pt nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1-/- mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1-/- mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage.

  20. Experimental Tityus serrulatus scorpion envenomation: age- and sex-related differences in symptoms and mortality in mice

    Directory of Open Access Journals (Sweden)

    Pucca MB

    2011-01-01

    Full Text Available Among the various methods for evaluating animal venom toxicity, the calculation of the median lethal dose (LD50 is the most widely used. Although different protocols can be used to calculate the LD50, the source of the venom and the method of extraction, as well as the strain, age, and sex of the animal model employed, should be taken into consideration. The objective of the present study was to evaluate the influence of sex and age on the toxicity of Tityus serrulatus scorpion venom in Swiss mice. Although the symptoms of envenomation were similar in male and female animals, female mice proved to be more resistant to the venom. In females, age had no impact on the susceptibility to scorpion envenomation. Male mice were more sensitive to T. serrulatus venom. Moreover, in males, age was an important parameter since sensitivity to the venom increased with age.

  1. Ageing Fxr Deficient Mice Develop Increased Energy Expenditure, Improved Glucose Control and Liver Damage Resembling NASH

    OpenAIRE

    Bjursell, Mikael; Wedin, Marianne; Admyre, Therése; Hermansson, Majlis; Böttcher, Gerhard; Göransson, Melker; Lindén, Daniel; Bamberg, Krister; Oscarsson, Jan; Bohlooly-Y, Mohammad

    2013-01-01

    Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow d...

  2. Immunolocalization of nestin in pancreatic tissue of mice at different ages

    OpenAIRE

    Raj K Dorisetty, Sashi G Kiran, Malathi R Umrani, Sesikeran Boindala, Ramesh R Bhonde, Vijayalakshmi Venkatesan

    2008-01-01

    AIM: To localize nestin positive cells (NPC) in pancreatic tissue of mice of different ages.METHODS: Paraffin sections of 6-8 μm of fixed pancreatic samples were mounted on poly-L-lysine coated slides and used for Immunolocalization using appropriate primary antibodies (Nestin, Insulin, Glucagon), followed by addition of a fluorescently labeled secondary antibody. The antigen-antibody localization was captured using a confocal microscope (Leica SP 5 series).RESULTS: In 3-6 d pups, the NPC wer...

  3. Lung vitamin E transport processes are affected by both age and environmental oxidants in mice

    International Nuclear Information System (INIS)

    Despite the physiological importance of alpha-tocopherol (AT), the molecular mechanisms involved in maintaining cellular and tissue tocopherol levels remain to be fully characterized. Scavenger receptor B1 (SRB1), one of a large family of scavenger receptors, has been shown to facilitate AT transfer from HDL to peripheral tissues via apo A-1-mediated processes and to be important in the delivery of AT to the lung cells. In the present studies the effects of age and two environmental oxidants ozone (O3) (0.25 ppm 6 h/day) and cigarette smoke (CS) (60 mg/m3 6 h/day) for 4 days on selected aspects of AT transport in murine lung tissues were assessed. While AT levels were 25% higher (p 3 or CS at the doses used had no effect. Gene expression levels, determined by RT-PCR of AT transport protein (ATTP), SRB1, CD36, ATP binding cassette 3 (ABCA3) and ABCA1 and protein levels, determined by Western blots for SRB1, ATTP and ABCA1 were assessed. Aged mouse lung showed a lower levels of ATTP, ABCA3 and SRB1 and a higher level CD36 and ABCA1. Acute exposure to either O3 or CS induced declines in ATTP and SRB1 in both aged and young mice lung. CD36 increased in both young and aged mice lung upon exposure to O3 and CS. These findings suggest that both age and environmental oxidant exposure affect pathways related to lung AT homeostasis and do so in a way that favors declines in lung AT. However, given the approach taken, the effects cannot be traced to changes in these pathways or AT content in any specific lung associated cell type and thus highlight the need for further follow-up studies looking at specific lung associated cell types

  4. Improved muscle function and quality after diet intervention with leucine-enriched whey and antioxidants in antioxidant deficient aged mice

    Science.gov (United States)

    van Dijk, Miriam; Dijk, Francina J.; Bunschoten, Annelies; van Dartel, Dorien A.M.; van Norren, Klaske; Walrand, Stephane; Jourdan, Marion; Verlaan, Sjors; Luiking, Yvette

    2016-01-01

    Antioxidant (AOX) deficiencies are commonly observed in older adults and oxidative stress has been suggested to contribute to sarcopenia. Here we investigate if 1) low levels of dietary antioxidants had a negative impact on parameters of muscle mass, function and quality, and 2) to study if nutritional interventions with AOX and/or leucine-enriched whey protein could improve these muscle parameters in aged mice. 18-months-old mice were fed a casein-based antioxidant-deficient (lowox) diet or a casein-based control-diet (CTRL) for 7 months. During the last 3 months, lowox-mice were subjected to either: a) continued lowox, b) supplementation with vitamin A/E, Selenium and Zinc (AOX), c) substitution of casein with leucine-enriched whey protein (PROT) or d) a combination of both AOX and PROT (TOTAL). After 7 months lowox-mice displayed lower muscle strength and more muscle fatigue compared to CTRL. Compared to lowox-mice, PROT-mice showed improved muscle power, grip strength and less muscle fatigue. AOX-mice showed improved oxidative status, less muscle fatigue, improved grip strength and mitochondrial dynamics compared to lowox-mice. The TOTAL-mice showed the combined effects of both interventions compared to lowox-mice. In conclusion, nutritional intervention with AOX and/or leucine-enriched whey protein can play a role in improving muscle health in a AOX-deficient mouse model. PMID:26943770

  5. Improved muscle function and quality after diet intervention with leucine-enriched whey and antioxidants in antioxidant deficient aged mice.

    Science.gov (United States)

    van Dijk, Miriam; Dijk, Francina J; Bunschoten, Annelies; van Dartel, Dorien A M; van Norren, Klaske; Walrand, Stephane; Jourdan, Marion; Verlaan, Sjors; Luiking, Yvette

    2016-04-01

    Antioxidant (AOX) deficiencies are commonly observed in older adults and oxidative stress has been suggested to contribute to sarcopenia. Here we investigate if 1) low levels of dietary antioxidants had a negative impact on parameters of muscle mass, function and quality, and 2) to study if nutritional interventions with AOX and/or leucine-enriched whey protein could improve these muscle parameters in aged mice. 18-months-old mice were fed a casein-based antioxidant-deficient (lowox) diet or a casein-based control-diet (CTRL) for 7 months. During the last 3 months, lowox-mice were subjected to either: a) continued lowox, b) supplementation with vitamin A/E, Selenium and Zinc (AOX), c) substitution of casein with leucine-enriched whey protein (PROT) or d) a combination of both AOX and PROT (TOTAL). After 7 months lowox-mice displayed lower muscle strength and more muscle fatigue compared to CTRL. Compared to lowox-mice, PROT-mice showed improved muscle power, grip strength and less muscle fatigue. AOX-mice showed improved oxidative status, less muscle fatigue, improved grip strength and mitochondrial dynamics compared to lowox-mice. The TOTAL-mice showed the combined effects of both interventions compared to lowox-mice. In conclusion, nutritional intervention with AOX and/or leucine-enriched whey protein can play a role in improving muscle health in a AOX-deficient mouse model. PMID:26943770

  6. The retinoic acid receptor agonist Am80 increases hippocampal ADAM10 in aged SAMP8 mice.

    Science.gov (United States)

    Kitaoka, Kazuyoshi; Shimizu, Noriyuki; Ono, Koji; Chikahisa, Sachiko; Nakagomi, Madoka; Shudo, Koichi; Ishimura, Kazunori; Séi, Hiroyoshi; Yoshizaki, Kazuo

    2013-09-01

    The retinoic acid (RA, a vitamin A metabolite) receptor (RAR) is a transcription factor. Vitamin A/RA administration improves the Alzheimer's disease (AD)- and age-related attenuation of memory/learning in mouse models. Recently, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as a key molecule in RA-mediated anti-AD mechanisms. We investigated the effect of chronic administration of the RAR agonist Am80 (tamibarotene) on ADAM10 expression in senescence-accelerated mice (SAMP8). Moreover, we estimated changes in the expression of the amyloid precursor protein (APP), amyloid beta (Aβ), and hairy/enhancer of split (Hes), which are mediated by ADAM10. Spatial working memory and the levels of a hippocampal proliferation marker (Ki67) were also assessed in these mice. ADAM10 mRNA and protein expression was significantly reduced in the hippocampus of 13-month-old SAMP8 mice; their expression improved significantly after Am80 administration. Further, after Am80 administration, the expression levels of Hes5 and Ki67 were restored and the deterioration of working memory was suppressed, whereas APP and Aβ levels remained unchanged. Our results suggest that Am80 administration effectively improves dementia by activating the hippocampal ADAM10-Notch-Hes5 proliferative pathway. PMID:23624141

  7. Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice.

    Science.gov (United States)

    Roubertoux, Pierre L; Sluyter, Frans; Carlier, Michèle; Marcet, Brice; Maarouf-Veray, Fatima; Chérif, Chabane; Marican, Charlotte; Arrechi, Patricia; Godin, Fabienne; Jamon, Marc; Verrier, Bernard; Cohen-Salmon, Charles

    2003-09-01

    Several lines of evidence indicate an association between mitochondrial DNA (mtDNA) and the functioning of the nervous system. As neuronal development and structure as well as axonal and synaptic activity involve mitochondrial genes, it is not surprising that most mtDNA diseases are associated with brain disorders. Only one study has suggested an association between mtDNA and cognition, however. Here we provide direct evidence of mtDNA involvement in cognitive functioning. Total substitution of mtDNA was achieved by 20 repeated backcrosses in NZB/BlNJ (N) and CBA/H (H) mice with different mtDNA origins. All 13 mitochondrial genes were expressed in the brains of the congenic quartet. In interaction with nuclear DNA (nDNA), mtDNA modified learning, exploration, sensory development and the anatomy of the brain. The effects of mtDNA substitution persisted with age, increasing in magnitude as the mice got older. We observed different effects with input of mtDNA from N versus H mice, varying according to the phenotypes. Exchanges of mtDNA may produce phenotypes outside the range of scores observed in the original mitochondrial and nuclear combinations. These findings show that mitochondrial polymorphisms are not as neutral as was previously believed. PMID:12923532

  8. Sox4 Links Tumor Suppression to Accelerated Aging in Mice by Modulating Stem Cell Activation

    Directory of Open Access Journals (Sweden)

    Miguel Foronda

    2014-07-01

    Full Text Available Sox4 expression is restricted in mammals to embryonic structures and some adult tissues, such as lymphoid organs, pancreas, intestine, and skin. During embryogenesis, Sox4 regulates mesenchymal and neural progenitor survival, as well as lymphocyte and myeloid differentiation, and contributes to pancreas, bone, and heart development. Aberrant Sox4 expression is linked to malignant transformation and metastasis in several types of cancer. To understand the role of Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display accelerated aging and reduced cancer incidence. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4cKO in stratified epithelia. Sox4cKO mice show increased skin stem cell quiescence and resistance to chemical carcinogenesis concomitantly with downregulation of cell cycle, DNA repair, and activated hair follicle stem cell pathways. Altogether, these findings highlight the importance of Sox4 in regulating adult tissue homeostasis and cancer.

  9. Environmental enrichment strengthens corticocortical interactions and reduces amyloid-β oligomers in aged mice.

    Science.gov (United States)

    Mainardi, Marco; Di Garbo, Angelo; Caleo, Matteo; Berardi, Nicoletta; Sale, Alessandro; Maffei, Lamberto

    2014-01-01

    Brain aging is characterized by global changes which are thought to underlie age-related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-β (Aβ) oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE), a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP) recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Aβ oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Aβ oligomers and increased synthesis of the Aβ-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes. PMID:24478697

  10. ENVIRONMENTAL ENRICHMENT STRENGTHENS CORTICOCORTICAL INTERACTIONS AND REDUCES AMYLOID-β OLIGOMERS IN AGED MICE

    Directory of Open Access Journals (Sweden)

    Marco eMainardi

    2014-01-01

    Full Text Available Brain aging is characterized by global changes which are thought to underlie age-related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-β (Aβ oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE, a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Aβ oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Aβ oligomers and increased synthesis of the Aβ-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes.

  11. Age-related changes in the function and structure of the peripheral sensory pathway in mice.

    Science.gov (United States)

    Canta, Annalisa; Chiorazzi, Alessia; Carozzi, Valentina Alda; Meregalli, Cristina; Oggioni, Norberto; Bossi, Mario; Rodriguez-Menendez, Virginia; Avezza, Federica; Crippa, Luca; Lombardi, Raffaella; de Vito, Giuseppe; Piazza, Vincenzo; Cavaletti, Guido; Marmiroli, Paola

    2016-09-01

    This study is aimed at describing the changes occurring in the entire peripheral nervous system sensory pathway along a 2-year observation period in a cohort of C57BL/6 mice. The neurophysiological studies evidenced significant differences in the selected time points corresponding to childhood, young adulthood, adulthood, and aging (i.e., 1, 7, 15, and 25 months of age), with a parabolic course as function of time. The pathological assessment allowed to demonstrate signs of age-related changes since the age of 7 months, with a remarkable increase in both peripheral nerves and dorsal root ganglia at the subsequent time points. These changes were mainly in the myelin sheaths, as also confirmed by the Rotating-Polarization Coherent-Anti-stokes-Raman-scattering microscopy analysis. Evident changes were also present at the morphometric analysis performed on the peripheral nerves, dorsal root ganglia neurons, and skin biopsies. This extensive, multimodal characterization of the peripheral nervous system changes in aging provides the background for future mechanistic studies allowing the selection of the most appropriate time points and readouts according to the investigation aims. PMID:27459934

  12. Early signs of pathological cognitive aging in mice lacking high-affinity nicotinic receptors.

    Directory of Open Access Journals (Sweden)

    Eleni eKonsolaki

    2016-04-01

    Full Text Available In order to address pathological cognitive decline effectively, it is critical to adopt early preventive measures in individuals considered at risk. It is therefore essential to develop approaches that identify such individuals before the onset of irreversible dementia. Α deficient cholinergic system has been consistently implicated as one of the main factors associated with a heightened vulnerability to the aging process. In the present study we used mice lacking high affinity nicotinic receptors (β2-/-, which have been proposed as an animal model of accelerated/premature cognitive aging. Our aim was to identify behavioural signs that could serve as indicators or predictors of impending cognitive decline. We used test batteries in order to assess cognitive functions and additional tasks to investigate spontaneous behaviours, such as species-specific activities and exploration/locomotion in a novel environment. Our data confirm and extend the hypothesis that β2-/- animals exhibit age-related cognitive impairments, manifested in both spatial learning and recognition memory tasks. In addition, we reveal deficits in spontaneous behaviour and habituation processes earlier in life. To our knowledge, this is the first study to perform an extensive behavioural examination of an animal model of premature cognitive aging, and our results suggest that β2-nAChR dependent cognitive deterioration progressively evolves from initial subtle behavioural changes to global dementia due to the combined effect of the neuropathology and aging.

  13. Suppressing an anti-inflammatory cytokine reveals a strong age-dependent survival cost in mice.

    Directory of Open Access Journals (Sweden)

    Virginia Belloni

    Full Text Available BACKGROUND: The central paradigm of ecological immunology postulates that selection acts on immunity as to minimize its cost/benefit ratio. Costs of immunity may arise because the energetic requirements of the immune response divert resources that are no longer available for other vital functions. In addition to these resource-based costs, mis-directed or over-reacting immune responses can be particularly harmful for the host. In spite of the potential importance of immunopathology, most studies dealing with the evolution of the immune response have neglected such non resource-based costs. To keep the immune response under control, hosts have evolved regulatory pathways that should be considered when studying the target of the selection pressures acting on immunity. Indeed, variation in regulation may strongly modulate the negative outcome of immune activation, with potentially important fitness consequences. METHODOLOGY/PRINCIPAL FINDINGS: Here, we experimentally assessed the survival costs of reduced immune regulation by inhibiting an anti-inflammatory cytokine (IL-10 with anti-IL-10 receptor antibodies (anti-IL-10R in mice that were either exposed to a mild inflammation or kept as control. The experiment was performed on young (3 months and old (15 months individuals, as to further assess the age-dependent cost of suppressing immune regulation. IL-10 inhibition induced high mortality in old mice exposed to the mild inflammatory insult, whereas no mortality was observed in young mice. However, young mice experienced a transitory lost in body mass when injected with the anti-IL-10R antibodies, showing that the treatment was to a lesser extent also costly for young individuals. CONCLUSIONS: These results suggest a major role of immune regulation that deserves attention when investigating the evolution of immunity, and indicate that the capacity to down-regulate the inflammatory response is crucial for late survival and longevity.

  14. Evaluation of Effect of Oleuropein on Skin Wound Healing in Aged Male Balb/c Mice

    Directory of Open Access Journals (Sweden)

    Fereshteh Mehraein

    2014-03-01

    Full Text Available Objective: Olive oil and olive leaf extract are used for treatment of skin diseases and wounds in Iran. The main component of olive leaf extract is Oleuropein. This research is focused on the effects of Oleuropein on skin wound healing in aged male Balb/c mice. Materials and Methods: In this experimental study, Oleuropein was provided by Razi Herbal Medicine Institute, Lorestan, Iran. Twenty four male Balb/c mice, 16 months of age, were divided equally into control and experimental groups. Under ether anesthesia, the hairs on the back of neck of all groups were shaved and a 1 cm long full-thickness incision was made. The incision was then left un-sutured. The experimental group received intradermal injections with a daily single dose of 50 mg/kg Oleuropein for a total period of 7 days. The control group received only distilled water. On days 3 and 7 after making the incision and injections, mice were sacrificed, and the skin around incision area was dissected and stained by hematoxylin and eosin (H&E and Van Gieson’s methods for tissue analysis. In addition, western blot analysis was carried out to evaluate the level of vascular endothelial growth factor (VEGF protein expression. The statistical analysis was performed using SPSS (SPSS Inc., Chicago, USA. The t test was applied to assess the significance of changes between control and experimental groups. Results: Oleuropein not only reduced cell infiltration in the wound site on days 3 and 7 post incision, but also a significant increase in collagen fiber deposition and more advanced re- epithelialization were observed (p<0.05 in the experimental group as compared to the control group. The difference of hair follicles was not significant between the two groups at the same period of time. Furthermore, western blot analysis showed an increased in VEGF protein level from samples collected on days 3 and 7 post-incision of experimental group as compared to the control group (p<0.05. Conclusion

  15. Bach1 Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

    Directory of Open Access Journals (Sweden)

    Kazushige Ota

    2014-01-01

    Full Text Available Oxidative stress contributes to both aging and tumorigenesis. The transcription factor Bach1, a regulator of oxidative stress response, augments oxidative stress by repressing the expression of heme oxygenase-1 (HO-1 gene (Hmox1 and suppresses oxidative stress-induced cellular senescence by restricting the p53 transcriptional activity. Here we investigated the lifelong effects of Bach1 deficiency on mice. Bach1-deficient mice showed longevity similar to wild-type mice. Although HO-1 was upregulated in the cells of Bach1-deficient animals, the levels of ROS in Bach1-deficient HSCs were comparable to those in wild-type cells. Bach1−/−; p53−/− mice succumbed to spontaneous cancers as frequently as p53-deficient mice. Bach1 deficiency significantly altered transcriptome in the liver of the young mice, which surprisingly became similar to that of wild-type mice during the course of aging. The transcriptome adaptation to Bach1 deficiency may reflect how oxidative stress response is tuned upon genetic and environmental perturbations. We concluded that Bach1 deficiency and accompanying overexpression of HO-1 did not influence aging or p53 deficiency-driven tumorigenesis. Our results suggest that it is useful to target Bach1 for acute injury responses without inducing any apparent deteriorative effect.

  16. Enhanced inflammation in aged mice following infection with Streptococcus pneumoniae is associated with decreased IL-10 and augmented chemokine production.

    Science.gov (United States)

    Williams, Andrew E; José, Ricardo J; Brown, Jeremy S; Chambers, Rachel C

    2015-03-15

    Streptococcus pneumoniae is the most common cause of severe pneumonia in the elderly. However, the impact of aging on the innate inflammatory response to pneumococci is poorly defined. We compared the innate immune response in old vs. young adult mice following infection with S. pneumoniae. The accumulation of neutrophils recovered from bronchoalveolar lavage fluid and lung homogenates was increased in aged compared with young adult mice, although bacterial outgrowth was similar in both age groups, as were markers of microvascular leak. Aged mice had similar levels of IL-1β, TNF, IFN-γ, IL-17, and granulocyte colony-stimulating factor following S. pneumoniae infection, compared with young mice, but increased levels of the chemokines CXCL9, CXCL12, CCL3, CCL4, CCL5, CCL11, and CCL17. Moreover, levels of IL-10 were significantly lower in aged animals. Neutralization of IL-10 in infected young mice was associated with increased neutrophil recruitment but no decrease in bacterial outgrowth. Furthermore, IL-10 neutralization resulted in increased levels of CCL3, CCL5, and CXCL10. We conclude that aging is associated with enhanced inflammatory responses following S. pneumoniae infection as a result of a compromised immunomodulatory cytokine response. PMID:25595646

  17. Long-Lived αMUPA Mice Show Attenuation of Cardiac Aging and Leptin-Dependent Cardioprotection.

    Directory of Open Access Journals (Sweden)

    Esther Levy

    Full Text Available αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.

  18. Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice.

    Science.gov (United States)

    Li, Xue-Yan; Wang, Fang; Chen, Gui-Hai; Li, Xue-Wei; Yang, Qi-Gang; Cao, Lei; Yan, Wen-Wen

    2016-06-01

    Data shows that inflammation during pregnancy significantly exerts a long-term influence on offspring, such as increasing the risk of adult cognition decline in animals. However, it is unclear whether gestational inflammation affects the neurobehavioral and neurobiochemical outcomes in the mother-self during aging. In this study, pregnant CD-1 mice intraperitoneally received lipopolysaccharide (LPS) in two doses (25 and 50 g/kg, respectively) or normal saline daily during gestational days 15-17. At the age of 15 months, a battery of behavioral tasks was employed to evaluate their species-typical behaviors, sensorimotor ability, anxiety levels, and spatial learning and memory abilities. An immunohistochemical method was utilized preliminarily to detect neurobiochemical indicators consisting of amyloid-β, phosphorylated tau, presynaptic proteins synaptotagmin-1 and syntaxin-1, glial fibrillary acidic protein (GFAP), and histone-4 acetylation on the K8 site (H4K8ac). The behavioral results showed that LPS exposure during pregnancy exacerbated a decline in 15-month-old CD-1 mice's abilities to nest, their sensorimotor and spatial learning and memory capabilities, and increased their anxiety levels. The neurobiochemical results indicated that gestational LPS exposure also intensified age-related hippocampal changes, including increased amyloid-β42, phosphorylated tau, synaptotagmin-1 and GFAP, and decreased syntaxin-1 and H4K8ac. Our results suggested that the inflammatory insult during pregnancy could be an important risk factor for the development of Alzheimer's disease, and the H4K8 acetylation might play an important role in the underlying mechanism. This study offers a perspective for improving strategies that support healthy development and successful aging. PMID:27194408

  19. Paraquat induces selective dopaminergic nigrostriatal degeneration in aging C57BL/6 mice

    Institute of Scientific and Technical Information of China (English)

    LI Xia; YIN Jun; CHENG Chun-mei; SUN Jin-lai; LI Zheng; WU Ying-liang

    2005-01-01

    Background Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium), a widely used herbicide that is structurally similar to the known dopaminergic neurotoxicant MPTP (1-methyl-1,2,3,6-tetrahydropyridine), has been suggested as a potential etiologic factor for the development of Parkinson's disease (PD). Aging is an accepted risk factor for idiopathic Parkinson's disease. The aim of this study was to test the hypothesis that paraquat could induce PD-like nigrostriatal dopaminergic degeneration in aging C57BL/6 mice.Methods Senile male C57BL/6 mice were intraperitoneally injected with either saline or PQ at 2-day intervals for a total of 10 doses. Locomotor activity and performance on the pole test were measured 7 days after the last injection and animals were sacrificed one day later. Level of dopamine (DA) and its metabolites levels in the striatum were measured by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD), and numbers of tyrosine hydroxylase (TH) positive neurons were estimated using immunohistochemistry.Results Locomotor activities were significantly decreased and the behavioral performance on the pole test were significantly impaired in the PQ treated group. Level of DA and its metabolites levels in the striatum were declined by 8 days after the last injection. Immunohistochemical analyses showed that PQ was associated with a reduction in numbers of tyrosine hydroxylase positive neurons.Conclusions Long-term repeated exposes to PQ can selectively impair the nigrostriatal dopaminergic system of senile mice, suggesting that PQ could play an important role in the pathogenesis of Parkinson's disease (PD). Our results also validate a novel model of PD induced by exposure to a toxic environmental agent.

  20. Adult but Not Aged C57BL/6 Male Mice Are Capable of Using Geometry for Orientation

    Science.gov (United States)

    Schachner, Melitta; Morellini, Fabio; Fellini, Laetitia

    2006-01-01

    Geometry, e.g., the shape of the environment, can be used by numerous animal species to orientate, but data concerning the mouse are lacking. We addressed the question of whether mice are capable of using geometry for navigating. To test whether aging could affect searching strategies, we compared adult (3- to 5-mo old) and aged (20- to 21-mo old)…

  1. Assessing functional performance in the mdx mouse model.

    Science.gov (United States)

    Aartsma-Rus, Annemieke; van Putten, Maaike

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder for which no cure is available. Nevertheless, several potential pharmaceutical compounds and gene therapy approaches have progressed into clinical trials. With improvement in muscle function being the most important end point in these trials, a lot of emphasis has been placed on setting up reliable, reproducible, and easy to perform functional tests to pre clinically assess muscle function, strength, condition, and coordination in the mdx mouse model for DMD. Both invasive and noninvasive tests are available. Tests that do not exacerbate the disease can be used to determine the natural history of the disease and the effects of therapeutic interventions (e.g. forelimb grip strength test, two different hanging tests using either a wire or a grid and rotarod running). Alternatively, forced treadmill running can be used to enhance disease progression and/or assess protective effects of therapeutic interventions on disease pathology. We here describe how to perform these most commonly used functional tests in a reliable and reproducible manner. Using these protocols based on standard operating procedures enables comparison of data between different laboratories. PMID:24747372

  2. Early Signs of Pathological Cognitive Aging in Mice Lacking High-Affinity Nicotinic Receptors.

    Science.gov (United States)

    Konsolaki, Eleni; Tsakanikas, Panagiotis; Polissidis, Alexia V; Stamatakis, Antonios; Skaliora, Irini

    2016-01-01

    In order to address pathological cognitive decline effectively, it is critical to adopt early preventive measures in individuals considered at risk. It is therefore essential to develop approaches that identify such individuals before the onset of irreversible dementia. A deficient cholinergic system has been consistently implicated as one of the main factors associated with a heightened vulnerability to the aging process. In the present study we used mice lacking high affinity nicotinic receptors (β2-/-), which have been proposed as an animal model of accelerated/premature cognitive aging. Our aim was to identify behavioral signs that could serve as indicators or predictors of impending cognitive decline. We used test batteries in order to assess cognitive functions and additional tasks to investigate spontaneous behaviors, such as species-specific activities and exploration/locomotion in a novel environment. Our data confirm the hypothesis that β2-/- animals exhibit age-related cognitive impairments in spatial learning. In addition, they document age-related deficits in other areas, such as recognition memory, burrowing and nesting building, thereby extending the validity of this animal model for the study of pathological aging. Finally, our data reveal deficits in spontaneous behavior and habituation processes that precede the onset of cognitive decline and could therefore be useful as a non-invasive behavioral screen for identifying animals at risk. To our knowledge, this is the first study to perform an extensive behavioral assessment of an animal model of premature cognitive aging, and our results suggest that β2-nAChR dependent cognitive deterioration progressively evolves from initial subtle behavioral changes to global dementia due to the combined effect of the neuropathology and aging. PMID:27199738

  3. Enhanced humoral response to influenza vaccine in aged mice with a novel adjuvant, rOv-ASP-1.

    Science.gov (United States)

    Jiang, Jiu; Fisher, Erin M; Concannon, Mark; Lustigman, Sara; Shen, Hao; Murasko, Donna M

    2016-02-10

    Immunization is the best way to prevent seasonal epidemics and pandemics of influenza. There are two kinds of influenza vaccines available in the United States: an inactivated vaccine (TIV) and an attenuated vaccine; however, only TIV is approved for immunization of the elderly population. While the aged population has the highest rate of influenza vaccination, the protective efficacy is low as evidenced by elderly individuals having the highest mortality associated with influenza. Recently, we reported that an adjuvant derived from the helminth parasite Onchocerca volvulus, named O. volvulus activation-associated secreted protein-1 (Ov-ASP-1), can significantly enhance the protective efficacy of an inactivated vaccine (TIV) in young adult mice. In the current study, we examined whether this recombinant Ov-ASP-1 (rOv-ASP-1) can enhance the efficacy of TIV in aged mice as well. While primary immunization with TIV alone produced only a low level of influenza-specific antibodies (total IgG, IgG1, and IgG2c) in aged mice, the antibody levels were significantly increased after immunization with TIV+rOv-ASP-1. More importantly, the level of the total IgG in aged mice administered TIV+rOv-ASP-1 was comparable to that of young adult mice immunized with TIV alone. Co-administration of rOv-ASP-1 induced a low level of cross-reactive antibody and enhanced the protective efficacy of TIV in aged mice, reflected by significantly increased survival after challenge with a heterologous influenza virus. rOv-ASP-1 was also superior to the conventional adjuvant alum in inducing specific IgG after TIV immunization in aged mice, and in conferring protection after challenge. These results demonstrate that rOv-ASP-1 may serve as a potential adjuvant for influenza vaccine to improve the efficacy of protection in the elderly. PMID:26795365

  4. Influence of Age on Brain Edema Formation, Secondary Brain Damage and Inflammatory Response after Brain Trauma in Mice

    Science.gov (United States)

    Timaru-Kast, Ralph; Luh, Clara; Gotthardt, Philipp; Huang, Changsheng; Schäfer, Michael K.; Engelhard, Kristin; Thal, Serge C.

    2012-01-01

    After traumatic brain injury (TBI) elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. However, experimental TBI research is primarily performed in young animals. Aim of the present study was to clarify whether age affects functional outcome, neuroinflammation and secondary brain damage after brain trauma in mice. Young (2 months) and old (21 months) male C57Bl6N mice were anesthetized and subjected to a controlled cortical impact injury (CCI) on the right parietal cortex. Animals of both ages were randomly assigned to 15 min, 24 h, and 72 h survival. At the end of the observation periods, contusion volume, brain water content, neurologic function, cerebral and systemic inflammation (CD3+ T cell migration, inflammatory cytokine expression in brain and lung, blood differential cell count) were determined. Old animals showed worse neurological function 72 h after CCI and a high mortality rate (19.2%) compared to young (0%). This did not correlate with histopathological damage, as contusion volumes were equal in both age groups. Although a more pronounced brain edema formation was detected in old mice 24 hours after TBI, lack of correlation between brain water content and neurological deficit indicated that brain edema formation is not solely responsible for age-dependent differences in neurological outcome. Brains of old naïve mice were about 8% smaller compared to young naïve brains, suggesting age-related brain atrophy with possible decline in plasticity. Onset of cerebral inflammation started earlier and primarily ipsilateral to damage in old mice, whereas in young mice inflammation was delayed and present in both hemispheres with a characteristic T cell migration pattern. Pulmonary interleukin 1β expression was up-regulated after cerebral injury only in young, not aged mice. The results therefore indicate that old animals are prone to functional deficits and strong ipsilateral cerebral inflammation

  5. Influence of age on brain edema formation, secondary brain damage and inflammatory response after brain trauma in mice.

    Directory of Open Access Journals (Sweden)

    Ralph Timaru-Kast

    Full Text Available After traumatic brain injury (TBI elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. However, experimental TBI research is primarily performed in young animals. Aim of the present study was to clarify whether age affects functional outcome, neuroinflammation and secondary brain damage after brain trauma in mice. Young (2 months and old (21 months male C57Bl6N mice were anesthetized and subjected to a controlled cortical impact injury (CCI on the right parietal cortex. Animals of both ages were randomly assigned to 15 min, 24 h, and 72 h survival. At the end of the observation periods, contusion volume, brain water content, neurologic function, cerebral and systemic inflammation (CD3+ T cell migration, inflammatory cytokine expression in brain and lung, blood differential cell count were determined. Old animals showed worse neurological function 72 h after CCI and a high mortality rate (19.2% compared to young (0%. This did not correlate with histopathological damage, as contusion volumes were equal in both age groups. Although a more pronounced brain edema formation was detected in old mice 24 hours after TBI, lack of correlation between brain water content and neurological deficit indicated that brain edema formation is not solely responsible for age-dependent differences in neurological outcome. Brains of old naïve mice were about 8% smaller compared to young naïve brains, suggesting age-related brain atrophy with possible decline in plasticity. Onset of cerebral inflammation started earlier and primarily ipsilateral to damage in old mice, whereas in young mice inflammation was delayed and present in both hemispheres with a characteristic T cell migration pattern. Pulmonary interleukin 1β expression was up-regulated after cerebral injury only in young, not aged mice. The results therefore indicate that old animals are prone to functional deficits and strong ipsilateral cerebral

  6. Propeptide-mediated inhibition of myostatin increases muscle mass through inhibiting proteolytic pathways in aged mice.

    Science.gov (United States)

    Collins-Hooper, Henry; Sartori, Roberta; Macharia, Raymond; Visanuvimol, Korntip; Foster, Keith; Matsakas, Antonios; Flasskamp, Hannah; Ray, Steve; Dash, Philip R; Sandri, Marco; Patel, Ketan

    2014-09-01

    Mammalian aging is accompanied by a progressive loss of skeletal muscle, a process called sarcopenia. Myostatin, a secreted member of the transforming growth factor-β family of signaling molecules, has been shown to be a potent inhibitor of muscle growth. Here, we examined whether muscle growth could be promoted in aged animals by antagonizing the activity of myostatin through the neutralizing activity of the myostatin propeptide. We show that a single injection of an AAV8 virus expressing the myostatin propeptide induced an increase in whole body weights and all muscles examined within 7 weeks of treatment. Our cellular studies demonstrate that muscle enlargement was due to selective fiber type hypertrophy, which was accompanied by a shift toward a glycolytic phenotype. Our molecular investigations elucidate the mechanism underpinning muscle hypertrophy by showing a decrease in the expression of key genes that control ubiquitin-mediated protein breakdown. Most importantly, we show that the hypertrophic muscle that develops as a consequence of myostatin propeptide in aged mice has normal contractile properties. We suggest that attenuating myostatin signaling could be a very attractive strategy to halt and possibly reverse age-related muscle loss. PMID:24414825

  7. Long-term physical exercise retards trabecular bone loss in lumbar vertebrae of aging female mice

    Energy Technology Data Exchange (ETDEWEB)

    Silbermann, M.; Bar-Shira-Maymon, B.; Coleman, R.; Reznick, A.; Weisman, Y.; Steinhagen-Thiessen, E.; von der Mark, H.; von der Mark, K. (Rappaport Family Institute for Research in the Medical Sciences, Technion, Haifa (Israel))

    1990-02-01

    The present study examined the effect of long-term, moderate physical exercise on trabecular bone volume (TBV), calcium content, 3H-proline uptake, and the activities of alkaline and acid phosphatases in lumbar vertebrae of aging and senescent mice. It became apparent that if physical activity starts at an early stage of life, i.e., prior to middle age and is extended until old age, it exerts beneficial effects on trabecular bone mass and mineralization. Such a positive effect is not obtained if the training program is initiated after middle age. The training-induced reduction in bone loss was accompanied by a significant decrease in acid phosphatase activity whereas no changes took place with regard to the activity of alkaline phosphatase. Long-term physical exercise also enhanced the uptake of 3H-proline by lining cells along the bone trabecules. In spite of its moderate nature, the endured training program served as a stress factor for the involved animals, a fact that was manifested by an increase in the serum levels of corticosterone. Thus, it seems that whereas young animals respond favorably to such a stimulatory stress, older animals lose this ability of adaptation.

  8. Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age.

    Directory of Open Access Journals (Sweden)

    Amita Vaidya

    2014-07-01

    Full Text Available Accumulation of genome rearrangements is a characteristic of aged tissues. Since genome rearrangements result from faulty repair of DNA double strand breaks (DSBs, we hypothesized that DNA DSB repair becomes less efficient with age. The Non-Homologous End Joining (NHEJ pathway repairs a majority of DSBs in vertebrates. To examine age-associated changes in NHEJ, we have generated an R26NHEJ mouse model in which a GFP-based NHEJ reporter cassette is knocked-in to the ROSA26 locus. In this model, NHEJ repair of DSBs generated by the site-specific endonuclease, I-SceI, reconstitutes a functional GFP gene. In this system NHEJ efficiency can be compared across tissues of the same mouse and in mice of different age. Using R26NHEJ mice, we found that NHEJ efficiency was higher in the skin, lung, and kidney fibroblasts, and lower in the heart fibroblasts and brain astrocytes. Furthermore, we observed that NHEJ efficiency declined with age. In the 24-month old animals compared to the 5-month old animals, NHEJ efficiency declined 1.8 to 3.8-fold, depending on the tissue, with the strongest decline observed in the skin fibroblasts. The sequence analysis of 300 independent NHEJ repair events showed that, regardless of age, mice utilize microhomology sequences at a significantly higher frequency than expected by chance. Furthermore, the frequency of microhomology-mediated end joining (MMEJ events increased in the heart and lung fibroblasts of old mice, suggesting that NHEJ becomes more mutagenic with age. In summary, our study provides a versatile mouse model for the analysis of NHEJ in a wide range of tissues and demonstrates that DNA repair by NHEJ declines with age in mice, which could provide a mechanism for age-related genomic instability and increased cancer incidence with age.

  9. Rescue of dystrophin expression in mdx mouse muscle by RNA/DNA oligonucleotides

    OpenAIRE

    Rando, Thomas A.; Disatnik, Marie-Helene; Zhou, Lucy Z.-H.

    2000-01-01

    Chimeric RNA/DNA oligonucleotides (“chimeraplasts”) have been shown to induce single base alterations in genomic DNA both in vitro and in vivo. The mdx mouse strain has a point mutation in the dystrophin gene, the consequence of which is a muscular dystrophy resulting from deficiency of the dystrophin protein in skeletal muscle. To test the feasibility of chimeraplast-mediated gene therapy for muscular dystrophies, we used a chimeraplast (designated “MDX1”) designed to correct the point mutat...

  10. Influence of age and ways of treatment in the parasitemia in mice infected with Trypanosoma cruzi treated with high potency biotherapy

    OpenAIRE

    Silvana Marques Araujo; Fabiana Nabarro Ferraz; Camila Fernanda Brustolin; Neide Martins Moreira; Caroline Felicio Braga; Paula Fernanda Massini; Denise Lessa Aleixo

    2011-01-01

    Introduction: The infection of mice by Trypanosoma cruzi is well known, making this a good model for understanding the effect of highly diluted medications. Mice of different ages show different responses to biotherapic T. cruzi [1]. Other data from our laboratory using biotherapic treatment at low potencies show that long lasting treatment has a better effect in mice infected with T. cruzi. However, the use of high potency biotherapics in mice of different ages infected with T. cruzi has not...

  11. Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice.

    Directory of Open Access Journals (Sweden)

    Virginie F Labrousse

    Full Text Available Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA and eicosapentaenoic acid (EPA are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old and aged (22-month-old mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects.

  12. Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice.

    Directory of Open Access Journals (Sweden)

    Claudia Nicolaije

    Full Text Available Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for skeletal homeostasis with age and support the idea that accumulation of damage interferes with normal skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structure and strength.

  13. Effects of Long-Term Rice Bran Extract Supplementation on Survival, Cognition and Brain Mitochondrial Function in Aged NMRI Mice.

    Science.gov (United States)

    Hagl, Stephanie; Asseburg, Heike; Heinrich, Martina; Sus, Nadine; Blumrich, Eva-Maria; Dringen, Ralf; Frank, Jan; Eckert, Gunter P

    2016-09-01

    Aging represents a major risk factor for the development of neurodegenerative diseases like Alzheimer's disease (AD). As mitochondrial dysfunction plays an important role in brain aging and occurs early in the development of AD, the prevention of mitochondrial dysfunction might help to slow brain aging and the development of neurodegenerative diseases. Rice bran extract (RBE) contains high concentrations of vitamin E congeners and γ-oryzanol. We have previously shown that RBE increased mitochondrial function and protected from mitochondrial dysfunction in vitro and in short-term in vivo feeding studies. To mimic the use of RBE as food additive, we have now investigated the effects of a long-term (6 months) feeding of RBE on survival, behavior and brain mitochondrial function in aged NMRI mice. RBE administration significantly increased survival and performance of aged NMRI mice in the passive avoidance and Y-maze test. Brain mitochondrial dysfunction found in aged mice was ameliorated after RBE administration. Furthermore, data from mRNA and protein expression studies revealed an up-regulation of mitochondrial proteins in RBE-fed mice, suggesting an increase in mitochondrial content which is mediated by a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-dependent mechanism. Our findings suggest that a long-term treatment with a nutraceutical containing RBE could be useful for slowing down brain aging and thereby delaying or even preventing AD. PMID:27350374

  14. Sparing of extraocular muscle in aging and muscular dystrophies: A myogenic precursor cell hypothesis

    Energy Technology Data Exchange (ETDEWEB)

    Kallestad, Kristen M.; Hebert, Sadie L.; McDonald, Abby A.; Daniel, Mark L.; Cu, Sharon R.; McLoon, Linda K., E-mail: mcloo001@tc.umn.edu

    2011-04-01

    The extraocular muscles (EOM) are spared from pathology in aging and many forms of muscular dystrophy. Despite many studies, this sparing remains an enigma. The EOM have a distinct embryonic lineage compared to somite-derived muscles, and we have shown that they continuously remodel throughout life, maintaining a population of activated satellite cells even in aging. These data suggested the hypothesis that there is a population of myogenic precursor cells (mpcs) in EOM that is different from those in limb, with either elevated numbers of stem cells and/or mpcs with superior proliferative capacity compared to mpcs in limb. Using flow cytometry, EOM and limb muscle mononuclear cells were compared, and a number of differences were seen. Using two different cell isolation methods, EOM have significantly more mpcs per mg muscle than limb skeletal muscle. One specific subpopulation significantly increased in EOM compared to limb was positive for CD34 and negative for Sca-1, M-cadherin, CD31, and CD45. We named these the EOMCD34 cells. Similar percentages of EOMCD34 cells were present in both newborn EOM and limb muscle. They were retained in aged EOM, whereas the population decreased significantly in adult limb muscle and were extremely scarce in aged limb muscle. Most importantly, the percentage of EOMCD34 cells was elevated in the EOM from both the mdx and the mdx/utrophin{sup -/-} (DKO) mouse models of DMD and extremely scarce in the limb muscles of these mice. In vitro, the EOMCD34 cells had myogenic potential, forming myotubes in differentiation media. After determining a media better able to induce proliferation in these cells, a fusion index was calculated. The cells isolated from EOM had a 40% higher fusion index compared to the same cells isolated from limb muscle. The EOMCD34 cells were resistant to both oxidative stress and mechanical injury. These data support our hypothesis that the EOM may be spared in aging and in muscular dystrophies due to a

  15. Free-hand ultrasound guidance permits safe and efficient minimally invasive intrathymic injections in both young and aged mice.

    Science.gov (United States)

    Tuckett, Andrea Z; Zakrzewski, Johannes L; Li, Duan; van den Brink, Marcel R M; Thornton, Raymond H

    2015-04-01

    The goal of this study was to evaluate whether use of an aseptic free-hand approach to ultrasound-guided injection facilitates injection into the thymic gland in mice. We used this interventional radiology technique in young, aged and immunodeficient mice and found that the thymus was visible in all cases. The mean injection period was 8 seconds in young mice and 19 seconds in aged or immunodeficient mice. Injection accuracy was confirmed by intrathymic location of an injected dye or by in vivo bioluminescence imaging of injected luciferase-expressing cells. Accurate intrathymic injection was confirmed in 97% of cases. No major complications were observed. We conclude that an aseptic freehand technique for ultrasound-guided intrathymic injection is safe and accurate and reduces the time required for intrathymic injections. This method facilitates large-scale experiments and injection of individual thymic lobes and is clinically relevant. PMID:25701534

  16. Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice

    DEFF Research Database (Denmark)

    Babcock, Alicia A; Ilkjær, Laura; Clausen, Bettina H;

    2015-01-01

    latter cytokines was generally increased in APP/PS1 Tg mice. Microglia that phagocytosed endogenously-produced Aβ were only observed in APP/PS1 Tg mice. Differences in phagocytic index and total Aβ load were observed in microglia with specific cytokine profiles. Both phagocytic index and total Aβ load...... mice, we confirmed that the majority of neocortical CD11b(+)(CD45(+)) microglia were resident cells (GFP(-)) in APP/PS1 Tg mice, even after selectively analysing CD11b(+)CD45(high) cells, which are typically considered to be infiltrating cells. Together, our data demonstrate that cytokine expression is...... selectively correlated with age and Aβ pathology, and is associated with an altered Aβ load in phagocytic microglia from APP/PS1 Tg mice. These findings have implications for understanding the regulation of microglial cytokine production and phagocytosis of Aβ in Alzheimer's disease....

  17. Effect of Diet and Age on Arterial Stiffening Due to Atherosclerosis in ApoE(-/-) Mice.

    Science.gov (United States)

    Cilla, M; Pérez, M M; Peña, E; Martínez, M A

    2016-07-01

    This work analyzes the progressive stiffening of the aorta due to atherosclerosis development of both ApoE(-/-) and C57BL/6J mice fed on a Western (n = 5) and a normal (n = 5) chow diet for the ApoE(-/-) group and on a normal chow diet (n = 5) for the C57BL/6J group. Sets of 5 animals from the three groups were killed after 10, 20, 30 and 40 weeks on their respective diets (corresponding to 17, 27, 37 and 47 weeks of age). Mechanical properties (inflation test and axial residual stress measurements) and histological properties were compared for both strains, ApoE(-/-) on the hyper-lipidic diet and both ApoE(-/-) and C57BL/6J on the normal diet, after the same period and after different periods of diet. The results indicated that the aorta stiffness in the ApoE(-/-) and C57BL/6J mice under normal diet remained approximately constant irrespective of their age. However, the arterial stiffness in the ApoE(-/-) on the hyper-lipidic diet increased over time. Statistical differences were found between the group after 10 weeks and the groups after 30 and 40 weeks of a hyper-lipidic diet. Comparing the hyper-lipidic and normal diet mice, statistical differences were also found between both diets in all cases after 40 weeks of diet, frequently after 30 weeks, and in some cases after 20 weeks. The early stages of lesion corresponded to the first 2 weeks of diet. Advanced lesions were found at 30 weeks and, finally, the aorta was completely damaged after 40 weeks of diet. In conclusion, we found substantial changes in the mechanical properties of the aorta walls of the ApoE(-/-) mice fed with the hyper-lipidic diet compared to the normal chow diet groups for both the ApoE(-/-) and C57BL/6J groups. These findings could serve as a reference for the study of changes in the arterial wall properties in cases of atherosclerosis. PMID:26502169

  18. [Effect of flavonoids from Sophora flavescens in aging mice induced by D-galactos].

    Science.gov (United States)

    Fan, Hong-yan; Gu, Rao-sheng; Ren, Kuang; Wang, Yan-chun; Yao, Zhen; Shen, Nan; Liu, Shi-bing

    2015-11-01

    To investigate the effect of flavonoids from Sophora flavescens in aging mice induced by D-galactose and its mechanism. Totally 60 mice were randomly divided into six groups: the control group, the model group, the piracetam group (positive control group) and flavonoids from S. flavescens low, medium and high doses groups. Except for the control group, all of the rest groups were subcutaneously injected with D-galactose (160 mg x kg(-1)) for successively 30 days to establish the sub-acute senescent model. Meanwhile, flavonoids from S. flavescens low, medium and high doses groups were respectively administered with 150, 300 and 600 mg xkg-('1)of flavonoids from S. flavescens for 30 days. The learning and memory abilities of mice were determined by avoiding darkness ex-eriment and jumping stair experiment. The contents of malondialdehyde (MDA) tumor necrosis factor-aα NF-aα the activities of superoxide dismutase (SOD) monoamine oxidase-B (MAO-B) Na'(+)K'(+)-ATPase and Ca2(+ )-ATPase in the brain of mice were deter-ined respectively after the behavioral experiments. The activity of lactic dehydrogenase ( DH) in blood serum was also determined and analyzed by microscope after HE staining to observe the changes in hippocampal organizational structure. Compared with the model group, flavonoids from S. favescens medium and high doses groups showed significantly increases in the latency of avoiding darkness and jumping stair experiments; flavonoids from S. fllvescens low, medium and high doses groups and the piracetam group showed de-reases in the numbers of errors in avoiding darkness experiment; the flavonoids from S. flavescens high dose group and the piracetam group showed reduction- n the number of errors in jumping stair experiment (P memory ability of senescent mice induced by D-galactose. Its mechanism may be correlated with the enhancement of anti-oxidative actions by lowering TNF-aαcontent, which results in the stability of cell membrane and the reduction in

  19. Sustained beta-cell dysfunction but normalized islet mass in aged thrombospondin-1 deficient mice.

    Directory of Open Access Journals (Sweden)

    Carl Johan Drott

    Full Text Available Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1, that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ∼15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.

  20. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    International Nuclear Information System (INIS)

    Research highlights: → Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. → We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. → Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. → Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient-related hormones such as leptin

  1. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    Energy Technology Data Exchange (ETDEWEB)

    Hamrick, Mark W., E-mail: mhamrick@mail.mcg.edu [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Herberg, Samuel; Arounleut, Phonepasong [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); He, Hong-Zhi [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Shiver, Austin [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Qi, Rui-Qun [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Zhou, Li [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Department of Internal Medicine, Henry Ford Health System, Detroit, MI (United States); Isales, Carlos M. [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); and others

    2010-09-24

    Research highlights: {yields} Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. {yields} We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. {yields} Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. {yields} Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient

  2. Regenerative hair waves in aging mice and extra-follicular modulators Follistatin, Dkk1 and Sfrp4

    OpenAIRE

    Chen, Chih-Chiang; Murray, Philip J.; Jiang, Ting Xin; Plikus, Maksim V; Chang, Yun-Ting; Lee, Oscar K.; Widelitz, Randall B; Chuong, Cheng Ming

    2014-01-01

    Hair cycling is modulated by factors both intrinsic and extrinsic to hair follicles. Cycling defects lead to conditions such as aging associated alopecia. Recently we demonstrated that mouse skin exhibits regenerative hair waves, reflecting a coordinated regenerative behavior in follicle populations. Here, we use this model to explore the regenerative behavior of aging mouse skin. Old mice (>18 months) tracked over several months show that with progressing age hair waves slow down, wave propa...

  3. Short-Term Long Chain Omega3 Diet Protects from Neuroinflammatory Processes and Memory Impairment in Aged Mice

    OpenAIRE

    Virginie F Labrousse; Nadjar, Agnès; Joffre, Corinne; Costes, Laurence; Aubert, Agnès; Grégoire, Stéphane; Bretillon, Lionel; Layé, Sophie

    2012-01-01

    Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs) has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this...

  4. Liver Fatty Acid Binding Protein Gene-Ablated Female Mice Exhibit Increased Age-Dependent Obesity123

    OpenAIRE

    Martin, Gregory G.; Atshaves, Barbara P.; McIntosh, Avery L.; Mackie, John T.; Kier, Ann B.; Schroeder, Friedhelm

    2008-01-01

    Previous work done in our laboratory suggested a role for liver fatty acid binding protein (L-FABP) in obesity that develops in aging female L-FABP gene-ablated (−/−) mice. To examine this possibility in more detail, cohorts of wild-type (+/+) and L-FABP (−/−) female mice were fed a standard low-fat nonpurified rodent diet for up to 18 mo. Various obesity-related parameters were examined including body weight and fat and lean tissue mass. Obesity in (−/−) mice was associated with increased ex...

  5. Ampicillin-Improved Glucose Tolerance in Diet-Induced Obese C57BL/6NTac Mice Is Age Dependent

    DEFF Research Database (Denmark)

    Rune, I.; Hansen, C. H. F.; Ellekilde, M.;

    2013-01-01

    different ages or not at all. We found that both diet and Ampicillin significantly changed the gut microbiota composition in the animals. Furthermore, there was a significant improvement in glucose tolerance in Ampicillin-treated, five-week-old mice compared to nontreated mice in the control group. At study...... high-fat diet mice, and a lower tolerogenic dendritic cell percentage was found both in relation to high-fat diet and late Ampicillin treatment. The results support our hypothesis that a "window" exists early in life in which an alteration of the gut microbiota affects glucose tolerance as well as...

  6. A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice.

    Science.gov (United States)

    Wiesmann, Maximilian; Zerbi, Valerio; Jansen, Diane; Haast, Roy; Lütjohann, Dieter; Broersen, Laus M; Heerschap, Arend; Kiliaan, Amanda J

    2016-01-01

    APOE ε4 (apoE4) polymorphism is the main genetic determinant of sporadic Alzheimer's disease (AD). A dietary approach (Fortasyn) including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF), functional connectivity (FC), gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10-12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT) mice. However, 16-18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging. PMID:27034849

  7. A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice

    Directory of Open Access Journals (Sweden)

    Maximilian Wiesmann

    2016-01-01

    Full Text Available APOE ε4 (apoE4 polymorphism is the main genetic determinant of sporadic Alzheimer’s disease (AD. A dietary approach (Fortasyn including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF, functional connectivity (FC, gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10–12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT mice. However, 16–18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging.

  8. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice.

    Science.gov (United States)

    de Picciotto, Natalie E; Gano, Lindsey B; Johnson, Lawrence C; Martens, Christopher R; Sindler, Amy L; Mills, Kathryn F; Imai, Shin-Ichiro; Seals, Douglas R

    2016-06-01

    We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD(+) intermediate, increases arterial SIRT1 activity and reverses age-associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium-dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)-mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age-associated impairment in EDD was restored in OC by the superoxide (O2-) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s(-1) vs. 337 ± 3 cm s(-1) ) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2- production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen-I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO-mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s(-1) ) and EM (3694 ± 315 kPa), normalized O2- production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen-I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD(+) threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age-related arterial dysfunction by decreasing oxidative stress. PMID:26970090

  9. Effects of Saikokaryukotsuboreito on Spermatogenesis and Fertility in Aging Male Mice

    Institute of Scientific and Technical Information of China (English)

    Zhi-Jun Zang; Su-Yun Ji; Ya-Nan Zhang; Yong Gao; Bin Zhang

    2016-01-01

    Background:Aspermia caused by exogenous testosterone limit its usage in late-onset hypogonadism (LOH) patients desiring fertility.Saikokaryukotsuboreito (SKRBT) is reported to improve serum testosterone and relieve LOH-related symptoms.However,it is unclear whether SKRBT affects fertility.We aimed to examine the effects of SKRBT on spermatogenesis and fertility in aging male mice.Methods:Thirty aging male mice were randomly assigned to three groups.Mice were orally administered with phosphate-buffer solution or SKRBT (300 mg/kg,daily) or received testosterone by subcutaneous injections (10 mg/kg,every 3 days).Thirty days later,each male mouse was mated with two female mice.All animals were sacrificed at the end of 90 days.Intratesticular testosterone (ITT) levels,quality of sperm,expression of synaptonemal complex protein 3 (SYCP3),and fertility were assayed.Results:In the SKRBT-treated group,ITT,quality of sperm,and expression of SYCP3 were all improved compared with the control group (ITT:85.50± 12.31 ng/gvs.74.10± 11.45 ng/g,P=0.027;sperm number:[14.94± 4.63] × 106 cells/ml vs.[8.79±4.38] × 106 cells/ml,P =0.002;sperm motility:43.16 ± 9.93% vs.33.51 ± 6.98%,P =0.015;the number of SYCP3-positive cells/tubule:77.50 ± 11.01 ng/ml vs.49.30 ± 8.73 ng/ml,P < 0.001;the expression of SYCP3 protein:1.23 ± 0.09 vs.0.84 ± 0.10,P < 0.001),but fertility was not significantly changed (P > 0.05,respectively).In the testosterone-treated group,ITT,quality of sperm,and expression of SYCP3 were markedly lower than the control group (ITT:59.00 ± 8.67,P =0.005;sperm number:[4.34 ± 2.45] × l06 cells/ml,P =0.018;sperm motility:19.53 ± 7.69%,P =0.001;the number of SYCP3-positive cells/tubule:30.00 ± 11.28,P < 0.001;the percentage of SYCP3-positive tubules/section 71.98 ± 8.88%,P =0.001;the expression of SYCP3 protein:0.71 ± 0.09,P < 0.001),and fertility was also suppressed (P < 0.05,respectively).Conclusion:SKRBT had no adverse effect on fertility

  10. Berberine alleviates postoperative cognitive dysfunction by suppressing neuroinflammation in aged mice.

    Science.gov (United States)

    Zhang, Zhijie; Li, Xiuhua; Li, Fayin; An, Lijun

    2016-09-01

    Postoperative cognitive dysfunction (POCD) is a significant cause of morbidity after surgery, especially for the elderly. Accumulating evidence has demonstrated that neuroinflammation plays a key role in the pathogenesis of POCD. Thus, we hypothesized that berberine, an isoquinoline alkaloid with anti-inflammatory effects, could improve surgery-induced cognitive impairment. Twenty-month-old male C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. For the interventional studies, mice received berberine (10mg/kg) or vehicle intraperitoneally. For the in vitro study, we examined the effects of berberine on lipopolysaccharide (LPS)-induced inflammatory mediators by cultured BV2 cells. Behavioral tests, expressions of IBA1, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 were performed at the indicated time points. In the present study, we showed that surgery impaired the contextual fear memory, as evidenced by the significantly decreased freezing time to the context. This behavioral change coincided with marked increases in IBA1, TNF-α, IL-1β, and IL-6 in the prefrontal cortex and hippocampus only at 24h but not 7 d after surgery. In BV2 cells, LPS induced significantly increased TNF-α and IL-1β expressions. Notably, berberine treatment rescued surgery-induced cognitive impairment and inhibited the release of IBA1, IL-1β, and IL-6 in the hippocampus. In line with the in vivo study, berberine treatment suppressed LPS-stimulated production of TNF-α and IL-1β in BV2 cells. In conclusion, our study suggests that berberine could alleviate POCD by suppressing neuroinflammation in aged mice. PMID:27376853

  11. Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage.

    Directory of Open Access Journals (Sweden)

    Kotaro Azuma

    Full Text Available Steroid and xenobiotic receptor (SXR and its murine ortholog, pregnane X receptor (PXR, are nuclear receptors that are expressed at high levels in the liver and the intestine where they function as xenobiotic sensors that induce expression of genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our results indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging.

  12. Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage.

    Science.gov (United States)

    Azuma, Kotaro; Casey, Stephanie C; Urano, Tomohiko; Horie-Inoue, Kuniko; Ouchi, Yasuyoshi; Blumberg, Bruce; Inoue, Satoshi

    2015-01-01

    Steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR), are nuclear receptors that are expressed at high levels in the liver and the intestine where they function as xenobiotic sensors that induce expression of genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our results indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging. PMID:25749104

  13. Do long-lived mutant and calorie-restricted mice share common anti-aging mechanisms?—a pathological point of view

    OpenAIRE

    Ikeno, Yuji; Lew, Christie M.; Cortez, Lisa A.; Webb, Celeste R.; Lee, Shuko; Gene B Hubbard

    2006-01-01

    Rodent models are an invaluable resource for studying the mechanism of mammalian aging. In recent years, the availability of transgenic and knockout mouse models has facilitated the study of potential mechanisms of aging. Since 1996, aging studies with several long-lived mutant mice have been conducted. Studies with the long-lived mutant mice, Ames and Snell dwarf, and growth hormone receptor/binding protein knockout mice, are currently providing important clues regarding the role of the grow...

  14. Ischemic postconditioning confers cardioprotection and prevents reduction of Trx-1 in young mice, but not in middle-aged and old mice.

    Science.gov (United States)

    Perez, Virginia; D Annunzio, Verónica; Mazo, Tamara; Marchini, Timoteo; Caceres, Lourdes; Evelson, Pablo; Gelpi, Ricardo J

    2016-04-01

    Thioredoxin-1 (Trx-1) is part of an antioxidant system that maintains the cell redox homeostasis but their role on ischemic postconditioning (PostC) is unknown. The aim of this work was to determine whether Trx-1 participates in the cardioprotective mechanism of PostC in young, middle-aged, and old mice. Male FVB young (Y: 3 month-old), middle-aged (MA: 12 month-old), and old (O: 20 month-old) mice were used. Langendorff-perfused hearts were subjected to 30 min of ischemia and 120 min of reperfusion (I/R group). After ischemia, we performed 6 cycles of R/I (10 s each) followed by 120 min of reperfusion (PostC group). We measured the infarct size (triphenyltetrazolium); Trx-1, total and phosphorylated Akt, and GSK3β expression (Western blot); and the GSH/GSSG ratio (HPLC). PostC reduced the infarct size in young mice (I/R-Y: 52.3 ± 2.4 vs. PostC-Y: 40.0 ± 1.9, p aged and old mice groups. Trx-1 expression decreased after I/R, and the PostC prevented the protein degradation in young animals (I/R-Y: 1.05 ± 0.1 vs. PostC-Y: 0.52 ± .0.07, p aged and old groups. Cytosolic Akt and GSK3β phosphorylation increased in the PostC compared with the I/R group only in young animals. Our results suggest that PostC prevents Trx-1 degradation, decreasing oxidative stress and allowing the activation of Akt and GSK3β to exert its cardioprotective effect. This protection mechanism is not activated in middle-aged and old animals. PMID:26932791

  15. Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy

    Science.gov (United States)

    The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the diet...

  16. Circadian rhythms of body temperature and locomotor activity in aging BALB/c mice: early and late life span predictors.

    Science.gov (United States)

    Basso, Andrea; Del Bello, Giovanna; Piacenza, Francesco; Giacconi, Robertina; Costarelli, Laura; Malavolta, Marco

    2016-08-01

    Impairment of one or more parameters of circadian rhythms (CR) of body temperature (BT) and locomotor activity (LMA) are considered among the hallmarks of mammalian aging. These alterations are frequently used as markers for imminent death in laboratory mice. However, there are still contradictory data for particular strains and it is also uncertain which changes might predict senescence changes later in life, including the force of mortality. In the present paper we use telemetry to study LMA and CR of BT during aging of BALB/c mice. At our knowledge this is the first time that CR of BT and LMA are investigated in this strain in a range of age covering the whole lifespan, from young adult up to very old age. CR of BT was analyzed with a cosine model using a cross sectional approach and follow-up measurements. The results show that BT, LMA, amplitude, goodness-of-fit (GoF) to circadian cycle of temperature decrease with different shapes during chronological age. Moreover, we found that the % change of amplitude and BT in early life (5-19 months) can predict the remaining lifespan of the mice. Later in life (22-32 months), best predictors are single measurements of LMA and GoF. The results of this study also offer potential measures to rapidly identifying freely unrestrained mice with the worst longitudinal outcome and against which existing or novel biomarkers and treatments may be assessed. PMID:26820297

  17. Measures of Healthspan as Indices of Aging in Mice-A Recommendation.

    Science.gov (United States)

    Richardson, Arlan; Fischer, Kathleen E; Speakman, John R; de Cabo, Rafael; Mitchell, Sarah J; Peterson, Charlotte A; Rabinovitch, Peter; Chiao, Ying A; Taffet, George; Miller, Richard A; Rentería, René C; Bower, James; Ingram, Donald K; Ladiges, Warren C; Ikeno, Yuji; Sierra, Felipe; Austad, Steven N

    2016-04-01

    Over the past decade, a large number of discoveries have shown that interventions (genetic, pharmacological, and nutritional) increase the lifespan of invertebrates and laboratory rodents. Therefore, the possibility of developing antiaging interventions for humans has gone from a dream to a reality. However, it has also become apparent that we need more information than just lifespan to evaluate the translational potential of any proposed antiaging intervention to humans. Information is needed on how an intervention alters the "healthspan" of an animal, that is, how the physiological functions that change with age are altered. In this report, we describe the utility and the limitations of assays in mice currently available for measuring a wide range of physiological functions that potentially impact quality of life. We encourage investigators and reviewers alike to expect at minimum an overall assessment of health in several domains across several ages before an intervention is labeled as "increasing healthspan." In addition, it is important that investigators indicate any tests in which the treated group did worse or did not differ statistically from controls because overall health is a complex phenotype, and no intervention discovered to date improves every aspect of health. Finally, we strongly recommend that functional measurements be performed in both males and females so that sex differences in the rate of functional decline in different domains are taken into consideration. PMID:26297941

  18. Aging Exacerbates Depressive-like Behavior in Mice in Response to Activation of the Peripheral Innate Immune System

    OpenAIRE

    Godbout, Jonathan P.; Moreau, Maïté; Lestage, Jacques; Chen, Jing; Sparkman, Nathan L; O’Connor, Jason; Castanon, Nathalie; Kelley, Keith W.; Dantzer, Robert; Johnson, Rodney W.

    2007-01-01

    Exposure to peripheral infections may be permissive to cognitive and behavioral complications in the elderly. We have reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response and prolonged sickness behavior in aged BALB/c mice. Because LPS also causes depressive behavior, the purpose of this study was to determine whether aging is associated with an exacerbated depressive-like response. We confirmed that LP...

  19. Exercise does not enhance aged bone's impaired response to artificial loading in C57Bl/6 mice

    OpenAIRE

    Meakin, Lee B.; Udeh, Chinedu; Galea, Gabriel L.; Lanyon, Lance E.; Price, Joanna S.

    2015-01-01

    Bones adapt their structure to their loading environment and so ensure that they become, and are maintained, sufficiently strong to withstand the loads to which they are habituated. The effectiveness of this process declines with age and bones become fragile fracturing with less force. This effect in humans also occurs in mice which experience age-related bone loss and reduced adaptation to loading. Exercise engenders many systemic and local muscular physiological responses as well as engende...

  20. Early Shifts of Brain Metabolism by Caloric Restriction Preserve White Matter Integrity and Long-Term Memory in Aging Mice

    OpenAIRE

    Janet eGuo; Vikas eBakshi; Ai-Ling eLin

    2015-01-01

    Preservation of brain integrity with age is highly associated with lifespan determination. Caloric restriction (CR) has been shown to increase longevity and healthspan in various species; however, its effects on preserving living brain functions in aging remain largely unexplored. In the study, we used multimodal, non-invasive neuroimaging (PET/MRI/MRS) to determine in vivo brain glucose metabolism, energy metabolites, and white matter structural integrity in young and old mice fed with eithe...

  1. Age-dependent separation of class-specific suppressor cells in thymus of SJL/J mice

    International Nuclear Information System (INIS)

    The thymus of SJL/J mice of age 3-6 weeks has been previously shown to contain suppressor cells that inhibit the antibody response of lymph node cells to SRBC. The effect of these suppressor cells disappears as the animals age (24 weeks or more). The authors find that these aged animals acquire thymic suppressor cells which suppress the generation of cytotoxic T-cells both in vitro and in vivo. Although such suppressors are not present in the thymuses of young SJL/J mice, suppression can be induced by treatment with estrogen and progesterone. The differentiation of functionally different suppressor cell populations in thymus may be affected by both age and horomonal status. Lymph node cells were mixed with γ-irradiated spleen cells in a culture medium. Varying numbers of thymocytes were added and after 4-5 days incubation the number of cytotoxic T-cells was assayed using a 51Cr-release assay. Antibody formation in vivo was tested in γ-irradiated mice. The graft versus host reaction was tested in X-irradiated mice. (Auth.)

  2. Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits.

    Science.gov (United States)

    Mehla, Jogender; Chauhan, Balwantsinh C; Chauhan, Neelima B

    2014-01-01

    Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD. PMID:24121970

  3. A higher oxidative status accelerates senescence and aggravates age-dependent disorders in SAMP strains of mice.

    Science.gov (United States)

    Hosokawa, Masanori

    2002-11-01

    The SAM strain of mice is actually a group of related inbred strains consisting of series of SAMP (accelerated senescence-prone, short-lived) and SAMR (accelerated senescence-resistant, longer-lived) strains. Comparing with the SAMR strains, the SAMP strains of mice show a more accelerated senescence process, shorter lifespan, and an earlier onset and more rapid progress of age-associated pathological phenotypes similar to several geriatric disorders observed in humans, including senile osteoporosis, degenerative joint disease, age-related deficits in learning and memory, olfactory bulb and forebrain atrophy, presbycusis and retinal atrophy, senile amyloidosis, immunosenescence, senile lungs, and diffuse medial thickening of the aorta. The higher oxidative stress observed in the SAMP strains of mice are partly caused by mitochondrial dysfunction, and may be one cause of the senescence acceleration and age-dependent alterations in cell structure and function, including neuronal cell degeneration. This senescence acceleration is also observed during senescence/crisis in cultures of isolated fibroblast-like cells from SAMP strains of mice, and was associated with a hyperoxidative status. These observations suggest that the SAM strains are useful tools in the attempt to understand the mechanisms of age-dependent degeneration of cells and tissues, and their aggravation, and to develop clinical interventions. PMID:12470893

  4. Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice.

    Science.gov (United States)

    Alcántara-González, Faviola; Mendoza-Perez, Claudia Rebeca; Zaragoza, Néstor; Juarez, Ismael; Arroyo-García, Luis Enrique; Gamboa, Citlalli; De La Cruz, Fidel; Zamudio, Sergio; Garcia-Dolores, Fernando; Flores, Gonzalo

    2012-11-01

    Cerebrolysin (Cbl) shows neurotrophic and neuroprotective properties while donepezil (Dnp) is a potent acetylcholinesterase (AChE) inhibitor, both drugs are prescribed for Alzheimer's disease (AD) treatment. Previous studies have shown that the Dnp and Cbl administered separately, modify dendritic morphology of neurons in the prefrontal cortex and hippocampus in senile rodents. Since the deficit of neurotrophic factor activity is implicated in the degeneration of cholinergic neurons of basal forebrain, a combination therapy of Dnp and Cbl has been tested recently in Alzheimer's patients. However, the plastic changes that may underlie this combined treatment have not yet been explored. We present here the effect of the combined administration of Cbl and Dnp on dendritic morphology in brain regions related to learning and memory in aged mice. The Golgi-Cox staining protocol and Sholl analysis were used for studying dendritic changes. Cbl and Dnp were administrated daily for 2 months to 9-months-old mice. Locomotor activity was assessed, as well as the dendritic morphology of neurons in several limbic regions was analyzed. Results showed that Cbl and Dnp induced an increase in locomotor activity without synergistic effect. The Cbl or Dnp treatment modified the dendritic morphology of neurons from prefrontal cortex (PFC), dorsal hippocampus (DH), dentate gyrus (DG), and the shell of nucleus accumbens (NAcc). These changes show an increase in the total dendritic length and spine density, resulting in an improvement of dendritic arborization. Prominently, a synergistic effect of Cbl and Dnp was observed on branching order and total dendritic length of pyramidal neurons from PFC. These results suggest that Dnp and Cbl may induce plastic changes in a manner independent of each other, but could enhance their effect in target cells from PFC. PMID:22826038

  5. Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice.

    Science.gov (United States)

    Hogan, Thea; Gossel, Graeme; Yates, Andrew J; Seddon, Benedict

    2015-12-15

    Understanding how our T-cell compartments are maintained requires knowledge of their population dynamics, which are typically quantified over days to weeks using the administration of labels incorporated into the DNA of dividing cells. These studies present snapshots of homeostatic dynamics and have suggested that lymphocyte populations are heterogeneous with respect to rates of division and/or death, although resolving the details of such heterogeneity is problematic. Here we present a method of studying the population dynamics of T cells in mice over timescales of months to years that reveals heterogeneity in rates of division and death with respect to the age of the host at the time of thymic export. We use the transplant conditioning drug busulfan to ablate hematopoetic stem cells in young mice but leave the peripheral lymphocyte compartments intact. Following their reconstitution with congenically labeled (donor) bone marrow, we followed the dilution of peripheral host T cells by donor-derived lymphocytes for a year after treatment. Describing these kinetics with mathematical models, we estimate rates of thymic production, division and death of naive CD4 and CD8 T cells. Population-averaged estimates of mean lifetimes are consistent with earlier studies, but we find the strongest support for a model in which both naive T-cell pools contain kinetically distinct subpopulations of older host-derived cells with self-renewing capacity that are resistant to displacement by naive donor lymphocytes. We speculate that these incumbent cells are conditioned or selected for increased fitness through homeostatic expansion into the lymphopenic neonatal environment. PMID:26607449

  6. Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age

    OpenAIRE

    Shoji, Hirotaka; Takao, Keizo; Hattori, Satoko; Miyakawa, Tsuyoshi

    2016-01-01

    Background Aging is considered to be associated with progressive changes in the brain and its associated sensory, motor, and cognitive functions. A large number of studies comparing young and aged animals have reported differences in various behaviors between age-cohorts, indicating behavioral dysfunctions related to aging. However, relatively little is known about behavioral changes from young adulthood to middle age, and the effect of age on behavior during the early stages of life remains ...

  7. A mild impairment of mitochondrial electron transport has sex-specific effects on lifespan and aging in mice.

    Directory of Open Access Journals (Sweden)

    Bryan G Hughes

    Full Text Available Impairments of various aspects of mitochondrial function have been associated with increased lifespan in various model organisms ranging from Caenorhabditis elegans to mice. For example, disruption of the function of the 'Rieske' iron-sulfur protein (RISP of complex III of the mitochondrial electron transport chain can result in increased lifespan in the nematode worm C. elegans. However, the mechanisms by which impaired mitochondrial function affects aging remain under investigation, including whether or not they require decreased electron transport. We have generated knock-in mice with a loss-of-function Risp mutation that is homozygous lethal. However, heterozygotes (Risp(+/P224S were viable and had decreased levels of RISP protein and complex III enzymatic activity. This decrease was sufficient to impair mitochondrial respiration and to decrease overall metabolic rate in males, but not females. These defects did not appear to exert an overtly deleterious effect on the health of the mutants, since young Risp(+/P224S mice are outwardly normal, with unaffected performance and fertility. Furthermore, biomarkers of oxidative stress were unaffected in both young and aged animals. Despite this, the average lifespan of male Risp(+/P224S mice was shortened and aged Risp(+/P224S males showed signs of more rapidly deteriorating health. In spite of these differences, analysis of Gompertz mortality parameters showed that Risp heterozygosity decreased the rate of increase of mortality with age and increased the intrinsic vulnerability to death in both sexes. However, the intrinsic vulnerability was increased more dramatically in males, which resulted in their shortened lifespan. For females, the slower acceleration of age-dependent mortality results in significantly increased survival of Risp(+/P224S mice in the second half of lifespan. These results demonstrate that even relatively small perturbations of the mitochondrial electron transport chain can

  8. N-Acetylmannosamine improves sleep-wake quality in middle-aged mice: relevance to autonomic nervous function.

    Science.gov (United States)

    Kuwahara, Masayoshi; Ito, Koichi; Hayakawa, Koji; Yagi, Shintaro; Shiota, Kunio

    2015-01-01

    Aging is associated with a variety of physiological changes originating peripherally and centrally, including within the autonomic nervous system. Sleep-wake disturbances constitute reliable hallmarks of aging in several animal species and humans. Recent studies have been interested in N-acetylmannosamine (ManNAc) a potential therapeutic agent for improving quality of life, as well as preventing age-related cognitive decline. In this study, ManNAc (5.0 mg/ml) was administered in the drinking water of middle-aged male C57BL/6J mice (55 weeks old) for 7 days. Mice were housed under a 12:12 h light:dark cycle at 23-24 °C. We evaluated bio-behavioral activity using electrocardiogram, body temperature and locomotor activity recorded by an implanted telemetry transmitter. To estimate sleep-wake profile, surface electroencephalogram and electromyogram leads connected to a telemetry transmitter were also implanted in mice. Autonomic nervous activity was evaluated using power spectral analysis of heart rate variability. ManNAc-treated mice spent more time in a wakeful state and less time in slow wave sleep during the dark phase. Parasympathetic nervous activity was increased following ManNAc treatment, then the sympatho-vagal balance was shifted predominance of parasympathetic nervous system. Furthermore, improvement in sleep-wake pattern was associated with increased parasympathetic nervous activity. These results suggest that ManNAc treatment can improve bio-behavioral activity and sleep-wake quality in middle-aged mice. This may have implications for improving sleep patterns in elderly humans. PMID:25443216

  9. Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A

    OpenAIRE

    Vallejo, Abbe N.; Joshua J Michel; Bale, Laurie K.; Lemster, Bonnie H.; Borghesi, Lisa; Conover, Cheryl A.

    2009-01-01

    Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension. Since immune function is an important determinant of individual fitness, we examined the natural immune ecology of PAPPA−/− mice and their wild-type littermates reared under specific pathogen-free condition with aging. Whereas wild-type mice exhibit classic age-dependent thymic atrophy,...

  10. Differential requirement for utrophin in the induced pluripotent stem cell correction of muscle versus fat in muscular dystrophy mice.

    Directory of Open Access Journals (Sweden)

    Amanda J Beck

    Full Text Available Duchenne muscular dystrophy (DMD is an incurable degenerative muscle disorder. We injected WT mouse induced pluripotent stem cells (iPSCs into mdx and mdx∶utrophin mutant blastocysts, which are predisposed to develop DMD with an increasing degree of severity (mdx <<< mdx∶utrophin. In mdx chimeras, iPSC-dystrophin was supplied to the muscle sarcolemma to effect corrections at morphological and functional levels. Dystrobrevin was observed in dystrophin-positive and, at a lesser extent, utrophin-positive areas. In the mdx∶utrophin mutant chimeras, although iPSC-dystrophin was also supplied to the muscle sarcolemma, mice still displayed poor skeletal muscle histopathology, and negligible levels of dystrobrevin in dystrophin- and utrophin-negative areas. Not only dystrophin-expressing tissues are affected by iPSCs. Mdx and mdx∶utrophin mice have reduced fat/body weight ratio, but iPSC injection normalized this parameter in both mdx and mdx∶utrophin chimeras, despite the fact that utrophin was compromised in the mdx∶utrophin chimeric fat. The results suggest that the presence of utrophin is required for the iPSC-corrections in skeletal muscle. Furthermore, the results highlight a potential (utrophin-independent non-cell autonomous role for iPSC-dystrophin in the corrections of non-muscle tissue like fat, which is intimately related to the muscle.

  11. Age-dependent changes in lipid peroxide levels in peripheral organs, but not in brain, in senescence-accelerated mice.

    Science.gov (United States)

    Matsugo, S; Kitagawa, T; Minami, S; Esashi, Y; Oomura, Y; Tokumaru, S; Kojo, S; Matsushima, K; Sasaki, K

    2000-01-01

    The tissue concentration of lipid peroxides was determined in the brain, heart, liver, lung and kidney of accelerated senescence-prone (SAMP-8) and -resistant (SAMR-1) mice at 3, 6 and 9 months of age by a method involving chemical derivatization and high performance liquid chromatography. The level of lipid peroxides in the brain did not show an age-dependent change, but at each age the brain level of lipid peroxides was significantly higher in SAMP-8 than in SAMR-1. In contrast, the lipid peroxide levels in the peripheral organs showed increases with aging in both strains, and they were significantly higher in SAMP-8 than in SAMR-1 at both 3 and 6 months of age (except at 3 months of age in the kidney). These results suggest that increased oxidative stress in the brain and peripheral organs is a cause of the senescence-related degeneration and impairments seen in SAMP-8. PMID:10643812

  12. Altered connexin 43 expression underlies age-dependent decrease of regulatory T cell suppressor function in nonobese diabetic mice.

    Science.gov (United States)

    Kuczma, Michal; Wang, Cong-Yi; Ignatowicz, Leszek; Gourdie, Robert; Kraj, Piotr

    2015-06-01

    Type 1 diabetes is one of the most extensively studied autoimmune diseases, but the cellular and molecular mechanisms leading to T cell-mediated destruction of insulin-producing β cells are still not well understood. In this study, we show that regulatory T cells (T(regs)) in NOD mice undergo age-dependent loss of suppressor functions exacerbated by the decreased ability of activated effector T cells to upregulate Foxp3 and generate T(regs) in the peripheral organs. This age-dependent loss is associated with reduced intercellular communication mediated by gap junctions, which is caused by impaired upregulation and decreased expression of connexin 43. Regulatory functions can be corrected, even in T cells isolated from aged, diabetic mice, by a synergistic activity of retinoic acid, TGF-β, and IL-2, which enhance connexin 43 and Foxp3 expression in T(regs) and restore the ability of conventional CD4(+) T cells to upregulate Foxp3 and generate peripherally derived T(regs). Moreover, we demonstrate that suppression mediated by T(regs) from diabetic mice is enhanced by a novel reagent, which facilitates gap junction aggregation. In summary, our report identifies gap junction-mediated intercellular communication as an important component of the T(reg) suppression mechanism compromised in NOD mice and suggests how T(reg) mediated immune regulation can be improved. PMID:25911751

  13. Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites

    OpenAIRE

    Frye, Cheryl A.; Walf, Alicia A.

    2009-01-01

    There may be a role of age-related decline in androgen production and/or its metabolism for late-onset depression disorders of men and women. Thus, the antidepressant-like effects of testosterone (T) and its metabolites are of interest. Given that these androgens have disparate mechanisms of action, it is important to begin to characterize and compare their effects in an aged animal model. We hypothesized that there would be sex differences in depression behavior of aged mice and that androge...

  14. Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice

    OpenAIRE

    Jung Yoon Park; Mi-Ook Cho; Shanique Leonard; Brent Calder; I Saira Mian; Woo Ho Kim; Susan Wijnhoven; Harry van Steeg; James Mitchell; van der Horst, Gijsbertus T. J.; Jan Hoeijmakers; Pinchas Cohen; Jan Vijg; Yousin Suh

    2008-01-01

    Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD) mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discov...

  15. Effects of Age and Parity on Mammary Gland Lesions and Progenitor Cells in the FVB/N-RC Mice

    OpenAIRE

    Raafat, Ahmed; Strizzi, Luigi; Lashin, Karim; Ginsburg, Erika; McCurdy, David; Salomon, David; Smith, Gilbert H.; Medina, Daniel; Callahan, Robert

    2012-01-01

    The FVB/N mouse strain is extensively used in the development of animal models for breast cancer research. Recently it has been reported that the aging FVB/N mice develop spontaneous mammary lesions and tumors accompanied with abnormalities in the pituitary glands. These observations have a great impact on the mouse models of human breast cancer. We have developed a population of inbred FVB/N mice (designated FVB/N-RC) that have been genetically isolated for 20 years. To study the effects of ...

  16. Interleukin-21 administration to aged mice rejuvenates their peripheral T-cell pool by triggering de novo thymopoiesis.

    Science.gov (United States)

    Al-Chami, E; Tormo, A; Pasquin, S; Kanjarawi, R; Ziouani, S; Rafei, M

    2016-04-01

    The vaccination efficacy in the elderly is significantly reduced compared to younger populations due to thymic involution and age-related intrinsic changes affecting their naïve T-cell compartment. Interleukin (IL)-21 was recently shown to display thymostimulatory properties. Therefore, we hypothesized that its administration to ageing hosts may improve T-cell output and thus restore a competent peripheral T-cell compartment. Indeed, an increase in the production of recent thymic emigrants (RTEs) attributable to intrathymic expansion of early thymic progenitors (ETPs), double-negative (DN), and double-positive (DP) thymocytes as well as thymic epithelial cell (TEC) was observed in recombinant (r)IL-21-treated aged mice. In sharp contrast, no alterations in the frequency of bone marrow (BM)-derived progenitors were detected following rIL-21 administration. Enhanced production of naïve T cells improved the T-cell receptor (TCR) repertoire diversity and re-established a pool of T cells exhibiting higher levels of miR-181a and diminished amounts of the TCR-inhibiting phosphatases SHP-2 and DUSP5/6. As a result, stimulation of T cells derived from rIL-21-treated aged mice displayed enhanced activation of Lck, ZAP-70, and ERK, which ultimately boosted their IL-2 production, CD25 expression, and proliferation capabilities in comparison with T cells derived from control aged mice. Consequently, aged rIL-21-treated mice vaccinated using a tyrosinase-related protein 2 (Trp2)-derived peptide exhibited a substantial delay in B16 tumor growth and improved survival. The results of this study highlight the immunorestorative function of rIL-21 paving its use as a strategy for the re-establishment of effective immunity in the elderly. PMID:26762709

  17. Adverse effects of AMP-activated protein kinase alpha2-subunit deletion and high-fat diet on heart function and ischemic tolerance in aged female mice.

    Science.gov (United States)

    Slámová, K; Papoušek, F; Janovská, P; Kopecký, J; Kolář, F

    2016-03-14

    AMP-activated protein kinase (AMPK) plays a role in metabolic regulation under stress conditions, and inadequate AMPK signaling may be also involved in aging process. The aim was to find out whether AMPK alpha2-subunit deletion affects heart function and ischemic tolerance of adult and aged mice. AMPK alpha2(-/-) (KO) and wild type (WT) female mice were compared at the age of 6 and 18 months. KO mice exhibited subtle myocardial AMPK alpha2-subunit protein level, but no difference in AMPK alpha1-subunit was detected between the strains. Both alpha1- and alpha2-subunits of AMPK and their phosphorylation decreased with advanced age. Left ventricular fractional shortening was lower in KO than in WT mice of both age groups and this difference was maintained after high-fat feeding. Infarct size induced by global ischemia/reperfusion of isolated hearts was similar in both strains at 6 months of age. Aged WT but not KO mice exhibited improved ischemic tolerance compared with the younger group. High-fat feeding for 6 months during aging abolished the infarct size-reduction in WT without affecting KO animals; nevertheless, the extent of injury remained larger in KO mice. The results demonstrate that adverse effects of AMPK alpha2-subunit deletion and high-fat feeding on heart function and myocardial ischemic tolerance in aged female mice are not additive. PMID:26596312

  18. Exercise does not enhance aged bone's impaired response to artificial loading in C57Bl/6 mice.

    Science.gov (United States)

    Meakin, Lee B; Udeh, Chinedu; Galea, Gabriel L; Lanyon, Lance E; Price, Joanna S

    2015-12-01

    Bones adapt their structure to their loading environment and so ensure that they become, and are maintained, sufficiently strong to withstand the loads to which they are habituated. The effectiveness of this process declines with age and bones become fragile fracturing with less force. This effect in humans also occurs in mice which experience age-related bone loss and reduced adaptation to loading. Exercise engenders many systemic and local muscular physiological responses as well as engendering local bone strain. To investigate whether these physiological responses influence bones' adaptive responses to mechanical strain we examined whether a period of treadmill exercise influenced the adaptive response to an associated period of artificial loading in young adult (17-week) and old (19-month) mice. After treadmill acclimatization, mice were exercised for 30 min three times per week for two weeks. Three hours after each exercise period, right tibiae were subjected to 40 cycles of non-invasive axial loading engendering peak strain of 2250 με. In both young and aged mice exercise increased cross-sectional muscle area and serum sclerostin concentration. In young mice it also increased serum IGF1. Exercise did not affect bone's adaptation to loading in any measured parameter in young or aged bone. These data demonstrate that a level of exercise sufficient to cause systemic changes in serum, and adaptive changes in local musculature, has no effect on bone's response to loading 3h later. This study provides no support for the beneficial effects of exercise on bone in the elderly being mediated by systemic or local muscle-derived effects rather than local adaptation to altered mechanical strain. PMID:26142929

  19. Supplementation of selenium-enriched yeast attenuates age-dependent transcriptional changes of heart in mitochondrial DNA mutator mice

    Directory of Open Access Journals (Sweden)

    Rijin Xiao

    2014-03-01

    Full Text Available Background: Age is a major risk factor in developing heart diseases and has been associated with profound transcriptional changes in mammalian tissues. Low tissue selenium has recently been linked to several age-related diseases, including cardiovascular disease. This study investigated the global effects of age and dietary supplementation of selenium on heart transcriptional profiles in POLG mutator mice. Methods: Heart transcription profiles from young (2-month-old and old (13-month-old animals fed either a control diet or a diet supplemented with 1.0 mg selenium from seleniumenriched yeast (SP/kg diet were obtained and validated using microarray and real-time RTPCR techniques. Results: Aging led to significant transcriptional changes, where the expression of 1942 genes in old animals was changed by a fold change larger than 2.0, when compared to young animals. Age-regulated genes are associated with cardiovascular system development, immune and inflammatory response, and cellular oxidative stress response. Multiple genes linked with cardiomyocyte apoptosis, hypertrophy, and cardiac fibrosis, such as Myh7, Lcn2, Spp1, and Serpine1, were significantly up-regulated in old animals. SP supplementation also caused significant transcriptional changes in the heart, especially in old mice where many age-dependent transcriptional changes were totally or partially reversed by SP. Upstream regulator analysis further indicated that genes for Foxo1 and Foxo3, two transcriptional regulators involved in the regulation of cardiac muscle remodeling, were significantly activated by SP, suggesting that Foxo-mediated transcriptional activities play important roles in the anti-aging properties of SP. Functional Foods in Health and Disease 2014; 4(3:98- 119 Page 99 of 119 Conclusions: Results of this study indicate that SP supplementation attenuated age-related transcriptional changes in the heart of old POLG mice, which implies a potential clinical application of

  20. Effects of aging on time course of neovascularization-related gene expression following acute hindlimb ischemia in mice

    Institute of Scientific and Technical Information of China (English)

    WANG Jin-song; LIU Xia; XUE Zhen-yi; Lee Alderman; Justin U. Tilan; Remi Adenika; Stephen E. Epstein; Mary Susan Burnett

    2011-01-01

    Background Molecular analysis of neovascularization related genes by time course in response to ischemia has not been described in the context of aging. We aimed to provide a progressively deeper understanding of how aging compromises neovascularization.Methods Young (3-month) and old (18-month) C57BI mice were subjected to left hindlimb ischemia. Necrosis score was evaluated in calf muscles. Calf muscles,peripheral blood,bone marrow were harvested at different time points. The expressions of matrix metalloproteiniase-9 (MMPg),endothelial nitric oxide synthase (eNOS),vascular endothelial growth factor (VEGF),stromal derived growth factor-1 (SDF1),hypoxia inducible factor-1α (HIF1α),VEGF receptor-1(Fit1),VEGF receptor-2 (Flk1),angiopoietin-1 (Ang1),CD133,CD26 were detected by RT-PCR or Western blotting.White blood cells were counted in the peripheral blood. Gene expression data were compared by two-way analysis of variance.Results MMP9,HIF-1α and SDF-1 were more upregulated during acute ischemia in old vs. young mice,reflecting increased ischemia in aging mice. However VEGF and eNOS exhibited lower expression in old vs. young mice,despite greater ischemia intensity. Ang1 and Flk1 showed similar expression in old vs. young mice. MMP9 peaked earlier in peripheral blood in young vs. old mice. Concurrent decreasing CD26 and increasing CD133 expression in aging bonemarrow suggest aging impairs progenitor cell mobilization,Conclusions Our results indicate that a complex array of defects occur with aging that interfere with optimal neovascularization. These include potential impaired mobilization of progenitor cells to ischemic tissue,decreased levels of eNOS and VEGF and delayed responses to ischemia.ZLEr. WANG Jin-song,Division of Vascular Surgery,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510080,China (Tel:86-20-87333440.Fax:86-20-87333242. Email:wangjs@mail.sysu.edu.cn)This work was supported by NIH RO1 HL085003-01A2,NNSF30100179.

  1. Chronic pyruvate supplementation increases exploratory activity and brain energy reserves in young and middle-aged mice

    Directory of Open Access Journals (Sweden)

    Hennariikka eKoivisto

    2016-03-01

    Full Text Available Numerous studies have reported neuroprotective effects of pyruvate when given in systemic injections. Impaired glucose uptake and metabolism are found in Alzheimer's disease (AD and in AD mouse models. We tested whether dietary pyruvate supplementation is able to provide added energy supply to brain and thereby attenuate aging- or AD-related cognitive impairment. Mice received ~ 800 mg/kg/day Na-pyruvate in their chow for 2- 6 months. In middle-aged wild-type mice and in 6.5-month-old APP/PS1 mice, pyruvate facilitated spatial learning and increased exploration of a novel odor. However, in passive avoidance task for fear memory, the treatment group was clearly impaired. Independent of age, long-term pyruvate increased explorative behavior, which likely explains the paradoxical impairment in passive avoidance. We also assessed pyruvate effects on body weight, muscle force and endurance, and found no effects. Metabolic post-mortem assays revealed increased energy compounds in nuclear magnetic resonance spectroscopy as well as increased brain glycogen storages in the pyruvate group. Pyruvate supplementation may counteract aging-related behavioral impairment but its beneficial effect seems related to increased explorative activity rather than direct memory enhancement.

  2. Do long-lived mutant and calorie-restricted mice share common anti-aging mechanisms?--a pathological point of view.

    Science.gov (United States)

    Ikeno, Yuji; Lew, Christie M; Cortez, Lisa A; Webb, Celeste R; Lee, Shuko; Hubbard, Gene B

    2006-06-01

    Rodent models are an invaluable resource for studying the mechanism of mammalian aging. In recent years, the availability of transgenic and knockout mouse models has facilitated the study of potential mechanisms of aging. Since 1996, aging studies with several long-lived mutant mice have been conducted. Studies with the long-lived mutant mice, Ames and Snell dwarf, and growth hormone receptor/binding protein knockout mice, are currently providing important clues regarding the role of the growth hormone/insulin like growth factor-1 axis in the aging process. Interestingly, these studies demonstrate that these long-lived mutant mice have physiological characteristics that are similar to the effects of calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, a question remains to be answered: do these long-lived mutant and calorie-restricted mice extend their lifespan through a common underlying mechanism? PMID:19943137

  3. Histamine 1 receptor knock out mice show age-dependent susceptibility to status epilepticus and consequent neuronal damage.

    Science.gov (United States)

    Kukko-Lukjanov, Tiina-Kaisa; Grönman, Maria; Lintunen, Minnamaija; Laurén, Hanna B; Michelsen, Kimmo A; Panula, Pertti; Holopainen, Irma E

    2012-06-01

    The central histaminergic neuron system is an important regulator of activity stages such as arousal and sleep. In several epilepsy models, histamine has been shown to modulate epileptic activity and histamine 1 (H1) receptors seem to play a key role in this process. However, little is known about the H1 receptor-mediated seizure regulation during the early postnatal development, and therefore we examined differences in severity of kainic acid (KA)-induced status epilepticus (SE) and consequent neuronal damage in H1 receptor knock out (KO) and wild type (WT) mice at postnatal days 14, 21, and 60 (P14, P21, and P60). Our results show that in P14 H1 receptor KO mice, SE severity and neuronal damage were comparable to those of WT mice, whereas P21 KO mice had significantly decreased survival, more severe seizures, and enhanced neuronal damage in various brain regions, which were observed only in males. In P60 mice, SE severity did not differ between the genotypes, but in KO group, neuronal damage was significantly increased. Our results suggest that H1 receptors could contribute to regulation of seizures and neuronal damage age-dependently thus making the histaminergic system as a challenging target for novel drug design in epilepsy. PMID:22348791

  4. Endpoint measures in the mdx mouse relevant for muscular dystrophy pre-clinical studies

    OpenAIRE

    Kobayashi, Yvonne M.; Rader, Erik P; Crawford, Robert W.; Campbell, Kevin P.

    2011-01-01

    Loss of mobility influences the quality of life for patients with neuromuscular diseases. Common measures of mobility and chronic muscle damage are the six-minute walk test and serum creatine kinase. Despite extensive pre-clinical studies of therapeutic approaches, characterization of these measures is incomplete. To address this, a six-minute ambulation assay, serum creatine kinase, and myoglobinuria were investigated for the mdx mouse, a dystrophinopathy mouse model commonly used in pre-cli...

  5. A reporter mouse for optical imaging of inflammation in mdx muscles

    OpenAIRE

    Martinez, L.; Ermolova, NV; Ishikawa, TO; Stout, DB; Herschman, HR; Spencer, MJ

    2015-01-01

    © 2015 Martinez et al.; licensee BioMed Central. Background: Duchenne muscular dystrophy (DMD) is due to mutations in the gene coding for human DMD; DMD is characterized by progressive muscle degeneration, inflammation, fat accumulation, and fibrosis. The mdx mouse model of DMD lacks dystrophin protein and undergoes a predictable disease course. While this model has been a valuable resource for pre-clinical studies aiming to test therapeutic compounds, its utility is compromised by a lack of ...

  6. Age-dependent changes in diastolic Ca{sup 2+} and Na{sup +} concentrations in dystrophic cardiomyopathy: Role of Ca{sup 2+} entry and IP{sub 3}

    Energy Technology Data Exchange (ETDEWEB)

    Mijares, Alfredo [Instituto Venezolano de Investigaciones Científicas, Centro de Biofísica y Bioquímica, Caracas (Venezuela, Bolivarian Republic of); Altamirano, Francisco [Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616 (United States); Kolster, Juan [Centro de Investigaciones Biomédicas, México D.F. (Mexico); Adams, José A. [Division of Neonatology, Mount Sinai Medical Center, Miami, FL 33140 (United States); López, José R., E-mail: jrlopez@ucdavis.edu [Instituto Venezolano de Investigaciones Científicas, Centro de Biofísica y Bioquímica, Caracas (Venezuela, Bolivarian Republic of); Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616 (United States)

    2014-10-03

    Highlights: • Age-dependent increase in [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} in mdx cardiomyocytes. • Gadolinium significantly reduced both [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} at all ages. • IP{sub 3}-pathway inhibition reduced cations concentrations in dystrophic cardiomyocytes. - Abstract: Duchenne muscular dystrophy (DMD) is a lethal X-inherited disease caused by dystrophin deficiency. Besides the relatively well characterized skeletal muscle degenerative processes, DMD is also associated with a dilated cardiomyopathy that leads to progressive heart failure at the end of the second decade. The aim of the present study was to characterize the diastolic Ca{sup 2+} concentration ([Ca{sup 2+}]{sub d}) and diastolic Na{sup +} concentration ([Na{sup +}]{sub d}) abnormalities in cardiomyocytes isolated from 3-, 6-, 9-, and 12-month old mdx mice using ion-selective microelectrodes. In addition, the contributions of gadolinium (Gd{sup 3+})-sensitive Ca{sup 2+} entry and inositol triphosphate (IP{sub 3}) signaling pathways in abnormal [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} were investigated. Our results showed an age-dependent increase in both [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} in dystrophic cardiomyocytes compared to those isolated from age-matched wt mice. Gd{sup 3+} treatment significantly reduced both [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} at all ages. In addition, blockade of the IP{sub 3}-pathway with either U-73122 or xestospongin C significantly reduced ion concentrations in dystrophic cardiomyocytes. Co-treatment with U-73122 and Gd{sup 3+} normalized both [Ca{sup 2+}]{sub d} and [Na{sup +}]{sub d} at all ages in dystrophic cardiomyocytes. These data showed that loss of dystrophin in mdx cardiomyocytes produced an age-dependent intracellular Ca{sup 2+} and Na{sup +} overload mediated at least in part by enhanced Ca{sup 2+} entry through Gd{sup 3+} sensitive transient receptor potential channels (TRPC), and by IP{sub 3} receptors.

  7. Lack of effect on the chromosomal non-disjunction in aged female mice after low dose x-irradiation

    International Nuclear Information System (INIS)

    Karyotypes were determined in 1064 embryos of aged C57/BL mothers. The virgin female mice were irradiated with 0, 4, 8 or 16 R of X-rays, respectively, and placed with young untreated males 5 days after irradiation. 10.5-days old embryos were recovered from the uterus. Aneuploid embryos classified as alive (heart beats observed at the dissection) were 1 monosomic in the control group (496 embryos) and 2 trisomics in the irradiated group (568 embryos). The number of aneuploid embryos classified as dead was 4 trisomic cases in the control group and 3 trisomics in the irradiated group. The data indicate that trisomic embryos are not uncommon in the mouse but are eliminated in post-implantation death. In contrast to the results of Yamamoto et al. the present data do not demonstrate an increased frequency of chromosome abnormalities in embryos of aged mice X-irradiated before mating as compared to non-irradiated ones

  8. Isolation Housing Exacerbates Alzheimer’s Disease-Like Pathophysiology in Aged APP/PS1 Mice

    OpenAIRE

    Huang, Huang; Wang, Linmei; Cao, Min; Marshall, Charles; Gao, Junying; XIAO, NA; Hu, Gang; Xiao, Ming

    2015-01-01

    Background: Alzheimer’s disease is a neurodegenerative disease characterized by gradual declines in social, cognitive, and emotional functions, leading to a loss of expected social behavior. Social isolation has been shown to have adverse effects on individual development and growth as well as health and aging. Previous experiments have shown that social isolation causes an early onset of Alzheimer’s disease-like phenotypes in young APP695/PS1-dE9 transgenic mice. However, the interactions be...

  9. Age-related trends in gene expression in the chemosensory-nasal mucosae of senescence-accelerated mice.

    Science.gov (United States)

    Getchell, Thomas V; Peng, Xuejun; Stromberg, Arnold J; Chen, Kuey-Chu; Paul Green, C; Subhedar, Nishikant K; Shah, Dharmen S; Mattson, Mark P; Getchell, Marilyn L

    2003-04-01

    We have utilized high-density GeneChip oligonucleotide arrays to investigate the use of the senescence-accelerated mouse (SAM) as a biogerontological resource to identify patterns of gene expression in the chemosensory-nasal mucosa. Gene profiling in chronologically young and old mice of the senescence-resistant (SAMR) and senescence-prone (SAMP) strains revealed 133 known genes that were modulated by a three-fold or greater change either in one strain or the other or in both strains during aging. We also identified known genes in our study which based on their encoded proteins were identified as aging-related genes in the aging neocortex and cerebellum of mice as reported by Lee et al. (2000) [Nat. Genet. 25 (2000) 294]. Changes in gene profiles for chemosensory-related genes including olfactory and vomeronasal receptors, sensory transduction-associated proteins, and odor and pheromone transport molecules in the young SAMR and SAMP were compared with age-matched C57BL/6J mice. An analysis of known gene expression profiles suggests that changes in the expression of immune factor genes and genes associated with cell cycle progression and cell death were particularly prominent in the old SAM strains. A preliminary cellular validation study supported the dysregulation of cell cycle-related genes in the old SAM strains. The results of our initial study indicated that the use of the SAM models of aging could provide substantive information leading to a more fundamental understanding of the aging process in the chemosensory-nasal mucosa at the genomic, molecular, and cellular levels. PMID:12605961

  10. High preservation of CpG cytosine methylation patterns at imprinted gene loci in liver and brain of aged mice.

    Directory of Open Access Journals (Sweden)

    Silvia Gravina

    Full Text Available A gradual loss of the correct patterning of 5-methyl cytosine marks in gene promoter regions has been implicated in aging and age-related diseases, most notably cancer. While a number of studies have examined DNA methylation in aging, there is no consensus on the magnitude of the effects, particularly at imprinted loci. Imprinted genes are likely candidate to undergo age-related changes because of their demonstrated plasticity in utero, for example, in response to environmental cues. Here we quantitatively analyzed a total of 100 individual CpG sites in promoter regions of 11 imprinted and non-imprinted genes in liver and cerebral cortex of young and old mice using mass spectrometry. The results indicate a remarkably high preservation of methylation marks during the aging process in both organs. To test if increased genotoxic stress associated with premature aging would destabilize DNA methylation we analyzed two DNA repair defective mouse models showing a host of premature aging symptoms in liver and brain. However, also in these animals, at the end of their life span, we found a similarly high preservation of DNA methylation marks. We conclude that patterns of DNA methylation in gene promoters of imprinted genes are surprisingly stable over time in normal, postmitotic tissues and that the multiple documented changes with age are likely to involve exceptions to this pattern, possibly associated with specific cellular responses to age-related changes other than genotoxic stress.

  11. Aged neuronal nitric oxide knockout mice show preserved olfactory learning in both social recognition and odor-conditioning tasks

    OpenAIRE

    Keith Maurice Kendrick

    2015-01-01

    There is evidence for both neurotoxic and neuroprotective roles of nitric oxide (NO) in the brain and changes in the expression of the neuronal isoform of nitric oxide synthase (nNOS) gene occur during aging. The current studies have investigated potential support for either a neurotoxic or neuroprotective role of NO derived from nNOS in the context of aging by comparing olfactory learning and locomotor function in young compared to old nNOS knockout (nNOS/-) and wildtype control mice. Tasks ...

  12. Aged neuronal nitric oxide knockout mice show preserved olfactory learning in both social recognition and odor-conditioning tasks

    OpenAIRE

    James, Bronwen M.; Li, Qin; Luo, Lizhu; Kendrick, Keith M.

    2015-01-01

    There is evidence for both neurotoxic and neuroprotective roles of nitric oxide (NO) in the brain and changes in the expression of the neuronal isoform of NO synthase (nNOS) gene occur during aging. The current studies have investigated potential support for either a neurotoxic or neuroprotective role of NO derived from nNOS in the context of aging by comparing olfactory learning and locomotor function in young compared to old nNOS knockout (nNOS−/−) and wildtype control mice. Tasks involving...

  13. Effects of exercise and dietary epigallocatechin gallate and β-alanine on skeletal muscle in aged mice.

    Science.gov (United States)

    Pence, Brandt D; Gibbons, Trisha E; Bhattacharya, Tushar K; Mach, Houston; Ossyra, Jessica M; Petr, Geraldine; Martin, Stephen A; Wang, Lin; Rubakhin, Stanislav S; Sweedler, Jonathan V; McCusker, Robert H; Kelley, Keith W; Rhodes, Justin S; Johnson, Rodney W; Woods, Jeffrey A

    2016-02-01

    Aging leads to sarcopenia and loss of physical function. We examined whether voluntary wheel running, when combined with dietary supplementation with (-)-epigallocatechin-3-gallate (EGCG) and β-alanine (β-ALA), could improve muscle function and alter gene expression in the gastrocnemius of aged mice. Seventeen-month-old BALB/cByJ mice were given access to a running wheel or remained sedentary for 41 days while receiving either AIN-93M (standard feed) or AIN-93M containing 1.5 mg·kg(-1) EGCG and 3.43 mg·kg(-1) β-ALA. Mice underwent tests over 11 days from day 29 to day 39 of the study period, including muscle function testing (grip strength, treadmill exhaustive fatigue, rotarod). Following a rest day, mice were euthanized and gastrocnemii were collected for analysis of gene expression by quantitative PCR. Voluntary wheel running (VWR) improved rotarod and treadmill exhaustive fatigue performance and maintained grip strength in aged mice, while dietary intervention had no effect. VWR increased gastrocnemius expression of several genes, including those encoding interleukin-6 (Il6, p = 0.001), superoxide dismutase 1 (Sod1, p = 0.046), peroxisome proliferator-activated receptor gamma coactivator 1-α (Ppargc1a, p = 0.013), forkhead box protein O3 (Foxo3, p = 0.005), and brain-derived neurotrophic factor (Bdnf, p = 0.008), while reducing gastrocnemius levels of the lipid peroxidation marker 4-hydroxynonenal (p = 0.019). Dietary intervention alone increased gastrocnemius expression of Ppargc1a (p = 0.033) and genes encoding NAD-dependent protein deacetylase sirtuin-1 (Sirt1, p = 0.039), insulin-like growth factor I (Igf1, p = 0.003), and macrophage marker CD11b (Itgam, p = 0.016). Exercise and a diet containing β-ALA and EGCG differentially regulated gene expression in the gastrocnemius of aged mice, while VWR but not dietary intervention improved muscle function. We found no synergistic effects between dietary intervention and VWR. PMID:26761622

  14. Age-related changes in the motricity of the inbred mice strains 129/sv and C57BL/6j.

    Science.gov (United States)

    Serradj, Najet; Jamon, Marc

    2007-02-12

    The development of motor skills was studied at different stages in the life of the mouse, focusing on three key aspects of motor development: early rhythmic motor activities prior to the acquisition of quadruped locomotion, motor skills in young adults, and the effect of aging on motor skills. The age-related development pattern was analysed and compared in two strains of major importance for genomic studies (C57Bl6/j and 129/sv). Early rhythmic air-stepping activities by l-dopa injected mice showed similar overall development in both strains; differences were observed with greater beating frequency and less inter-limb coordination in 129/sv, suggesting that 129/sv had a different maturation process. Performance on the rotarod by young adult C57Bl6/j gradually improved between 1 and 3 months, but then declined with age; performance on the treadmill also declined with an age-related increase in fatigability. Overall performance by 129/sv mice was lower than C57Bl6/j, and the age-related pattern of change was different, with 129/sv having relatively stable performance over time. Inter-strain differences and their possible causes, in particular the role of dopaminergic pathways, are discussed together with repercussions affecting mutant phenotyping procedures. PMID:17126421

  15. Impact of age on the cerebrovascular proteomes of wild-type and Tg-SwDI mice.

    Directory of Open Access Journals (Sweden)

    James L Searcy

    Full Text Available The structural integrity of cerebral vessels is compromised during ageing. Abnormal amyloid (Aβ deposition in the vasculature can accelerate age-related pathologies. The cerebrovascular response associated with ageing and microvascular Aβ deposition was defined using quantitative label-free shotgun proteomic analysis. Over 650 proteins were quantified in vessel-enriched fractions from the brains of 3 and 9 month-old wild-type (WT and Tg-SwDI mice. Sixty-five proteins were significantly increased in older WT animals and included several basement membrane proteins (nidogen-1, basement membrane-specific heparan sulfate proteoglycan core protein, laminin subunit gamma-1 precursor and collagen alpha-2(IV chain preproprotein. Twenty-four proteins were increased and twenty-one decreased in older Tg-SwDI mice. Of these, increases in Apolipoprotein E (APOE and high temperature requirement serine protease-1 (HTRA1 and decreases in spliceosome and RNA-binding proteins were the most prominent. Only six shared proteins were altered in both 9-month old WT and Tg-SwDI animals. The age-related proteomic response in the cerebrovasculature was distinctly different in the presence of microvascular Aβ deposition. Proteins found differentially expressed within the WT and Tg-SwDI animals give greater insight to the mechanisms behind age-related cerebrovascular dysfunction and pathologies and may provide novel therapeutic targets.

  16. Age-Dependent Decrease in Chaperone Activity Impairs MANF Expression, Leading to Purkinje Cell Degeneration in Inducible SCA17 Mice

    Science.gov (United States)

    Yang, Su; Huang, Shanshan; Gaertig, Marta A.; Li, Xiao-Jiang; Li, Shihua

    2016-01-01

    SUMMARY Although protein-misfolding-mediated neurodegenerative diseases have been linked to aging, how aging contributes to selective neurodegeneration remains unclear. We established spinocerebellar ataxia 17 (SCA17) knockin mice that inducibly express one copy of mutant TATA box binding protein (TBP) at different ages by tamoxifen-mediated Cre recombination. We find that more mutant TBP accumulates in older mouse and that this accumulation correlates with age-related decreases in Hsc70 and chaperone activity. Consistently, older SCA17 mice experienced earlier neurological symptom onset and more severe Purkinje cell degeneration. Mutant TBP shows decreased association with XBP1s, resulting in the reduced transcription of mesencephalic astrocyte-derived neurotrophic factor (MANF), which is enriched in Purkinje cells. Expression of Hsc70 improves the TBP-XBP1s interaction and MANF transcription, and overexpression of MANF ameliorates mutant TBP-mediated Purkinje cell degeneration via protein kinase C (PKC)-dependent signaling. These findings suggest that the age-related decline in chaperone activity affects polyglutamine protein function that is important for the viability of specific types of neurons. PMID:24462098

  17. Prevention of Neuromusculoskeletal Frailty in Slow-Aging Ames Dwarf Mice: Longitudinal Investigation of Interaction of Longevity Genes and Caloric Restriction

    OpenAIRE

    Arum, Oge; Rasche, Zachary Andrew; Rickman, Dustin John; Bartke, Andrzej

    2013-01-01

    Ames dwarf (Prop1 df/df ) mice are remarkably long-lived and exhibit many characteristics of delayed aging and extended healthspan. Caloric restriction (CR) has similar effects on healthspan and lifespan, and causes an extension of longevity in Ames dwarf mice. Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old) or old (128 ± 14 w.o.) mice. At the examined ages, strength was improved by dwarfism, CR, and d...

  18. Single administration of a novel γ-secretase modulator ameliorates cognitive dysfunction in aged C57BL/6J mice.

    Science.gov (United States)

    Hayama, Tatsuya; Murakami, Koji; Watanabe, Tomomichi; Maeda, Ryota; Kamata, Makoto; Kondo, Shinichi

    2016-02-15

    Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early onset of Alzheimer's disease (AD). These proteins comprise the catalytic domain of γ-secretase, which catalyzes the cleavage of β-amyloid (Aβ) from amyloid precursor protein (APP). In recent reports, PS1 and PS2 were linked to the modulation of intracellular calcium ion (Ca(2+)) dynamics, a key regulator of synaptic function. Ca(2+) dysregulation and synaptic dysfunction are leading hypothesis of cognitive dysfunctions during aging and AD progression. Accordingly, manipulations of presenilins by small molecules may have therapeutic potential for the treatment of cognitive dysfunction. In an accompanying report, we showed that chronic treatment with compound-1, a novel γ-secretase modulator (GSM), reduced Aβ production and ameliorated cognitive dysfunction in Tg2576 APP transgenic mice. Accordingly, in the present study we showed that single oral administration of compound-1 at 1 and 3mg/kg ameliorated cognitive dysfunction in aged non-transgenic mice. Moreover, compound-1 enhanced synaptic plasticity in hippocampal slices from aged C57BL/6J mice and increased messenger RNA (mRNA) expression of the immediate early gene c-fos, which has been shown to be related to synaptic plasticity in vivo. Finally, compound-1 modulated Ca(2+) signals through PS1 in mouse embryonic fibroblast cells. Taken together, compound-1 ameliorates both Aβ pathology and age-related cognitive dysfunctions. Hence, compound-1 may have potential as an early intervention for the cognitive declines that are commonly diagnosed in aged subjects, such as mild cognitive impairment (MCI) and prodromal AD. PMID:26707406

  19. In Vivo Antioxidant and Anti-Skin-Aging Activities of Ethyl Acetate Extraction from Idesia polycarpa Defatted Fruit Residue in Aging Mice Induced by D-Galactose

    Directory of Open Access Journals (Sweden)

    Yang Ye

    2014-01-01

    Full Text Available Two different concentrations of D-galactose (D-gal induced organism and skin aging in Kunming mice were used to examine comprehensively the antioxidant and antiaging activities of ethyl acetate extraction (EAE from Idesia polycarpa defatted fruit residue for the first time. The oxygen radical absorbance capacity (ORAC of EAE was 13.09 ± 0.11 μmol Trolox equivalents (TE/mg, which showed EAE had great in vitro free radical scavenging and antioxidant activity. Biochemical indexes and morphological analysis of all tested tissues showed that EAE could effectively improve the total antioxidant capacity (T-AOC of the antioxidant defense system of the aging mice, enhance the activities of superoxide dismutase (SOD, catalase (CAT, and glutathione peroxidase (GSH-Px of tissues and serum, increase glutathione (GSH content and decrease the malondialdehyde (MDA content, and maintain the skin collagen, elastin, and moisture content. Meanwhile, EAE could effectively attenuate the morphological damage in brain, liver, kidney, and skin induced by D-gal and its effect was not less than that of the well-known L-ascorbic acid (VC and α-tocopherol (VE. Overall, EAE is a potent natural antiaging agent with great antioxidant activity, which can be developed as a new medicine and cosmetic for the treatment of age-related conditions.

  20. Early maternal separation impacts cognitive flexibility at the age of first independence in mice.

    Science.gov (United States)

    Thomas, A Wren; Caporale, Natalia; Wu, Claudia; Wilbrecht, Linda

    2016-04-01

    Early life adversity is associated with increased risk for mental and physical health problems, including substance abuse. Changes in neural development caused by early life insults could cause or complicate these conditions. Maternal separation (MS) is a model of early adversity for rodents. Clear effects of MS have been shown on behavioral flexibility in rats, but studies of effects of MS on cognition in mice have been mixed. We hypothesized that previous studies focused on adult mice may have overlooked a developmental transition point when juvenile mice exhibit greater flexibility in reversal learning. Here, using a 4-choice reversal learning task we find that early MS leads to decreased flexibility in post-weaning juvenile mice, but no significant effects in adults. In a further study of voluntary ethanol consumption, we found that adult mice that had experienced MS showed greater cumulative 20% ethanol consumption in an intermittent access paradigm compared to controls. Our data confirm that the MS paradigm can reduce cognitive flexibility in mice and may enhance risk for substance abuse. We discuss possible interpretations of these data as stress-related impairment or adaptive earlier maturation in response to an adverse environment. PMID:26531108

  1. Effect of Glycowithanolides on Fucose Content in Salivary Glands of Aged Mice

    Directory of Open Access Journals (Sweden)

    R. N. Mote

    2013-03-01

    Full Text Available Glycowithanolides (WSG is the extract of Withania somnifera leaves was tested to find its effect on fucose content in salivary glands of D-galactose(Dg stressed adult and old male mice (Mus musculus. Adult and old male mice were divided in to protective group and curative group. Both the groups were further divided into four batchesviz. 1st is the control batch received 0.5 ml 0.9 % saline per day for 20 and 40 days for protective and curative group respectively. Mice from 2nd, 3rd and 4th batches of protective group received 0.5 ml D-galactose (Dg, Dg+ centrophenoxine(CPH and D-galactose (Dg + (WSG respectively for 20 days. Mice from 2nd, 3rd and 4th batches of curative group received 0.5 ml D-galactose (Dg for 20 days then followed by 0.5ml saline, centrophenoxine and WSG alone for further 20 days respectively. Fucose content (μg/mg proteins in salivary glands was estimated. In Dgalactose stressed adult and old mice it was decreased significantly, but restored by the treatment of WSG andcentrophenoxine. The restoration was not exactly up to the normal level but was near to the normal level in adult. In D-galactose stressed old mice there was restoration in fucose content but it was not like that of adult. Restoration was significantly higher in WSG treatment. Thus WSG can be used as a powerful natural antioxidant andantistresser.

  2. In Vivo Antioxidant and Anti-Skin-Aging Activities of Ethyl Acetate Extraction from Idesia polycarpa Defatted Fruit Residue in Aging Mice Induced by D-Galactose

    OpenAIRE

    Yang Ye; Ran-ran Jia; Lin Tang; Fang Chen

    2014-01-01

    Two different concentrations of D-galactose (D-gal) induced organism and skin aging in Kunming mice were used to examine comprehensively the antioxidant and antiaging activities of ethyl acetate extraction (EAE) from Idesia polycarpa defatted fruit residue for the first time. The oxygen radical absorbance capacity (ORAC) of EAE was 13.09 ± 0.11  μ mol Trolox equivalents (TE)/mg, which showed EAE had great in vitro free radical scavenging and antioxidant activity. Biochemical indexes and morph...

  3. Exercise intervention increases spontaneous locomotion but fails to attenuate dopaminergic system loss in a progressive MPTP model in aged mice.

    Science.gov (United States)

    Hood, Rebecca L; Liguore, William A; Moore, Cynthia; Pflibsen, Lacey; Meshul, Charles K

    2016-09-01

    While exercise is commonly recommended for PD patients to improve motor function, little is known about the disease-altering potential of exercise. Although others have demonstrated neuroprotective or neurorestorative effects of exercise in animal models of PD, the majority of these studies utilize young animals. In order to assess the effects of exercise intervention in a more clinically relevant model, we have subjected aged mice to progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioning and daily treadmill exercise, initiated early in the course of the disease. The MPTP model elicited a 55% reduction in striatal TH as measured by immunohistochemistry compared to sedentary controls, and exercise did not attenuate this loss in exercised MPTP animals. Furthermore, striatal TH and DAT loss, as assessed by western blotting, were not significantly impacted by treadmill exercise in MPTP-lesioned mice. We did find an increase in spontaneous locomotion in exercised mice that was not decreased by MPTP lesioning. This finding may be due, in part, to an increase in TH expression in the motor cortex in exercised MPTP mice. PMID:27350080

  4. Life span of C57 mice as influenced by radiation dose, dose rate, and age at exposure

    International Nuclear Information System (INIS)

    This study was designed to measure the life shortening of C57BL/6J male mice as a result of exposure to five external doses from 60Co gamma radiation delivered at six different dose rates. Total doses ranged from 20 to 1620 rad at exposure rates ranging from 0.7 to 36,000 R/day. The ages of the mice at exposure were newborn, 2, 6, or 15 months. Two replications were completed. Although death was the primary endpoint, we did perform gross necropsies. The life span findings are variable, but we found no consistent shortening compared to control life spans. Therefore, we cannot logically extrapolate life shortening to lower doses, from the data we have obtained. In general, the younger the animals were at the beginning of exposure, the longer their life spans were compared to those of controls. This relationship weakened at the higher doses and dose rates, as mice in these categories tended not to have significantly different life spans from controls. Using life span as a criterion, we find this study suggests that some threshold dosage may exist beyond which effects of external irradiation may be manifested. Up to this threshold, there is no shortening effect on life span compared to that of control mice. Our results are in general agreement with the results of other researchers investigating human and other animal life span effects on irradiation

  5. Recovery of induced mutations for X chromosome-linked muscular dystrophy in mice.

    OpenAIRE

    Chapman, V M; Miller, D R; Armstrong, D; Caskey, C. T.

    1989-01-01

    We have used elevated levels of plasma creatine phosphokinase activity to identify muscular dystrophy phenotypes in mice and to screen the progeny of chemical mutagen-treated male mice for X chromosome-linked muscular dystrophy mutations. We were not successful in identifying heterozygous carriers of these induced muscular dystrophy mutations in greater than 8000 progeny. However, we were highly successful in identifying three additional alleles of the characterized mdx locus. These alleles o...

  6. Age- and light-dependent development of localised retinal atrophy in CCL2(-/-CX3CR1(GFP/GFP mice.

    Directory of Open Access Journals (Sweden)

    Mei Chen

    Full Text Available Previous studies have shown that CCL2/CX3CR1 deficient mice on C57BL/6N background (with rd8 mutation have an early onset (6 weeks of spontaneous retinal degeneration. In this study, we generated CCL2(-/-CX3CR1(GFP/GFP mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2(-/-CX3CR1(GFP/GFP mice younger than 6 months. Patches of whitish/yellowish fundus lesions were observed in 17∼60% of 12-month, and 30∼100% of 18-month CCL2(-/-CX3CR1(GFP/GFP mice. Fluorescein angiography revealed no choroidal neovascularisation in these mice. Patches of retinal pigment epithelium (RPE and photoreceptor damage were detected in 30% and 50% of 12- and 18-month CCL2(-/-CX3CR1(GFP/GFP mice respectively, but not in wild-type mice. All CCL2(-/-CX3CR1(GFP/GFP mice exposed to extra-light (∼800lux, 6 h/day, 6 months developed patches of retinal atrophy, and only 20-25% of WT mice which underwent the same light treatment developed atrophic lesions. In addition, synaptophysin expression was detected in the outer nucler layer (ONL of area related to photoreceptor loss in CCL2(-/-CX3CR1(GFP/GFP mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL2(-/-CX3CR1(GFP/GFP mice. GABA expression was reduced in the inner retina of aged CCL2(-/-CX3CR1(GFP/GFP mice. Significantly increased Müller glial and microglial activation was observed in CCL2(-/-CX3CR1(GFP/GFP mice compared to age-matched WT mice. Macrophages from CCL2(-/-CX3CR1(GFP/GFP mice were less phagocytic, but expressed higher levels of iNOS, IL-1β, IL-12 and TNF-α under hypoxia conditions. Our results suggest that the deletions of CCL2 and CX3CR1 predispose mice to age- and light-mediated retinal damage. The CCL2/CX3CR1 deficient mouse may thus serve as a model for age-related atrophic degeneration of the RPE, including the dry type of macular degeneration, geographic atrophy.

  7. Whole-Body Vibration Partially Reverses Aging-Induced Increases in Visceral Adiposity and Hepatic Lipid Storage in Mice

    Science.gov (United States)

    van Dijk, Theo H.; Havinga, Rick; van der Zee, Eddy A.; Groen, Albert K.; Reijngoud, Dirk-Jan; Bakker, Barbara M.; van Dijk, Gertjan

    2016-01-01

    At old age, humans generally have declining muscle mass and increased fat deposition, which can increase the risk of developing cardiometabolic diseases. While regular physical activity postpones these age-related derangements, this is not always possible in the elderly because of disabilities or risk of injury. Whole-body vibration (WBV) training may be considered as an alternative to physical activity particularly in the frail population. To explore this possibility, we characterized whole-body and organ-specific metabolic processes in 6-month and 25-month old mice, over a period of 14 weeks of WBV versus sham training. WBV training tended to increase blood glucose turnover rates and stimulated hepatic glycogen utilization during fasting irrespective of age. WBV was effective in reducing white fat mass and hepatic triglyceride content only in old but not in young mice and these reductions were related to upregulation of hepatic mitochondrial uncoupling of metabolism (assessed by high-resolution respirometry) and increased expression of uncoupling protein 2. Because these changes occurred independent of changes in food intake and whole-body metabolic rate (assessed by indirect calorimetry), the liver-specific effects of WBV may be a primary mechanism to improve metabolic health during aging, rather than that it is a consequence of alterations in energy balance. PMID:26886917

  8. Whole-Body Vibration Partially Reverses Aging-Induced Increases in Visceral Adiposity and Hepatic Lipid Storage in Mice.

    Directory of Open Access Journals (Sweden)

    Aaffien C Reijne

    Full Text Available At old age, humans generally have declining muscle mass and increased fat deposition, which can increase the risk of developing cardiometabolic diseases. While regular physical activity postpones these age-related derangements, this is not always possible in the elderly because of disabilities or risk of injury. Whole-body vibration (WBV training may be considered as an alternative to physical activity particularly in the frail population. To explore this possibility, we characterized whole-body and organ-specific metabolic processes in 6-month and 25-month old mice, over a period of 14 weeks of WBV versus sham training. WBV training tended to increase blood glucose turnover rates and stimulated hepatic glycogen utilization during fasting irrespective of age. WBV was effective in reducing white fat mass and hepatic triglyceride content only in old but not in young mice and these reductions were related to upregulation of hepatic mitochondrial uncoupling of metabolism (assessed by high-resolution respirometry and increased expression of uncoupling protein 2. Because these changes occurred independent of changes in food intake and whole-body metabolic rate (assessed by indirect calorimetry, the liver-specific effects of WBV may be a primary mechanism to improve metabolic health during aging, rather than that it is a consequence of alterations in energy balance.

  9. BubR1 Insufficiency Impairs Liver Regeneration in Aged Mice after Hepatectomy through Intercalated Disc Abnormality.

    Science.gov (United States)

    Ikawa-Yoshida, Ayae; Matsumoto, Takuya; Okano, Shinji; Aoyagi, Yukihiko; Matsubara, Yutaka; Furuyama, Tadashi; Nakatsu, Yoshimichi; Tsuzuki, Teruhisa; Onimaru, Mitsuho; Ohkusa, Tomoko; Nomura, Masatoshi; Maehara, Yoshihiko

    2016-01-01

    A delay in liver regeneration after partial hepatectomy (PHx) leads to acute liver injury, and such delays are frequently observed in aged patients. BubR1 (budding uninhibited by benzimidazole-related 1) controls chromosome mitotic segregation through the spindle assembly checkpoint, and BubR1 down-regulation promotes aging-associated phenotypes. In this study we investigated the effects of BubR1 insufficiency on liver regeneration in mice. Low-BubR1-expressing mutant (BubR1(L/L)) mice had a delayed recovery of the liver weight-to-body weight ratio and increased liver deviation enzyme levels after PHx. Microscopic observation of BubR1(L/L) mouse liver showed an increased number of necrotic hepatocytes and intercalated disc anomalies, resulting in widened inter-hepatocyte and perisinusoidal spaces, smaller hepatocytes and early-stage microvilli atrophy. Up-regulation of desmocollin-1 (DSC1) was observed in wild-type, but not BubR1(L/L), mice after PHx. In addition, knockdown of BubR1 expression caused down-regulation of DSC1 in a human keratinocyte cell line. BubR1 insufficiency results in the impaired liver regeneration through weakened microstructural adaptation against PHx, enhanced transient liver failure and delayed hepatocyte proliferation. Thus, our data suggest that a reduction in BubR1 levels causes failure of liver regeneration through the DSC1 abnormality. PMID:27561386

  10. Biomarkers of aging, life span and spontaneous carcinogenesis in the wild type and HER-2 transgenic FVB/N female mice.

    Science.gov (United States)

    Panchenko, Andrey V; Popovich, Irina G; Trashkov, Alexandr P; Egormin, Peter A; Yurova, Maria N; Tyndyk, Margarita L; Gubareva, Ekaterina A; Artyukin, Ilia N; Vasiliev, Andrey G; Khaitsev, Nikolai V; Zabezhinski, Mark A; Anisimov, Vladimir N

    2016-04-01

    FVB/N wild type and transgenic HER-2/neu FVB/N female mice breed at N.N. Petrov Research Institute of Oncology were under observation until natural death without any special treatment. Age-related dynamics of body weight, food consumption and parameters of carbohydrate and lipid metabolism, level of nitric oxide, malonic dialdehyde, catalase, Cu, Zn-superoxide dismutase, vascular endothelial growth factor were studied in both mice strains. The parameters of life span and tumor pathology were studied as well. Cancer-prone transgenic HER-2/neu mice developed in 100 % multiple mammary adenocarcinomas and died before the age of 1 year. Forty tree percent of long-lived wild type mice survived the age of 2 years and 19 %-800 days. The total tumor incidence in wild type mice was 34 %. The age-associated changes in the level of serum IGF-1, glucose and insulin started much earlier in transgene HER-2/neu mice as compared with wild type FVB/N mice. It was suggested that transgenic HER-2/neu involves in initiation of malignization of mammary epithelial cells but also in acceleration of age-related hormonal and metabolic changes in turn promoting mammary carcinogenesis. PMID:26423570

  11. Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide

    Institute of Scientific and Technical Information of China (English)

    Yan JIANG; Jing ZHAO; Hui-jing QI; Xiao-lin LI; Shi-rong ZHANG; Daniel W.SONG; Chi-yang YU

    2013-01-01

    Busulfan/cyclophosphamide (Bu/Cy) conditioning regimen has been widely used to treat cancer patients,while their effects on major internal organs in females are not fully understood.We treated female mice with Bu/Cy,and examined the histopathology of major internal organs on Day 30 after the treatment.The results show that Bu/Cy treatment affected the ovaries most extensively,while it had less effect on the spleen,lungs,and kidneys,and no effect on the heart,liver,stomach,and pancreas.To better understand the effect of Bu/Cy on the ovaries,we counted follicles,and determined the levels of ovarian steroids.The Bu/Cy-treated mice showed a reduction of primordial and primary follicles (P<0.01) on Day 30 and a marked loss of follicles at all developmental stages (P<0.01) on Day 60.Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%,respectively.Thus,there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice; this is a profile similar to what is found in women with premature ovarian failure (POF).The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF.

  12. Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal ERK and PI3K activation

    OpenAIRE

    Fan, Lu; Zhao, Zaorui; Orr, Patrick T.; Chambers, Cassie H.; Michael C. Lewis; Frick, Karyn M.

    2010-01-01

    We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17β-estradiol (E2) to enhance novel object recognition in young ovariectomized mice (Fernandez et al., 2008). Here, we asked whether E2 has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, and whether these effects depend on ERK and phosphatidylinositol 3-kinase (PI3K)/Akt activation. We first demonstrated that intracerebroventricular (ICV) E2...

  13. Anti-free radical, anti-oxidative ability and anti-fatigue effects of Huanshaodan An experiment of aging mice

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    BACKGROUND: In the theory of traditional Chinese medicine, aging is mainly thought renal deficiency caused renal failure, mainly involving decline of kidney-Yang and deficiency of kidney-essence.Huanshaodan, a Chinese traditional preparation for kidney-replenishing essence, was used to be the preparation for reinforcing renal deficiency and preventing aging for aged people.OBJECTIVE: To observe the effects of Huanshaodan on swimming durance and the abilities of catalase(CAT) in serum and monoamine oxidase-B (MAO-B) in brain tissue as well as in vitro anti-oxidative ability of aging mouse.DESIGN: A controlled animal experiment.SETTING: College of Basic Medicine, Hunan University of Traditional Chinese Medicine.MATERIALS: Fifty-four healthy NIH mice, aged 18 months old, of either gender, weighing (48.9 ± 5.4) g,and one SD male rat, aged 16 months old, weighing 51.7 g, were provided by Animal Experimental Center,Hunan University of Traditional Chinese Medicine. Thirty NIH mice were randomly chosen for swimming test, and divided into experimental group and control group, with 15 in each; The other 24 NIH mice were used for enzyme activity assay, and also divided into experimental group and control group, with 12 in each.SD rat was used for in vitro anti-oxidative ability test. Huanshaodan water decoction was composed of Cheqianzi, Wuweizi, Huaishan, Danggui, Huangbai, Shudi, Baizhi, Niuxi, Baishen, Tusizi, Buguzhi,Roucongrong and Heshouwu 13 Chinese herbs.METHODS: This study was carried out in the Second Laboratory, Department of Biochemistry, Hunan University of Traditional Chinese Medicine in June 2006. Swimming and enzyme activity assay: Mice in the two experimental groups were intragastrically administrated with 10 μ L/g Huanshaodan water decoction.Mice in the two control groups were intragastrically administrated with the same amount of normal saline.All the mice were intragastrically administrated for 5 days, and they were free to access to medicine in the

  14. Interaction between diazepam and hippocampal corticosterone after acute stress: impact on memory in middle-aged mice

    Directory of Open Access Journals (Sweden)

    Daniel eBeracochea

    2011-04-01

    Full Text Available Benzodiazepines (BDZ are widely prescribed in the treatment of anxiety disorders associated to aging. Interestingly, whereas a reciprocal interaction between the GABAergic system and HPA axis has been evidenced, there is to our knowledge no direct evaluation of the impact of BDZ on both hippocampus (HPC corticosterone concentrations and HPC-dependent memory in stressed middle-aged subjects. We showed previously that an acute stress induced in middle-aged mice severe memory impairments in a hippocampus-dependent task, and increased in parallel hippocampus corticosterone concentrations, as compared to non stressed middle-aged controls (Tronche et al., 2010. Based on these findings, the aims of the present study were to evidence the impact of diazepam (a positive allosteric modulator of the GABA-A receptor on HPC glucocorticoids concentrations and in parallel on HPC-dependent memory in acutely stressed middle-aged mice.Microdialysis experiments showed an interaction between diazepam doses and corticosterone concentrations into the HPC. From 0.25 mg/kg to 0.5 mg/kg, diazepam dose-dependently reduces intra-HPC corticosterone concentrations and in parallel, dose-dependently increased hippocampal-dependent memory performance. In contrast, the highest (1.0mg/kg diazepam dose induces a reduction in HPC corticosterone concentration, which was of greater magnitude as compared to the two other diazepam doses, but however decreased the hippocampal-dependent memory performance. In summary, our study provides first evidence that diazepam restores in stressed middle-aged animals the hippocampus-dependent response, in relation with HPC corticosterone concentrations. Overall, our data illustrate how stress and benzodiazepines could modulate cognitive functions depending on hippocampus activity.

  15. Prevention of neuromusculoskeletal frailty in slow-aging ames dwarf mice: longitudinal investigation of interaction of longevity genes and caloric restriction.

    Directory of Open Access Journals (Sweden)

    Oge Arum

    Full Text Available Ames dwarf (Prop1 (df/df mice are remarkably long-lived and exhibit many characteristics of delayed aging and extended healthspan. Caloric restriction (CR has similar effects on healthspan and lifespan, and causes an extension of longevity in Ames dwarf mice. Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old or old (128 ± 14 w.o. mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age. This study serves as a particularly important example of knowledge related to addressing aging-associated diseases and disorders that results from studies in long-lived mammals.

  16. The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4⁺ T-cell compartment.

    Science.gov (United States)

    Nusser, Anja; Nuber, Natko; Wirz, Oliver F; Rolink, Hannie; Andersson, Jan; Rolink, Antonius

    2014-10-01

    Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8-12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4(+) T-cell dependent, since old (40-50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age-related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4(+) T cells that promote ANA production were radioresistant. Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T-cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T-cell homeostasis may drive the onset of some autoimmune features. PMID:25044476

  17. Effect of sex and age on the frequency of tumors arising in non-linear mice exposed to total gamma irradiation

    International Nuclear Information System (INIS)

    The effect of sex and age of nonlinear mice on the frequency of tumours was studied. Nonlinear mice of the SHK colony of both sexes were gamma-irradiated with 137Cs. The histological material, frequency and time of tumour appearance were investigated in dependence on age. Single exposure accelerated the appearance of tumours of the hemopoietic tissue in females and lung and liver tumours in males. The irradiation increased the frequency of tumour appearance in females. The frequency of mammary gland tumours increased under irradiation of females of older age. Ovary tumours developed irrespective of mouse age by the time of irradiation. Average longevity reduced only in young females

  18. Premature aging phenotype in mice lacking high affinity nicotinic receptors: region specific changes in layer V pyramidal cell morphology

    Directory of Open Access Journals (Sweden)

    Eleni Konsolaki

    2014-02-01

    Full Text Available The mechanisms by which aging leads to alterations in brain structure and cognitive deficits are unclear. A central yet presently unresolved issue in aging research concerns the distinction between normal/successful aging, consisting of a moderate decline in cognitive performance, and pathological aging, manifested as mild cognitive impairment or full-blown neurodegeneration and dementia. In particular, it has been proposed that the age-related decline in cognitive abilities may be an age-related escalation of early-life cognitive limitations, rather than an abruptly emerging neuropathological process that occurs in old age (Elias et al., 2000; Small et al., 2000; Sarter and Bruno, 2004; Amieva et al., 2005; Tyas et al., 2007. In this scenario, early abnormalities or incompletely matured neural systems would interact with age-related processes to explain the cognitive decline in later ages. However this proposal remains controversial (Nilsson et al., 2009; Salthouse, 2009 and, to our knowledge, has not been explored at the morphological/structural level. Hence it is important to identify factors that may confer a predisposition to pathological aging and examine how they interact with the process of aging per se. One such factor is the integrity of the cholinergic system: cholinergic basal forebrain neurons and their projections to the cortex show increased vulnerability to aging (Fischer et al., 1987; Altavista et al., 1990; Casu et al., 2002 and cognitive decline is associated with selective loss of neuronal nicotinic acetylcholine receptor (nAChR function (Hellstrom-Lindahl and Court, 2000; Schliebs and Arendt, 2011. In this respect, animals with specific cholinergic deficits are important tools for understanding the neurobiology of successful aging. One such animal model is the β2-/- mouse, in which the gene encoding the β2 subunit of the nAChR is genetically deleted (Picciotto et al., 1995. Aged β2-/- mice have been proposed as a model of

  19. The antioxidant effect of astaxanthin is higher in young mice than aged: a region specific study on brain.

    Science.gov (United States)

    Al-Amin, Md Mamun; Akhter, Samiha; Hasan, Ahmed Tasdid; Alam, Tanzir; Nageeb Hasan, S M; Saifullah, A R M; Shohel, Mohammad

    2015-10-01

    Astaxanthin is a potential antioxidant which shows neuroprotective property. We aimed to investigate the age-dependent and region-specific antioxidant effects of astaxanthin in mice brain. Animals were divided into 4 groups; treatment young (3 months, n = 6) (AY), treatment old (16 months, n = 6) (AO), placebo young (3 months, n = 6) (PY) and placebo old (16 months, n = 6) (PO) groups. Treatment group was given astaxanthin (2 mg/kg/day, body weight), and placebo group was given 100 μl of 0.9% normal saline orally to the healthy Swiss albino mice for 4 weeks. The level of non-enzymatic oxidative markers namely malondialdehyde (MDA); nitric oxide (NO); advanced protein oxidation product (APOP); glutathione (GSH) and the activity of enzymatic antioxidants i.e.; catalase (CAT) and superoxide dismutase (SOD) were determined from the isolated brain regions. Treatment with astaxanthin significantly (p Astaxanthin markedly (p astaxanthin is age-dependent, higher in young in compared to the aged brain. PMID:26116165

  20. In silico analysis of gene expression profiles in the olfactory mucosae of aging senescence-accelerated mice.

    Science.gov (United States)

    Getchell, Thomas V; Peng, Xuejun; Green, C Paul; Stromberg, Arnold J; Chen, Kuey-Chu; Mattson, Mark P; Getchell, Marilyn L

    2004-08-01

    We utilized high-density Affymetrix oligonucleotide arrays to investigate gene expression in the olfactory mucosae of near age-matched aging senescence-accelerated mice (SAM). The senescence-prone (SAMP) strain has a significantly shorter lifespan than does the senescence-resistant (SAMR) strain. To analyze our data, we applied biostatistical methods that included a correlation analysis to evaluate sources of methodologic and biological variability; a two-sided t-test to identify a subpopulation of Present genes with a biologically relevant P-value SAMRs (SAMR-Os, 12.5 months). Volcano plots related the variability in the mean hybridization signals as determined by the two-sided t-test to fold changes in gene expression. The genes were categorized into the six functional groups used previously in gene profiling experiments to identify candidate genes that may be relevant for senescence at the genomic and cellular levels in the aging mouse brain (Lee et al. [2000] Nat Genet 25:294-297) and in the olfactory mucosa (Getchell et al. [2003] Ageing Res Rev 2:211-243), which serves several functions that include chemosensory detection, immune barrier function, xenobiotic metabolism, and neurogenesis. Because SAMR-Os and SAMP-Os have substantially different median lifespans, we related the rate constant alpha in the Gompertz equation on aging to intrinsic as opposed to environmental mechanisms of senescence based on our analysis of genes modulated during aging in the olfactory mucosa. PMID:15248299

  1. Aging impairs hippocampus-dependent long-term memory for object location in mice

    OpenAIRE

    Wimmer, Mathieu; Hernandez, Pepe; Blackwell, Jennifer; Abel, Ted

    2011-01-01

    The decline in cognitive function that accompanies normal aging has a negative impact on the quality of life of the elderly and their families. Studies in humans and rodents show that spatial navigation and other hippocampus-dependent functions are particularly vulnerable to the deleterious effects of aging. However, reduced motor activity and alterations in the stress response that accompany normal aging can hinder the ability to study certain cognitive behaviors in aged animals. In an attem...

  2. BDNF pathway is involved in the protective effects of SS-31 on isoflurane-induced cognitive deficits in aging mice.

    Science.gov (United States)

    Wu, Jing; Zhang, Mingqiang; Li, Huihui; Sun, Xiaoru; Hao, Shuangying; Ji, Muhuo; Yang, Jianjun; Li, Kuanyu

    2016-05-15

    Mitochondrial dysfunction has been linked to the earliest pathogenesis of isoflurane-induced cognitive impairments in developing or aging mammalian brain. However, its molecular mechanism is poorly understood and a pharmacologic treatment to rapidly reverse mitochondrial dysfunction is lacking. Fifteen-month-old male C57BL/6 mice were exposed to isoflurane for two hours following intraperitoneal administration of mitochondrion-targeted peptide SS-31 or vehicle with 30min interval. The hippocampus was immediately removed for biochemical assays and mitochondria isolation after inhalation. Behavioral tests were evaluated by the open field test and fear conditioning test 24h after the experiment. We showed that cognitive deficits induced by exposure of the aging mice to isoflurane were accompanied by mitochondrial dysfunction in hippocampus due to loss of the enzymatic activity of complex I. This loss resulted in the increase of reactive oxygen species production, decrease of ATP production and mitochondrial membrane potential, and opening of mitochondrial permeability transition pore. Further, we provided evidence that the BDNF signaling pathway was involved in this process to regulate synaptic plasticity-related proteins, for instance, downregulation of synapsin 1, PSD-95 and p-CREB, and upregulation of NR2A, NR2B, CaMKIIα and CaMKIIβ. Of note, the isoflurane-induced cognitive deficits were rescued by SS-31 through reversal of mitochondrial dysfunction, which facilitated the regulation of BDNF signaling including the expression reversal of aforementioned important synaptic-signaling proteins in aging mice. Our data demonstrate that reversing mitochondrial dysfunction by SS-31 enhances BDNF signaling pathway and synaptic plasticity, and provides protective effects on cognitive function, thereby support the notion that SS-31 may have therapeutic benefits for elderly humans undertaking anesthesia. PMID:26944333

  3. Long term low dose rate irradiation causes recovery from type II diabetes and suppression of aging in type II diabetes-prone mice

    International Nuclear Information System (INIS)

    The effects of low dose rate gamma irradiation on model C57BL/KsJ-db/db mice with Type II diabetes mellitus was investigated. These mice develop Type II diabetes by 10 weeks of age, due to obesity, and are characterized by hyperinsulinemia. A group of 12 female 10-week old mice were irradiated at 0.65 mGy/hr in the low dose rate irradiation facility in the Low Dose Radiation Research Center. The urine glucose levels of all of the mice were strongly positive at the beginning of the irradiation. In the irradiated group, a decrease in the glucose level was observed in three mice, one in the 35th week, another in the 52nd week and the third in the 80th week. No recovery from the diabetes was observed in the 12 mice of non-irradiated control group. There was no systematic change of body weight or consumption of food and drinking water between the irradiated group and the non-irradiated group or between the recovered mice and the non-recovered mice. Survival was better in the irradiated group. The surviving fraction at the age of 90 weeks was 75 % in the irradiated group but only 40 % in the non-irradiated. A marked difference was also observed in the appearance of the coat hair, skin and tail. The irradiated group was in much better condition. Mortality was delayed and the healthy appearance was prolonged in the irradiated mice by about 20-30 weeks compared with the control mice. These results suggest that the low dose irradiation modified the condition of the diabetic mice, leading not only to recovery from diabetes, but also to suppression of the aging process

  4. Aged Tgfβ2/Gdnf double-heterozygous mice show no morphological and functional alterations in the nigrostriatal system

    OpenAIRE

    Heermann, Stephan; Opazo, Felipe; Falkenburger, Björn; Krieglstein, Kerstin; Spittau, Björn

    2010-01-01

    Loss of dopaminergic neurons in the substantia nigra pars compacta and the resulting decrease in striatal dopamine levels are the hallmarks of Parkinson’s disease. Tgfβ and Gdnf have been identified as neurotrophic factors for dopaminergic midbrain neurons in vivo and in vitro. Haploinsufficiency for either Tgfβ or Gdnf led to dopaminergic deficits. In this study we therefore analyzed the nigrostriatal system of aged Tgfβ2 +/−/Gdnf +/− double-heterozygous mice. Unexpectedly, we found no morph...

  5. Vulnerability to nicotine self-administration in adolescent mice correlates with age-specific expression of α4* nicotinic receptors.

    Science.gov (United States)

    Renda, Anthony; Penty, Nora; Komal, Pragya; Nashmi, Raad

    2016-09-01

    The majority of smokers begin during adolescence, a developmental period with a high susceptibility to substance abuse. Adolescents are affected differently by nicotine compared to adults, with adolescents being more vulnerable to nicotine's rewarding properties. It is unknown if the age-dependent molecular composition of a younger brain contributes to a heightened susceptibility to nicotine addiction. Nicotine, the principle pharmacological component of tobacco, binds and activates nicotinic acetylcholine receptors (nAChRs) in the brain. The most prevalent is the widely expressed α4-containing (α4*) subtype which mediates reward and is strongly implicated in nicotine dependence. Exposing different age groups of mice, postnatal day (P) 44-86 days old, to a two bottle-choice oral nicotine self-administration paradigm for five days yielded age-specific consumption levels. Nicotine self-administration was elevated in the P44 group, peaked at P54-60 and was drastically lower in the P66 through P86 groups. We also quantified α4* nAChR expression via spectral confocal imaging of brain slices from α4YFP knock-in mice, in which the α4 nAChR subunit is tagged with a yellow fluorescent protein. Quantitative fluorescence revealed age-specific α4* nAChR expression in dopaminergic and GABAergic neurons of the ventral tegmental area. Receptor expression showed a strong positive correlation with daily nicotine dose, suggesting that α4* nAChR expression levels are age-specific and may contribute to the propensity to self-administer nicotine. PMID:27102349

  6. ADAM12 Alleviates the Skeletal Muscle Pathology in mdx Dystrophic Mice

    OpenAIRE

    Kronqvist, Pauliina; Kawaguchi, Nobuko; Albrechtsen, Reidar; Xu, Xiufeng; Schrøder, Henrik Daa; Moghadaszadeh, Behzad; Nielsen, Finn Cilius; Fröhlich, Camilla; Engvall, Eva; Wewer, Ulla M.

    2002-01-01

    Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 over...

  7. Debio-025 is more effective than prednisone in reducing muscular pathology in mdx mice

    OpenAIRE

    Wissing, Erin R.; Millay, Douglas P.; Vuagniaux, Grégoire; Molkentin, Jeffery D.

    2010-01-01

    Muscular dystrophy results in the progressive wasting and necrosis of skeletal muscle. Glucocorticoids such as prednisone have emerged as a front-line treatment for many forms of this disease. Recently, Debio-025, a cyclophilin inhibitor that desensitizes the mitochondrial permeability pore and subsequent cellular necrosis, was shown to improve pathology in 3 different mouse models of muscular dystrophy. However it is not known if Debio-025 can work in conjunction with prednisone, or how it c...

  8. Systemic microdystrophin gene delivery improves skeletal muscle structure and function in old dystrophic mdx mice

    OpenAIRE

    Gregorevic, Paul; Blankinship, Michael J; Allen, James M.; Jeffrey S. Chamberlain

    2008-01-01

    Restoring dystrophin expression in the muscles of patients with Duchenne muscular dystrophy (DMD) may halt or reverse the degenerative wasting and weakness that causes premature death. However, the therapeutic efficacy of an intervention may be limited by the extent of disease progression prior to treatment. In the present study, we considered the potential for ameliorating pathology in a mouse model of advanced-state muscular dystrophy via systemic administration of recombinant adeno-associa...

  9. Selective modulation through the glucocorticoid receptor ameliorates muscle pathology in mdx mice

    OpenAIRE

    Huynh, Tony; Uaesoontrachoon, Kitipong; Quinn, James L; Tatem, Kathleen S; Heier, Christopher R; Jack H. Van der Meulen; Yu, Qing; Harris, Mark; Nolan, Christopher J.; Haegeman, Guy; Grounds, Miranda D.; Nagaraju, Kanneboyina

    2013-01-01

    The over-expression of NF-κB signalling in both muscle and immune cells contribute to the pathology in dystrophic muscle. The anti-inflammatory properties of glucocorticoids, mediated predominantly through monomeric glucocorticoid receptor inhibition of transcription factors such as NF-κB (transrepression), are postulated to be an important mechanism for their beneficial effects in Duchenne muscular dystrophy. Chronic glucocorticoid therapy is associated with adverse effects on metabolism, gr...

  10. Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice

    OpenAIRE

    Verma, Mayank; Asakura, Yoko; Hirai, Hiroyuki; Watanabe, Shuichi; Tastad, Christopher; Fong, Guo-Hua; Ema, Masatsugu; Call, Jarrod A.; Lowe, Dawn A.; Asakura, Atsushi

    2010-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease caused by mutations in the gene coding for the protein dystrophin. Recent work demonstrates that dystrophin is also found in the vasculature and its absence results in vascular deficiency and abnormal blood flow. This induces a state of ischemia further aggravating the muscular dystrophy pathogenesis. For an effective form of therapy of DMD, both the muscle and the vasculature need to be addressed. To reveal the develo...

  11. An attempt to enhance neurogenesis of mdx mice via aerobic exercise and myostatin inhibition

    OpenAIRE

    Ylikulju, Teemu

    2013-01-01

    Duchennen lihasdystrofia (DMD) on perinnöllinen sairaus, jonka esiintyvyys on noin 1/3600 poikavauvasta. Siihen liittyy lihasten heikkoutta, rappeutumista ja kognitiivista vajavaisuutta. Taudin aiheuttaa mutatoitunut geeni dystrophiini proteiinille. On esitetty, että kognitiivinen vajavaisuus johtuu taudin vaikutuksesta ehkäistä neurogeneesiä. Neurogeneesi on prosessi, joka jatkuvasti synnyttää uusia hermosoluja pääasiallisesti subventikulaari alueella ja hippokampuksen dentate gyruksella....

  12. Partial correction of the dwarf phenotype by non-viral transfer of the growth hormone gene in mice: Treatment age is critical.

    Science.gov (United States)

    Higuti, Eliza; Cecchi, Cláudia R; Oliveira, Nélio A J; Lima, Eliana R; Vieira, Daniel P; Aagaard, Lars; Jensen, Thomas G; Jorge, Alexander A L; Bartolini, Paolo; Peroni, Cibele N

    2016-02-01

    Non-viral transfer of the growth hormone gene to different muscles of immunodeficient dwarf (lit/scid) mice is under study with the objective of improving phenotypic correction via this particular gene therapy approach. Plasmid DNA was administered into the exposed quadriceps or non-exposed tibialis cranialis muscle of lit/scid mice followed by electroporation, monitoring several growth parameters. In a 6-month bioassay, 50μg DNA were injected three times into the quadriceps muscle of 80-day old mice. A 50% weight increase, with a catch-up growth of 21%, together with a 16% increase for nose-to-tail and tail lengths (catch-up=19-21%) and a 24-28% increase for femur length (catch-up=53-60%), were obtained. mIGF1 serum levels were ~7-fold higher than the basal levels for untreated mice, but still ~2-fold lower than in non-dwarf scid mice. Since treatment age was found to be particularly important in a second bioassay utilizing 40-day old mice, these pubertal mice were compared in a third bioassay with adult (80-day old) mice, all treated twice with 50μg DNA injected into each tibialis cranialis muscle, via a less invasive approach. mIGF1 concentrations at the same level as co-aged scid mice were obtained 15days after administration in pubertal mice. Catch-up growth, based on femur length (77%), nose-to-tail (36%) and tail length (39%) increases was 40 to 95% higher than those obtained upon treating adult mice. These data pave the way for the development of more effective pre-clinical assays in pubertal dwarf mice for the treatment of GH deficiency via plasmid-DNA muscular administration. PMID:26774398

  13. Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes

    Directory of Open Access Journals (Sweden)

    J.A. Berti

    2005-03-01

    Full Text Available We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo AI, lecithin-cholesterol acyl transferase (LCAT and cholesteryl ester transfer protein (CETP, or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R² of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R² = 0.22, P < 0.001 and CETP (R² = 0.13, P < 0.01 expression reduced lesion size, the LCAT (R² = 0.16, P < 0.005 and LCAT/AI (R² = 0.13, P < 0.003 genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific athero genic scenarios.

  14. Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes

    OpenAIRE

    J.A. Berti; de Faria, E.C.; H.C.F. Oliveira

    2005-01-01

    We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosc...

  15. Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice

    OpenAIRE

    Cummins, Nathan W.; Weaver, Eric A.; May, Shannon M.; Croatt, Anthony J.; Foreman, Oded; Kennedy, Richard B.; Poland, Gregory A.; Michael A. Barry; Nath, Karl A.; Badley, Andrew D.

    2012-01-01

    Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genom...

  16. B Cell Production of Both OPG and RANKL is Significantly Increased in Aged Mice

    OpenAIRE

    Li, Yan; Terauchi, Masakazu; Vikulina, Tatyana; Roser-Page, Susanne; Weitzmann, M.N.

    2014-01-01

    Aging is a risk factor for osteoclastic bone loss and bone fracture. Receptor activator of NF-κB ligand (RANKL) is the key effector cytokine for osteoclastogenesis and bone resorption, and is moderated by its decoy receptor osteoprotegerin (OPG). The development of an inflammatory environment during aging leads to increased bone resorption and loss of bone mineral density (BMD). Interestingly, animal and clinical studies show that OPG is actually increased in aging but fails to fully compensa...

  17. [Information theory of ageing: studying the effect of bone marrow transplantation on the life span of mice].

    Science.gov (United States)

    Karnaukhov, A V; Karnaukhova, E V; Sergievich, L A; Karnaukhova, N A; Karnaukhova, N A; Bogdanenko, E V; Smirnov, A A; Manokhina, I A; Karnaukhov, V N

    2014-01-01

    In this paper the method of life span extension of multicellular organisms (human) using the reservation of stem cells followed by autotransplantation has been proposed. As the efficiency of this method results from the information theory of ageing, it is important to verify it experimentally testing the basic concepts of the theory. Taking it into consideration, the experiment on the bone marrow transplantation to old mice from young closely-related donors of the inbred line was carried out. It has been shown, that transplanted animals exhibited a survival advantage, a mean life span increased by 34% as compared to the control. This result not only demonstrates the efficiency of the proposed method for life span extension of multicellular organisms, but also confirms the basis of the information theory of ageing. PMID:25707248

  18. Serum cholinesterases are differentially regulated in normal and dystrophin-deficient mutant mice

    Directory of Open Access Journals (Sweden)

    Andrea R. Durrant

    2012-06-01

    Full Text Available The cholinesterases, acetylcholinesterase and butyrylcholinesterase (pseudocholinesterase, are abundant in the nervous system and in other tissues. The role of acetylcholinesterase in terminating transmitter action in the peripheral and central nervous system is well understood. However, both knowledge of the function(s of the cholinesterases in serum, and of their metabolic and endocrine regulation under normal and pathological conditions, is limited. This study investigates acetylcholinesterase and butyrylcholinesterase in sera of dystrophin-deficient mdx mutant mice, an animal model for the human Duchenne muscular dystrophy and in control healthy mice. The data show systematic and differential variations in the concentrations of both enzymes in the sera, and specific changes dictated by alteration of hormonal balance in both healthy and dystrophic mice. While acetylcholinesterase in mdx-sera is elevated, butyrylcholinesterase is markedly diminished, resulting in an overall cholinesterase decrease compared to sera of healthy controls. The androgen testosterone (T is a negative modulator of butyrylcholinesterase, but not of acetylcholinesterase, in male mouse sera. T-removal elevated both butyrylcholinesterase activity and the butyrylcholinesterase/acetylcholinesterase ratio in mdx male sera to values resembling those in healthy control male mice. Mechanisms of regulation of the circulating cholinesterases and their impairment in the dystrophic mice are suggested, and clinical implications for diagnosis and treatment are considered.

  19. Investigation and identification of etiologies involved in the development of acquired hydronephrosis in aged laboratory mice with the use of high-frequency ultrasound imaging

    Directory of Open Access Journals (Sweden)

    Danielle A. Springer

    2014-08-01

    Full Text Available Laboratory mice develop naturally occurring lesions that affect biomedical research. Hydronephrosis is a recognized pathologic abnormality of the mouse kidney. Acquired hydronephrosis can affect any mouse, as it is caused by any naturally occurring disease that impairs free urine flow. Many etiologies leading to this condition are of particular significance to aging mice. Non-invasive ultrasound imaging detects renal pelvic dilation, renal enlargement, and parenchymal loss for pre-mortem identification of this condition. High-frequency ultrasound transducers produce high-resolution images of small structures, ideal for detecting organ pathology in mice. Using a 40 MHz linear array transducer, we obtained high-resolution images of a diversity of pathologic lesions occurring within the abdomen of seven geriatric mice with acquired hydronephrosis that enabled a determination of the underlying etiology. Etiologies diagnosed from the imaging results include pyelonephritis, neoplasia, urolithiasis, mouse urologic syndrome, and spontaneous hydronephrosis, and were confirmed at necropsy. A retrospective review of abdominal scans from an additional 149 aging mice shows that the most common etiologies associated with acquired hydronephrosis are mouse urologic syndrome and abdominal neoplasia. This report highlights the utility of high-frequency ultrasound for surveying research mice for age-related pathology, and is the first comprehensive report of multiple cases of acquired hydronephrosis in mice.

  20. Elevation of Brain Magnesium Potentiates Neural Stem Cell Proliferation in the Hippocampus of Young and Aged Mice.

    Science.gov (United States)

    Jia, Shanshan; Liu, Yunpeng; Shi, Yang; Ma, Yihe; Hu, Yixin; Wang, Meiyan; Li, Xue

    2016-09-01

    In the adult brain, neural stem cells (NSCs) can self-renew and generate all neural lineage types, and they persist in the sub-granular zone (SGZ) of the hippocampus and the sub-ventricular zone (SVZ) of the cortex. Here, we show that dietary-supplemented - magnesium-L-threonate (MgT), a novel magnesium compound designed to elevate brain magnesium regulates the NSC pool in the adult hippocampus. We found that administration of both short- and long-term regimens of MgT, increased the number of hippocampal NSCs. We demonstrated that in young mice, dietary supplementation with MgT significantly enhanced NSC proliferation in the SGZ. Importantly, in aged mice that underwent long-term (12-month) supplementation with MgT, MgT did not deplete the hippocampal NSC reservoir but rather curtailed the age-associated decline in NSC proliferation. We further established an association between extracellular magnesium concentrations and NSC self-renewal in vitro by demonstrating that elevated Mg(2+) concentrations can maintain or increase the number of cultured hippocampal NSCs. Our study also suggests that key signaling pathways for cell growth and proliferation may be candidate targets for Mg(2+) 's effects on NSC self-renewal. J. Cell. Physiol. 231: 1903-1912, 2016. © 2016 Wiley Periodicals, Inc. PMID:26754806

  1. 17ß-Estradiol Regulates Histone Alterations Associated with Memory Consolidation and Increases "Bdnf" Promoter Acetylation in Middle-Aged Female Mice

    Science.gov (United States)

    Fortress, Ashley M.; Kim, Jaekyoon; Poole, Rachel L.; Gould, Thomas J.; Frick, Karyn M.

    2014-01-01

    Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17ß-estradiol…

  2. Age-Related Declines in General Cognitive Abilities of Balb/C Mice and General Activity Are Associated with Disparities in Working Memory, Body Weight, and General Activity

    Science.gov (United States)

    Matzel, Louis D.; Grossman, Henya; Light, Kenneth; Townsend, David; Kolata, Stefan

    2008-01-01

    A defining characteristic of age-related cognitive decline is a deficit in general cognitive performance. Here we use a testing and analysis regimen that allows us to characterize the general learning abilities of young (3-5 mo old) and aged (19-21 mo old) male and female Balb/C mice. Animals' performance was assessed on a battery of seven diverse…

  3. AMPK Agonist AICAR Improves Cognition and Motor Coordination in Young and Aged Mice

    Science.gov (United States)

    Kobilo, Tali; Guerrieri, Davide; Zhang, Yongqing; Collica, Sarah C.; Becker, Kevin G.; van Praag, Henriette

    2014-01-01

    Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity. In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced…

  4. Normal photoresponses and altered b-wave responses to APB in the mdxCv3 mouse isolated retina ERG supports role for dystrophin in synaptic transmission

    OpenAIRE

    GREEN, DANIEL G.; Guo, Hao; PILLERS, DE-ANN M.

    2004-01-01

    The mdxCv3 mouse is a model for Duchenne muscular dystrophy (DMD). DMD is an X-linked disorder with defective expression of the protein dystrophin, and which is associated with a reduced b-wave and has other electroretinogram (ERG) abnormalities. To assess potential causes for the abnormalities, we recorded ERGs from pieces of isolated C57BL/6J and mdxCv3 mouse retinas, including measurements of transretinal and intraretinal potentials. The ERGs from the isolated mdxCv3 retina differ from tho...

  5. Suppressed retinal degeneration in aged wild type and APPswe/PS1ΔE9 mice by bone marrow transplantation.

    Directory of Open Access Journals (Sweden)

    Yue Yang

    Full Text Available Alzheimer's disease (AD is an age-related condition characterized by accumulation of neurotoxic amyloid β peptides (Aβ in brain and retina. Because bone marrow transplantation (BMT results in decreased cerebral Aβ in experimental AD, we hypothesized that BMT would mitigate retinal neurotoxicity through decreased retinal Aβ. To test this, we performed BMT in APPswe/PS1ΔE9 double transgenic mice using green fluorescent protein expressing wild type (wt mice as marrow donors. We first examined retinas from control, non-transplanted, aged AD mice and found a two-fold increase in microglia compared with wt mice, prominent inner retinal Aβ and paired helical filament-tau, and decreased retinal ganglion cell layer neurons. BMT resulted in near complete replacement of host retinal microglia with BMT-derived cells and normalized total AD retinal microglia to non-transplanted wt levels. Aβ and paired helical filament-tau were reduced (61.0% and 44.1% respectively in BMT-recipient AD mice, which had 20.8% more retinal ganglion cell layer neurons than non-transplanted AD controls. Interestingly, aged wt BMT recipients also had significantly more neurons (25.4% compared with non-transplanted aged wt controls. Quantitation of retinal ganglion cell layer neurons in young mice confirmed age-related retinal degeneration was mitigated by BMT. We found increased MHC class II expression in BMT-derived microglia and decreased oxidative damage in retinal ganglion cell layer neurons. Thus, BMT is neuroprotective in age-related as well as AD-related retinal degeneration, and may be a result of alterations in innate immune function and oxidative stress in BMT recipient mice.

  6. Recombinase-mediated reprogramming and dystrophin gene addition in mdx mouse induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Chunli Zhao

    Full Text Available A cell therapy strategy utilizing genetically-corrected induced pluripotent stem cells (iPSC may be an attractive approach for genetic disorders such as muscular dystrophies. Methods for genetic engineering of iPSC that emphasize precision and minimize random integration would be beneficial. We demonstrate here an approach in the mdx mouse model of Duchenne muscular dystrophy that focuses on the use of site-specific recombinases to achieve genetic engineering. We employed non-viral, plasmid-mediated methods to reprogram mdx fibroblasts, using phiC31 integrase to insert a single copy of the reprogramming genes at a safe location in the genome. We next used Bxb1 integrase to add the therapeutic full-length dystrophin cDNA to the iPSC in a site-specific manner. Unwanted DNA sequences, including the reprogramming genes, were then precisely deleted with Cre resolvase. Pluripotency of the iPSC was analyzed before and after gene addition, and ability of the genetically corrected iPSC to differentiate into myogenic precursors was evaluated by morphology, immunohistochemistry, qRT-PCR, FACS analysis, and intramuscular engraftment. These data demonstrate a non-viral, reprogramming-plus-gene addition genetic engineering strategy utilizing site-specific recombinases that can be applied easily to mouse cells. This work introduces a significant level of precision in the genetic engineering of iPSC that can be built upon in future studies.

  7. Recombinase-mediated reprogramming and dystrophin gene addition in mdx mouse induced pluripotent stem cells.

    Science.gov (United States)

    Zhao, Chunli; Farruggio, Alfonso P; Bjornson, Christopher R R; Chavez, Christopher L; Geisinger, Jonathan M; Neal, Tawny L; Karow, Marisa; Calos, Michele P

    2014-01-01

    A cell therapy strategy utilizing genetically-corrected induced pluripotent stem cells (iPSC) may be an attractive approach for genetic disorders such as muscular dystrophies. Methods for genetic engineering of iPSC that emphasize precision and minimize random integration would be beneficial. We demonstrate here an approach in the mdx mouse model of Duchenne muscular dystrophy that focuses on the use of site-specific recombinases to achieve genetic engineering. We employed non-viral, plasmid-mediated methods to reprogram mdx fibroblasts, using phiC31 integrase to insert a single copy of the reprogramming genes at a safe location in the genome. We next used Bxb1 integrase to add the therapeutic full-length dystrophin cDNA to the iPSC in a site-specific manner. Unwanted DNA sequences, including the reprogramming genes, were then precisely deleted with Cre resolvase. Pluripotency of the iPSC was analyzed before and after gene addition, and ability of the genetically corrected iPSC to differentiate into myogenic precursors was evaluated by morphology, immunohistochemistry, qRT-PCR, FACS analysis, and intramuscular engraftment. These data demonstrate a non-viral, reprogramming-plus-gene addition genetic engineering strategy utilizing site-specific recombinases that can be applied easily to mouse cells. This work introduces a significant level of precision in the genetic engineering of iPSC that can be built upon in future studies. PMID:24781921

  8. A comparative review of aging and B cell function in mice and humans

    OpenAIRE

    Scholz, Jean L.; Diaz, Alain; Riley, Richard L.; Cancro, Michael P.; Frasca, Daniela

    2013-01-01

    Immune system function declines with age. Here we review and compare age-associated changes in murine and human B cell pools and humoral immune responses. We summarize changes in B cell generation and homeostasis, as well as notable changes at the sub-cellular level; then discuss how these changes help to explain alterations in immune responses across the adult lifespan of the animal. In each section we compare and contrast findings in the mouse, arguably the best animal model of the aging im...

  9. Early-onset motor impairment and increased accumulation of phosphorylated α-synuclein in the motor cortex of normal aging mice are ameliorated by coenzyme Q.

    Science.gov (United States)

    Takahashi, Kazuhide; Ohsawa, Ikuroh; Shirasawa, Takuji; Takahashi, Mayumi

    2016-08-01

    Brain mitochondrial function declines with age; however, the accompanying behavioral and histological alterations that are characteristic of Parkinson's disease (PD) are poorly understood. We found that the mitochondrial oxygen consumption rate (OCR) and coenzyme Q (CoQ) content were reduced in aged (15-month-old) male mice compared to those in young (6-month-old) male mice. Concomitantly, motor functions, including the rate of movement and exploratory and voluntary motor activities, were significantly reduced in the aged mice compared to the young mice. In the motor cortex of the aged mouse brain, the accumulation of α-synuclein (α-syn) phosphorylated at serine129 (Ser129) significantly increased, and the level of vesicular glutamate transporter 1 (VGluT1) decreased compared with that in the young mouse brain. The administration of exogenous water-soluble CoQ10 to aged mice via drinking water restored the mitochondrial OCR, motor function, and phosphorylated α-syn and VGluT1 levels in the motor cortex. These results suggest that early-onset motor impairment and the increased accumulation of Ser129-phosphorylated α-syn in the motor cortex are ameliorated by the exogenous administration of CoQ10. PMID:27143639

  10. Artery Tertiary Lymphoid Organs Control Multilayered Territorialized Atherosclerosis B-Cell Responses in Aged ApoE−/− Mice

    Science.gov (United States)

    Srikakulapu, Prasad; Hu, Desheng; Yin, Changjun; Mohanta, Sarajo K.; Bontha, Sai Vineela; Peng, Li; Beer, Michael; Weber, Christian; McNamara, Coleen A.; Grassia, Gianluca; Maffia, Pasquale; Manz, Rudolf A.

    2016-01-01

    Objective— Explore aorta B-cell immunity in aged apolipoprotein E-deficient (ApoE−/−) mice. Approach and Results— Transcript maps, fluorescence-activated cell sorting, immunofluorescence analyses, cell transfers, and Ig-ELISPOT (enzyme-linked immunospot) assays showed multilayered atherosclerosis B-cell responses in artery tertiary lymphoid organs (ATLOs). Aging-associated aorta B-cell–related transcriptomes were identified, and transcript atlases revealed highly territorialized B-cell responses in ATLOs versus atherosclerotic lesions: ATLOs showed upregulation of bona fide B-cell genes, including Cd19, Ms4a1 (Cd20), Cd79a/b, and Ighm although intima plaques preferentially expressed molecules involved in non–B effector responses toward B-cell–derived mediators, that is, Fcgr3 (Cd16), Fcer1g (Cd23), and the C1q family. ATLOs promoted B-cell recruitment. ATLO B-2 B cells included naive, transitional, follicular, germinal center, switched IgG1+, IgA+, and IgE+ memory cells, plasmablasts, and long-lived plasma cells. ATLOs recruited large numbers of B-1 cells whose subtypes were skewed toward interleukin-10+ B-1b cells versus interleukin-10− B-1a cells. ATLO B-1 cells and plasma cells constitutively produced IgM and IgG and a fraction of plasma cells expressed interleukin-10. Moreover, ApoE−/− mice showed increased germinal center B cells in renal lymph nodes, IgM-producing plasma cells in the bone marrow, and higher IgM and anti–MDA-LDL (malondialdehyde-modified low-density lipoprotein) IgG serum titers. Conclusions— ATLOs orchestrate dichotomic, territorialized, and multilayered B-cell responses in the diseased aorta; germinal center reactions indicate generation of autoimmune B cells within the diseased arterial wall during aging. PMID:27102965

  11. Protective Effects of Punica Granatum Seeds Extract Against Aging and Scopolamine Induced Cognitive Impairments in Mice

    OpenAIRE

    Kumar, Sokindra; Maheshwari, Kamal Kishore; Singh, Vijender

    2008-01-01

    Dementia is one of the age related mental problems and characteristic symptom of various neurodegenerative diseases including Alzheimer's disease. This impairment probably is due to the vulnerability of the brain cells to increased oxidative stress during aging process. Many studies have shown that certain phenolic antioxidants attenuate neuronal cell death induced by oxidative stress. The present work was undertaken to assess the effect of ethanolic extract of Punica granatum seeds on cognit...

  12. Spatial cognition in adult and aged mice exposed to high-fat diet

    OpenAIRE

    Kesby, JP; Kim, JJ; M. Scadeng; Woods, G.; Kado, DM; Olefsky, JM; Jeste, DV; Achim, CL; Semenova, S

    2015-01-01

    © 2015 Kesby et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic ...

  13. Phenotypes of Aging Postovulatory Oocytes After Somatic Cell Nuclear Transfer in Mice.

    Science.gov (United States)

    Lee, Ah Reum; Shimoike, Takashi; Wakayama, Teruhiko; Kishigami, Satoshi

    2016-06-01

    Oocytes rapidly lose their developmental potential after ovulation, termed postovulatory oocyte aging, and often exhibit characteristic phenotypes, such as cytofragmentation, abnormal spindle shapes, and chromosome misalignments. Here, we reconstructed mouse oocytes using somatic cell nuclear transfer (SCNT) to reveal the effect of somatic cell-derived nuclei on oocyte physiology during aging. Normal oocytes started undergoing cytofragmentation 24 hours after oocyte collection; however, this occurred earlier in SCNT oocytes and was more severe at 48 hours, suggesting that the transferred somatic cell nuclei affected oocyte physiology. We found no difference in the status of acetylated α-tubulin (Ac-Tub) and α-tubulin (Tub) between normal and SCNT aging oocytes, but unlike normal oocytes, aging SCNT oocytes did not have astral microtubules. Interestingly, aging SCNT oocytes displayed more severely scattered chromosomes or irregularly shaped spindles. Observations of the microfilaments showed that, in normal oocytes, there was a clear actin ring beneath the plasma membrane and condensed microfilaments around the spindle (the actin cap) at 0 hours, and the actin filaments started degenerating at 1 hour, becoming completely disrupted and distributed to the cytoplasm at 24 hours. By contrast, in SCNT oocytes, an actin cap formed around the transplanted nuclei within 1 hour of SCNT, which was still present at 24 hours. Thus, SCNT oocytes age in a similar but distinct way, suggesting that they not only contain nuclei with abnormal epigenetics but are also physiologically different. PMID:27253626

  14. Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans.

    Science.gov (United States)

    Rufo, Anna; Del Fattore, Andrea; Capulli, Mattia; Carvello, Francesco; De Pasquale, Loredana; Ferrari, Serge; Pierroz, Dominique; Morandi, Lucia; De Simone, Michele; Rucci, Nadia; Bertini, Enrico; Bianchi, Maria Luisa; De Benedetti, Fabrizio; Teti, Anna

    2011-08-01

    Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro-computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-βA, and TGFβ2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients. PMID:21509823

  15. Recovery of immune competence following sublethal X irradiation of young and old mice: a model for studying age-related loss of immunologic homeostasis

    International Nuclear Information System (INIS)

    Age-related alteration in lymphohematopoietic homeostasis was assessed kinetically by determining immunologic and stem-cell regenerating capacities of young (5-7 months), middle-aged (13 months), and old (23-24 months) C3H and C57BL/6 mice following their exposure to 500 R. Immunologic activities were based on the ability of spleen cells to respond to sheep erythrocytes, phytohemagglutinin, and bacterial lipopolysaccharide. Stem-cell activity was based on the ability of splenic and bone marrow cells to form colonies in vivo. Reflective of age-related homeostatic imbalance was alteration in the (a) time of recovery, (b) rate of regeneration, and (c) capacity of the regenerating system to overshoot the preirradition steady-state level. Most of the immunologic parameters showed a delay in the time of recovery in old mice. In contrast, the time of recovery of stem cells in old mice was equal to or faster than that in young mice. Furthermore, the magnitude of regeneration of stem cells was greater in old than young mice. These results suggest that recovery of immunologic activities in old mice is delayed partly because of the inability of their stem cells to rapidly generate immunocompetent progenies

  16. A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice

    Directory of Open Access Journals (Sweden)

    Raquel Riquelme

    2010-06-01

    Full Text Available Insulin-like growth factor-I (IGF-I belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1−/− null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1+/+ and null Igf1−/− mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR recordings and in vivo MRI brain imaging. Igf1−/− null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1+/+ wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1−/− null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to

  17. The Brewed Rice Vinegar Kurozu Increases HSPA1A Expression and Ameliorates Cognitive Dysfunction in Aged P8 Mice.

    Directory of Open Access Journals (Sweden)

    Hiroaki Kanouchi

    Full Text Available Kurozu is a traditional Japanese rice vinegar. During fermentation and aging of the Kurozu liquid in an earthenware jar over 1 year, a solid residue called Kurozu Moromi is produced. In the present study, we evaluated whether concentrated Kurozu or Kurozu Moromi could ameliorate cognitive dysfunction in the senescence-accelerated P8 mouse. Senescence-accelerated P8 mice were fed 0.25% (w/w concentrated Kurozu or 0.5% (w/w Kurozu Moromi for 4 or 25 weeks. Kurozu suppressed cognitive dysfunction and amyloid accumulation in the brain, while Kurozu Moromi showed a tendency to ameliorate cognitive dysfunction, but the effect was not significant. We hypothesize that concentrated Kurozu has an antioxidant effect; however, the level of lipid peroxidation in the brain did not differ in senescence-accelerated P8 mice. DNA microarray analysis indicated that concentrated Kurozu increased HSPA1A mRNA expression, a protein that prevents protein misfolding and aggregation. The increase in HSPA1A expression by Kurozu was confirmed using quantitative real-time PCR and immunoblotting methods. The suppression of amyloid accumulation by concentrated Kurozu may be associated with HSPA1A induction. However, concentrated Kurozu could not increase HSPA1A expression in mouse primary neurons, suggesting it may not directly affect neurons.

  18. Effect of lifelong resveratrol supplementation and exercise training on skeletal muscle oxidative capacity in aging mice

    DEFF Research Database (Denmark)

    Ringholm, Stine; Olesen, Jesper; Pedersen, Jesper Thorhauge;

    2013-01-01

    The present study tested the hypothesis that lifelong resveratrol (RSV) supplementation counteracts an age-associated decrease in skeletal muscle oxidative capacity through peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and that RSV combined with lifelong exercise training (ET...

  19. A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength.

    Science.gov (United States)

    Arounleut, Phonepasong; Bialek, Peter; Liang, Li-Fang; Upadhyay, Sunil; Fulzele, Sadanand; Johnson, Maribeth; Elsalanty, Mohammed; Isales, Carlos M; Hamrick, Mark W

    2013-09-01

    Loss of muscle and bone mass with age are significant contributors to falls and fractures among the elderly. Myostatin deficiency is associated with increased muscle mass in mice, dogs, cows, sheep and humans, and mice lacking myostatin have been observed to show increased bone density in the limb, spine, and jaw. Transgenic overexpression of myostatin propeptide, which binds to and inhibits the active myostatin ligand, also increases muscle mass and bone density in mice. We therefore sought to test the hypothesis that in vivo inhibition of myostatin using an injectable myostatin propeptide (GDF8 propeptide-Fc) would increase both muscle mass and bone density in aged (24 mo) mice. Male mice were injected weekly (20 mg/kg body weight) with recombinant myostatin propeptide-Fc (PRO) or vehicle (VEH; saline) for four weeks. There was no difference in body weight between the two groups at the end of the treatment period, but PRO treatment significantly increased mass of the tibialis anterior muscle (+ 7%) and increased muscle fiber diameter of the extensor digitorum longus (+ 16%) and soleus (+ 6%) muscles compared to VEH treatment. Bone volume relative to total volume (BV/TV) of the femur calculated by microCT did not differ significantly between PRO- and VEH-treated mice, and ultimate force (Fu), stiffness (S), toughness (U) measured from three-point bending tests also did not differ significantly between groups. Histomorphometric assays also revealed no differences in bone formation or resorption in response to PRO treatment. These data suggest that while developmental perturbation of myostatin signaling through either gene knockout or transgenic inhibition may alter both muscle and bone mass in mice, pharmacological inhibition of myostatin in aged mice has a more pronounced effect on skeletal muscle than on bone. PMID:23832079

  20. Intermittent fasting favored the resolution of Salmonella typhimurium infection in middle-aged BALB/c mice.

    Science.gov (United States)

    Campos-Rodríguez, Rafael; Godínez-Victoria, Marycarmen; Reyna-Garfias, Humberto; Arciniega-Martínez, Ivonne Maciel; Reséndiz-Albor, Aldo Arturo; Abarca-Rojano, Edgar; Cruz-Hernández, Teresita Rocío; Drago-Serrano, Maria Elisa

    2016-02-01

    Intermittent fasting (IF) reportedly increases resistance and intestinal IgA response to Salmonella typhimurium infection in mature mice. The aim of this study was to explore the effect of aging on the aforementioned improved immune response found with IF. Middle-aged male BALB/c mice were submitted to IF or ad libitum (AL) feeding for 40 weeks and then orally infected with S. typhimurium. Thereafter, infected animals were all fed AL (to maximize their viability) until sacrifice on day 7 or 14 post-infection. We evaluated body weight, bacterial load (in feces, Peyer's patches, spleen and liver), total and specific intestinal IgA, lamina propria IgA+ plasma cells, plasma corticosterone, and messenger RNA (mRNA) expression of α-chain, J-chain, and the polymeric immunoglobulin receptor (pIgR) in liver and intestinal mucosa. In comparison with the infected AL counterpart, the infected IF group (long-term IF followed by post-infection AL feeding) generally had lower intestinal and systemic bacterial loads as well as higher total IgA on both post-infection days. Both infected groups showed no differences in corticosterone levels, body weight, or food and caloric intake. The increase in intestinal IgA was associated with enhanced pIgR mRNA expression in the intestine (day 7) and liver. Thus, to maintain body weight and caloric intake, IF elicited metabolic signals that possibly induced the increased hepatic and intestinal pIgR mRNA expression found. The increase in IgA probably resulted from intestinal IgA transcytosis via pIgR. This IgA response along with phagocyte-induced killing of bacteria in systemic organs (not measured) may explain the resolution of the S. typhimurium infection. PMID:26798034

  1. Pi-class glutathione-S-transferase-positive hepatocytes in aging B6C3F1 mice undergo apoptosis induced by dietary restriction.

    OpenAIRE

    Muskhelishvili, L; Turturro, A.; Hart, R W; James, S J

    1996-01-01

    Liver sections from aging ad libitum-fed and diet-restricted B6C3F1 male mice were evaluated immunohistochemically for pi-class glutathione S-transferase (GST-II). GST-II immunostaining of hepatocytes was diffuse and occurred in periportal regions of hepatic acinus, whereas perivenous areas were weakly stained or were stain-free. Expression of GST-II was significantly diminished in diet-restricted mice in all age groups and was associated with a marked decrease in liver tumor development. As ...

  2. Mouse ECG findings in aging, with conduction system affecting drugs and in cardiac pathologies: Development and validation of ECG analysis algorithm in mice

    OpenAIRE

    Merentie, Mari; Jukka A Lipponen; Hedman, Marja; Hedman, Antti; Hartikainen, Juha; Huusko, Jenni; Lottonen‐Raikaslehto, Line; Parviainen, Viktor; Laidinen, Svetlana; KARJALAINEN, Pasi A.; Ylä‐Herttuala, Seppo

    2015-01-01

    Abstract Mouse models are extremely important in studying cardiac pathologies and related electrophysiology, but very few mouse ECG analysis programs are readily available. Therefore, a mouse ECG analysis algorithm was developed and validated. Surface ECG (lead II) was acquired during transthoracic echocardiography from C57Bl/6J mice under isoflurane anesthesia. The effect of aging was studied in young (2–3 months), middle‐aged (14 months) and old (20–24 months) mice. The ECG changes associat...

  3. Rejection of large HPV-16 expressing tumors in aged mice by a single immunization of VacciMax® encapsulated CTL/T helper peptides

    OpenAIRE

    MacDonald Lisa; Korets-Smith Ella; Fuentes-Ortega Antar; Pohajdak Bill; Mansour Marc; Daftarian Pirouz M; Weir Genevieve; Brown Robert G; Kast W Martin

    2007-01-01

    Abstract The incidence of cancer increases significantly in later life, yet few pre-clinical studies of cancer immunotherapy use mice of advanced age. A novel vaccine delivery platform (VacciMax®,VM) is described that encapsulates antigens and adjuvants in multilamellar liposomes in a water-in-oil emulsion. The therapeutic potential of VM-based vaccines administered as a single dose was tested in HLA-A2 transgenic mice of advanced age (48–58 weeks old) bearing large palpable TC1/A2 tumors. Th...

  4. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer’s disease

    OpenAIRE

    Graham, Leah C.; Harder, Jeffrey M.; Ileana Soto; de Vries, Wilhelmine N.; Simon W M John; Gareth R Howell

    2016-01-01

    Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer’s disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the e...

  5. Photo-protective activity of pogostone against UV-induced skin premature aging in mice.

    Science.gov (United States)

    Wang, Xiu-Fen; Huang, Yan-Feng; Wang, Lan; Xu, Lie-Qiang; Yu, Xiu-Ting; Liu, Yu-Hong; Li, Cai-Lan; Zhan, Janis Ya-Xian; Su, Zi-Ren; Chen, Jian-Nan; Zeng, Hui-Fang

    2016-05-01

    Pogostone, a chemical constituent of patchouli oil, has been confirmed to possess favorable anti-inflammatory property. In the present study, we investigated the possible anti-photoaging potential of pogostone and the underlying mechanism against UV-induced skin damage in mice. The macroscopic and histopathological lesions were significantly ameliorated by pretreatment of pogostone as compared to the VC group. Furthermore, topical application of pogostone markedly increased the activities of the antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and observably decreased malonaldehyde (MDA) level. Analysis of inflammatory cytokines showed obvious down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) in the pogostone groups. In addition, pogostone pretreatment evidently inhibited the abnormal expression of matrix metalloproteinases (MMP-1 and MMP-3). Taken together, pogostone exhibited prominent photo-protective activity mainly by its antioxidative and anti-inflammatory properties, promising it as an effective alternative pharmaceutical therapy for photoaging. PMID:26929999

  6. n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice

    OpenAIRE

    Debora Cutuli; Maurizio Ronci; Cristina Neri; Stefano Farioli Vecchioli

    2014-01-01

    As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA) exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogen...

  7. Androgen Administration to Aged Male Mice Increases Anti-Anxiety Behavior and Enhances Cognitive Performance

    OpenAIRE

    Frye, Cheryl A.; Edinger, Kassandra; Sumida, Kanako

    2007-01-01

    Although androgen secretion is reduced with aging, and may underlie decrements in cognitive and affective performance, the effects and mechanisms of androgens to mediate these behaviors are not well understood. Testosterone (T), the primary male androgen, is aromatized to estrogen (E2), and reduced to dihydrotestosterone (DHT), which is converted to 5α-androstane, 3α, 17β-diol (3α-diol). To ascertain whether actions of the neuroactive metabolite of T, 3α-diol, mediates cognitive and affective...

  8. Palladium and Platinum Nanoparticles Attenuate Aging-Like Skin Atrophy via Antioxidant Activity in Mice

    OpenAIRE

    Shibuya, Shuichi; Ozawa, Yusuke; Watanabe, Kenji; Izuo, Naotaka; Toda, Toshihiko; Yokote, Koutaro; Shimizu, Takahiko

    2014-01-01

    Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In t...

  9. Age and sex dependence in tumorigenesis in mice by continuous low-dose-rate gamma-ray whole-body irradiation

    International Nuclear Information System (INIS)

    We investigated the dependency of sex and age in mice in the induction of neoplasms by gamma-rays from cesium-137 at a low dose rate of 0.375Gy/22h/day. Thymic lymphomas occurred significantly at the same incidence in both sexes, and more frequently when younger mice were exposed to radiation. Strain C57BL/6J mice were divided into 8 groups, which were whole-body irradiated with a total dose of 39Gy for 105 days each. The exposure was begun at 28 days of age (male:AM1, female:AF1), and then stepwise increasing the starting age by 105 days, i.e., from 133 days (AM2 and AF2), from 238 days (AM3 and AF3), and from 343 days (AM4 and AF4), respectively. Unirradiated mice served as control (UM and UF). The incidence of thymic lymphomas was about 60 % in AM1, AM2, AF1 and AF2, 40 % in AM3 and AF3 and 20 % in AF4 and AF4, demonstrating no sex dependency, but a distinct age dependency, for lymphomogenesis. It was proven that mice showed a tendency to become less susceptible to radiation induced thymic lymphoma with increasing age. Concomitantly, life-shortening also was caused, and the greater the degree of life-shortening was, the younger the mice were the start of exposure. Life-shortening was attributed to thymic lymphoma, and hemorrhage and infectious diseases due to the depletion of bone marrow cells. (author)

  10. Post activation depression of the Ia EPSP in motoneurones is reduced in both aged mice and in the G127X SOD1 model of Amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Hedegaard, Anne; Lehnhoff, Janna; Moldovan, Mihai;

    2014-01-01

    Post Activation Depression (PActD) is a long lasting depression of Ia afferent EPSPs in response to repetitive activation. This is of clinical relevance given its consistent reduction across a range of spastic disorders. We used in vivo intracellular recording in mice to explore changes in PActD in...... both normal aging and in the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). We used both wild type (WT) C57BL/6J mice and the G127X SOD1 transgenic model of ALS (Jonsson et al 2004)Mice were anaesthetized with Hypnorm (0.315mg/mL fentanyl-citrate +10mg/mL fluanisone), Midazolam (5mg...... and both PS G127X (P<0.0001) and S G127X (P<0.05) mice but no significant difference between PS and S G127X mice.Our result validate the use of mice models to study PActD and show that it is reduced in both normal aging (without spasticity) and in ALS (a disorder with spasticity) questioning a direct...

  11. Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress.

    Science.gov (United States)

    Arp, J Marit; Ter Horst, Judith P; Loi, Manila; den Blaauwen, Jan; Bangert, Eline; Fernández, Guillén; Joëls, Marian; Oitzl, Melly S; Krugers, Harm J

    2016-09-01

    Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated (i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal day 2 to 9 - affects conditioned fear in adult mice and (ii) whether these effects can be prevented by blocking glucocorticoid receptors (GRs) at adolescent age. In adult male and female mice, ELS did not affect freezing behavior to the first tone 24h after training in an auditory fear-conditioning paradigm. Exposure to repeated tones 24h after training also resulted in comparable freezing behavior in ELS and control mice, both in males and females. However, male (but not female) ELS compared to control mice showed significantly more freezing behavior between the tone-exposures, i.e. during the cue-off periods. Intraperitoneal administration of the GR antagonist RU38486 during adolescence (on postnatal days 28-30) fully prevented enhanced freezing behavior during the cue-off period in adult ELS males. Western blot analysis revealed no effects of ELS on hippocampal expression of glucocorticoid receptors, neither at postnatal day 28 nor at adult age, when mice were behaviorally tested. We conclude that ELS enhances freezing behavior in adult mice in a potentially safe context after cue-exposure, which can be normalized by brief blockade of glucocorticoid receptors during the critical developmental window of adolescence. PMID:27246249

  12. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.

    Directory of Open Access Journals (Sweden)

    Laura Leung

    Full Text Available Apolipoprotein (apo E4 is the major genetic risk factor for Alzheimer's disease (AD. ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive--but not NPY- or parvalbumin-positive-interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype.

  13. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors

    OpenAIRE

    Minetti, G. C; Colussi, C; R. Adami; C. Serra; Mozzetta, C; Parente, V.; Fortuni, S; Straino, S; Sampaolesi, Maurilio; Di Padova, M; Illi, B; Gallinari, P; Steinkuehler, C.; Capogrossi, M C; Sartorelli, V

    2006-01-01

    Pharmacological interventions that increase myofiber size counter the functional decline of dystrophic muscles(1,2). We show that deacetylase inhibitors increase the size of myofibers in dystrophin-deficient (MDX) and alpha-sarcoglycan (alpha-SG)-deficient mice by inducing the expression of the myostatin antagonist follistatin(3) in satellite cells. Deacetylase inhibitor treatment conferred on dystrophic muscles resistance to contraction-coupled degeneration and alleviated both morphological ...

  14. Dystrophin and Dysferlin Double Mutant Mice: A Novel Model For Rhabdomyosarcoma

    OpenAIRE

    Hosur, Vishnu; Kavirayani, Anoop; Riefler, Jennifer; Carney, Lisa M.B.; Lyons, Bonnie; Gott, Bruce; Gregory A Cox; Shultz, Leonard D.

    2012-01-01

    While researchers are yet to establish a link a between muscular dystrophy (MD) and sarcomas in human patients, literature suggests that MD genes dystrophin and dysferlin act as tumor suppressor genes in mouse models of MD. For instance, dystrophin deficient mdx and dysferlin deficient A/J mice, models of human Duchenne Muscular Dystrophy and Limb Girdle Muscular Dystrophy type 2B, respectively, develop mixed sarcomas with variable penetrance and latency. To further establish the correlation ...

  15. Time- and age-dependent effects of serotonin on gasping and autoresuscitation in neonatal mice.

    Science.gov (United States)

    Chen, Jianping; Magnusson, Jennifer; Karsenty, Gerard; Cummings, Kevin J

    2013-06-15

    The role of brain stem serotonin (5-hydroxytryptamine, 5-HT) in autoresuscitation in neonatal life is unclear. We hypothesized that a specific loss of 5-HT would compromise gasping and autoresuscitation mainly in the second postnatal week and that acute restoration of 5-HT would reverse the defects. We exposed postnatal day (P)4-5, P8-9, and P11-12 tryptophan-hydroxylase-2 knockout (TPH2(-/-)) and wild-type littermates (WT) to 10 episodes of anoxia (97% N2, 3% CO2), measuring survival, gasp latency, gasp frequency (fB), and the time required to restore eupnea and heart rate. We also tested P8-9 TPH2(-/-) mice after restoring 5-HT with a single injection of 5-hydroxytryptophan (5-HTP) 1-2 h before testing or with multiple injections beginning 24 h before testing. At P4-5 and P8-9, but not at P11-12, gasp latency and the recovery of eupnea were delayed ~2- to 3-fold in TPH2(-/-) pups compared with WT (P pups displayed reduced gasp fB (~20-30%; P rate recovery (~60%; P = 0.002) compared with WT littermates. TPH2(-/-) survival was reduced compared with WT (P pups, improved cardiorespiratory recovery and survival required 24 h of treatment. Our data suggest that 5-HT operates over a long time span (24 h) to improve survival during episodic severe hypoxia. Early in development (P4-9), 5-HT is critical for both respiratory and cardiovascular components of autoresuscitation; later (P11-12), it is critical mainly for cardiovascular components. Nevertheless, the effect of 5-HT deficiency on survival is most striking from P8 to P12. PMID:23558391

  16. Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice

    Science.gov (United States)

    Matsushita, Yuki; Sakai, Yasunari; Shimmura, Mitsunori; Shigeto, Hiroshi; Nishio, Miki; Akamine, Satoshi; Sanefuji, Masafumi; Ishizaki, Yoshito; Torisu, Hiroyuki; Nakabeppu, Yusaku; Suzuki, Akira; Takada, Hidetoshi; Hara, Toshiro

    2016-01-01

    Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8–10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6–8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain. PMID:26961412

  17. Maternal Obesity, Cage Density, and Age Contribute to Prostate Hyperplasia in Mice.

    Science.gov (United States)

    Benesh, Emily C; Gill, Jeff; Lamb, Laura E; Moley, Kelle H

    2016-02-01

    Identification of modifiable risk factors is gravely needed to prevent adverse prostate health outcomes. We previously developed a murine precancer model in which exposure to maternal obesity stimulated prostate hyperplasia in offspring. Here, we used generalized linear modeling to evaluate the influence of additional environmental covariates on prostate hyperplasia. As expected from our previous work, the model revealed that aging and maternal diet-induced obesity (DIO) each correlated with prostate hyperplasia. However, prostate hyperplasia was not correlated with the length of maternal DIO. Cage density positively associated with both prostate hyperplasia and offspring body weight. Expression of the glucocorticoid receptor in prostates also positively correlated with cage density and negatively correlated with age of the animal. Together, these findings suggest that prostate tissue was adversely patterned during early life by maternal overnutrition and was susceptible to alteration by environmental factors such as cage density. Additionally, prostate hyperplasia may be acutely influenced by exposure to DIO, rather than occurring as a response to worsening obesity and comorbidities experienced by the mother. Finally, cage density correlated with both corticosteroid receptor abundance and prostate hyperplasia, suggesting that overcrowding influenced offspring prostate hyperplasia. These results emphasize the need for multivariate regression models to evaluate the influence of coordinated variables in complicated animal systems. PMID:26243546

  18. Adipose stem cells' antagonism in glycosylation of D-galactose-induced skin aging of nude mice and its skin recovery function.

    Science.gov (United States)

    Wang, Haiying; Wei, Shuyue; Xue, Xinxin; You, Yuntian; Ma, Qiang

    2016-09-01

    This study aims to discuss adipose stem cells' (ASCs) antagonism in glycosylation of D-galactose-induced skin aging of nude mice and its skin recovery function; the study also aims to explore a new mechanism of anti-aging to provide clinical anti-aging therapy with new thoughts and methods. We selected 40 healthy specific pathogen-free (SPF) nude mice and divided them randomly into four groups which were: blank control group; D-galactose + phosphate buffer saline (PBS) group; D-galactose + ASCs treatment group; and D-galactose + aminoguanidine (AG) group. Results showed that the superoxide dismutase (SOD) level of mice in the D-galactose-induced model group (87.15 ± 4.95 U/g) decreased significantly compared with that of control group (146.21 ± 4.76 U/g), while malonaldehyde (MDA) level of mice in D-galactose induced model group (11.12 ± 2.08 nmol/mg) increased significantly compared with that of control group (5.46 ± 2.05 nmol/mg) (P bioluminescence, and they survive for a short time in the skin after transplantation, which provides a basis for the application of ASC transplantation in clinical practices. Moreover, ASCs can control glycosylation level of D-galactose-induced skin aging of nude mice, reverse expression of aging-related biomarkers as well as restrain formation of advanced glycation end products, which are similar to the effects of AG inhibitors of advanced glycation end products. Thus, ASCs can prevent glycosylation-induced skin aging as well as recover functions of skin. PMID:26916459

  19. Influence of age and sex on the spontaneous DNA damage detected by micronucleus test and comet assay in mice peripheral blood cells.

    Science.gov (United States)

    Heuser, Vanina Dahlström; de Andrade, Vanessa Moraes; Peres, Alessandra; Gomes de Macedo Braga, Luisa Maria; Bogo Chies, José Arthur

    2008-10-01

    We have investigated the normal variations in basal DNA damage detected by Comet assay in leukocytes and micronucleated erythrocytes (MNE) using the Micronucleus test (MN) in peripheral blood cells from 45 female and male mice from different age groups (newborns, 3.5, 12, and 104 weeks) to clarify age and sex-related changes. Comparison of basal DNA damage detected by Comet assay showed significantly increased values in 104 weeks old mice in relation to the other ages (P < or = 0.01), and newborn mice showed higher values in MNE frequency when compared to all the other groups (P < or = 0.01). A positive correlation was observed between Damage Frequency (r =0.382, P = 0.010) and Damage Index (r = 0.640, P < 0.001) and age. Age was also correlated with the ratio of polychromatic erythrocytes/normachromatic erythrocytes (PCE/NCE) (r = -0.473, P = 0.001), and the MNE frequency was positively correlated with the ratio of PCE/NCE (r = 0.454, P = 0.002). These results suggest an age-related slow down of DNA repair efficiency of DNA damage and/or DNA damage accumulation. Furthermore, data on the spontaneous MNE frequency indicate that the reticuloendothelial system matures with age, and there is a close relationship between erythropoiesis and micronucleus induction in erythrocytes. The influence of sex in the parameters analyzed was less clear. In conclusion, age seems to influence in basal DNA damage and should be considered in genotoxicity studies using mice. Finally, comparisons between assays must be made with care when different cells are compared (e.g. leukocytes and erythrocytes), as found with the Comet assay and MN test. PMID:18675925

  20. Age-related morphometric changes in the pineal gland. A comparative study between C57BLI6J and CBA mice

    OpenAIRE

    Cernuda-Cernuda, R.; Huerta, J.J.; Muñoz Llamosas, M.; Alvarez-Uría, M.; García-Fernández, J.M. (José Manuel)

    2000-01-01

    Relatively little is known about the effects of melatonin on the aging of the pineal, the organ which is the main place for synthesis of this hormone. Using simple morphometric methods, some parameters of the pineal gland, such as total volume, number of pinealocytes and pinealocyte volume were estimated in two mice strains: normal CBA and melatonin-deficient C57BLl6J. Two age groups, 6 weeks and 10 months, were studied in order to evaluate possible differentia...

  1. Age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in SAMP8 mice with trigeminal nerve damage.

    Science.gov (United States)

    He, Yifan; Zhu, Jihong; Huang, Fang; Qin, Liu; Fan, Wenguo; He, Hongwen

    2014-11-15

    The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory behaviors and structural changes in related brain regions, in a mouse model of Alzheimer's disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged (4-month-old) or elderly (7-month-old) senescence-accelerated mouse prone 8 (SAMP8) mice. When the middle-aged mice reached 8 months (middle-aged group 1) or 11 months (middle-aged group 2), and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learning and memory were performed, and the cholinergic system was examined in the hippocampus (Nissl staining and acetylcholinesterase histochemistry) and basal forebrain (choline acetyltransferase immunohistochemistry). In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic fibers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no significant differences in histology or behavior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present findings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer's disease, and indicate that

  2. 17β-Estradiol regulates histone alterations associated with memory consolidation and increases Bdnf promoter acetylation in middle-aged female mice

    OpenAIRE

    Fortress, Ashley M.; Kim, Jaekyoon; Rachel L Poole; Gould, Thomas J.; Frick, Karyn M.

    2014-01-01

    Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17β-estradiol (E2) to enhance object recognition memory consolidation requires histone H3 acetylation in the dorsal hippocampus. However, the extent to which histone ace...

  3. Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice.

    NARCIS (Netherlands)

    Edgar, D.; Shabalina, I.; Camara, Y.; Wredenberg, A.; Calvaruso, M.A.; Nijtmans, L.G.J.; Nedergaard, J.; Cannon, B.; Larsson, N.G.; Trifunovic, A.

    2009-01-01

    The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain fun

  4. Cd59a deficiency in mice leads to preferential innate immune activation in the retinal pigment epithelium-choroid with age.

    Science.gov (United States)

    Herrmann, Philipp; Cowing, Jill A; Cristante, Enrico; Liyanage, Sidath E; Ribeiro, Joana; Duran, Yanai; Abelleira Hervas, Laura; Carvalho, Livia S; Bainbridge, James W B; Luhmann, Ulrich F O; Ali, Robin R

    2015-09-01

    Dysregulation of the complement system has been implicated in the pathogenesis of age-related macular degeneration. To investigate consequences of altered complement regulation in the eye with age, we examined Cd59a complement regulator deficient (Cd59a(-/-)) mice between 4 and 15 months. In vivo imaging revealed an increased age-related accumulation of autofluorescent spots in Cd59a(-/-) mice, a feature that reflects accumulation of subretinal macrophages and/or microglia. Despite this activation of myeloid cells in the eye, Cd59a(-/-) mice showed normal retinal histology and function as well as normal choroidal microvasculature. With age, they revealed increased expression of activators of the alternative complement pathway (C3, Cfb, Cfd), in particular in the retinal pigment epithelium (RPE)-choroid but less in the retina. This molecular response was not altered by moderately-enhanced light exposure. Cd59a deficiency therefore leads to a preferential age-related dysregulation of the complement system in the RPE-choroid, that alone or in combination with light as a trigger, is not sufficient to cause choroidal vascular changes or retinal degeneration and dysfunction. This data emphasizes the particular vulnerability of the RPE-choroidal complex to dysregulation of the alternative complement pathway during aging. PMID:26234657

  5. Bioinformatics and Microarray Analysis of miRNAs in Aged Female Mice Model Implied New Molecular Mechanisms for Impaired Fracture Healing

    Science.gov (United States)

    He, Bing; Zhang, Zong-Kang; Liu, Jin; He, Yi-Xin; Tang, Tao; Li, Jie; Guo, Bao-Sheng; Lu, Ai-Ping; Zhang, Bao-Ting; Zhang, Ge

    2016-01-01

    Impaired fracture healing in aged females is still a challenge in clinics. MicroRNAs (miRNAs) play important roles in fracture healing. This study aims to identify the miRNAs that potentially contribute to the impaired fracture healing in aged females. Transverse femoral shaft fractures were created in adult and aged female mice. At post-fracture 0-, 2- and 4-week, the fracture sites were scanned by micro computed tomography to confirm that the fracture healing was impaired in aged female mice and the fracture calluses were collected for miRNA microarray analysis. A total of 53 significantly differentially expressed miRNAs and 5438 miRNA-target gene interactions involved in bone fracture healing were identified. A novel scoring system was designed to analyze the miRNA contribution to impaired fracture healing (RCIFH). Using this method, 11 novel miRNAs were identified to impair fracture healing at 2- or 4-week post-fracture. Thereafter, function analysis of target genes was performed for miRNAs with high RCIFH values. The results showed that high RCIFH miRNAs in aged female mice might impair fracture healing not only by down-regulating angiogenesis-, chondrogenesis-, and osteogenesis-related pathways, but also by up-regulating osteoclastogenesis-related pathway, which implied the essential roles of these high RCIFH miRNAs in impaired fracture healing in aged females, and might promote the discovery of novel therapeutic strategies. PMID:27527150

  6. Age-dependent effects of esculetin on mood-related behavior and cognition from stressed mice are associated with restoring brain antioxidant status.

    Science.gov (United States)

    Martín-Aragón, Sagrario; Villar, Ángel; Benedí, Juana

    2016-02-01

    Dietary antioxidants might exert an important role in the aging process by relieving oxidative damage, a likely cause of age-associated brain dysfunctions. This study aims to investigate the influence of esculetin (6,7-dihydroxycoumarin), a naturally occurring antioxidant in the diet, on mood-related behaviors and cognitive function and its relation with age and brain oxidative damage. Behavioral tests were employed in 11-, 17- and 22-month-old male C57BL/6J mice upon an oral 35day-esculetin treatment (25mg/kg). Activity of antioxidant enzymes, GSH and GSSG levels, GSH/GSSG ratio, and mitochondrial function were analyzed in brain cortex at the end of treatment in order to assess the oxidative status related to mouse behavior. Esculetin treatment attenuated the increased immobility time and enhanced the diminished climbing time in the forced swim task elicited by acute restraint stress (ARS) in the 11- and 17-month-old mice versus their counterpart controls. Furthermore, ARS caused an impairment of contextual memory in the step-through passive avoidance both in mature adult and aged mice which was partially reversed by esculetin only in the 11-month-old mice. Esculetin was effective to prevent the ARS-induced oxidative stress mostly in mature adult mice by restoring antioxidant enzyme activities, augmenting the GSH/GSSG ratio and increasing cytochrome c oxidase (COX) activity in cortex. Modulation of the mood-related behavior and cognitive function upon esculetin treatment in a mouse model of ARS depends on age and is partly due to the enhancement of redox status and levels of COX activity in cortex. PMID:26290950

  7. Age-related declines in general cognitive abilities of Balb/C mice are associated with disparities in working memory, body weight, and general activity

    OpenAIRE

    Matzel, Louis D.; Grossman, Henya; Light, Kenneth; Townsend, David; Kolata, Stefan

    2008-01-01

    A defining characteristic of age-related cognitive decline is a deficit in general cognitive performance. Here we use a testing and analysis regimen that allows us to characterize the general learning abilities of young (3–5 mo old) and aged (19–21 mo old) male and female Balb/C mice. Animals’ performance was assessed on a battery of seven diverse learning tasks. Aged animals exhibited deficits in five of the seven tasks and ranked significantly lower than their young counterparts in general ...

  8. Combined anti-inflammatory and anti-AGE drug treatments have a protective effect on intervertebral discs in mice with diabetes.

    Directory of Open Access Journals (Sweden)

    Svenja Illien-Junger

    Full Text Available OBJECTIVE: Diabetes and low back pain are debilitating diseases and modern epidemics. Diabetes and obesity are also highly correlated with intervertebral disc (IVD degeneration and back pain. Advanced-glycation-end-products (AGEs increase reactive-oxygen-species (ROS and inflammation, and are one cause for early development of diabetes mellitus. We hypothesize that diabetes results in accumulation of AGEs in spines and associated spinal pathology via increased catabolism. We present a mouse model showing that: 1 diabetes induces pathological changes to structure and composition of IVDs and vertebrae; 2 diabetes is associated with accumulation of AGEs, TNFα, and increased catabolism spinal structures; and 3 oral-treatments with a combination of anti-inflammatory and anti-AGE drugs mitigate these diabetes-induced degenerative changes to the spine. METHODS: Three age-matched groups of ROP-Os mice were compared: non-diabetic, diabetic (streptozotocin (STZ-induced, or diabetic mice treated with pentosan-polysulfate (anti-inflammatory and pyridoxamine (AGE-inhibitor. Mice were euthanized and vertebra-IVD segments were analyzed by μCT, histology and Immunohistochemistry. RESULTS: Diabetic mice exhibited several pathological changes including loss in IVD height, decreased vertebral bone mass, decreased glycosaminoglycan content and morphologically altered IVDs with focal deposition of tissues highly expressing TNFα, MMP-13 and ADAMTS-5. Accumulation of larger amounts of methylglyoxal suggested that AGE accumulation was associated with these diabetic degenerative changes. However, treatment prevented or reduced these pathological effects on vertebrae and IVD. CONCLUSION: This is the first study to demonstrate specific degenerative changes to nucleus pulposus (NP morphology and their association with AGE accumulation in a diabetic mouse model. Furthermore, this is the first study to demonstrate that oral-treatments can inhibit AGE-induced ROS and

  9. Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice

    OpenAIRE

    Harrison, F.E.; Hosseini, A. H.; McDonald, M. P.; May, J. M.

    2009-01-01

    Alzheimer's disease is a progressive and fatal neurodegenerative disease characterized by a build up of amyloid β (Aβ) deposits, elevated oxidative stress, and deterioration of the cholinergic system. The present study investigated short-term cognitive-enhancing effects of acute intraperitoneal (i.p.) Vitamin C (ascorbate) treatment in APP/PSEN1 mice, a mouse model of Alzheimer's disease. Middle-aged (12 months) and Very old (24 months) APP/PSEN1 bigenic and wild-type mice were treated with a...

  10. Age-dependent modifications of AMPA receptor subunit expression levels and related cognitive effects in 3xTg-AD mice

    Directory of Open Access Journals (Sweden)

    Pamela eCantanelli

    2014-08-01

    Full Text Available GluA1, GluA2, GluA3, and GluA4 are the constitutive subunits of AMPA receptors (AMPARs, the major mediators of fast excitatory transmission in the mammalian central nervous system. Most AMPARs are Ca2+-impermeable because of the presence of the GluA2 subunit. GluA2 mRNA undergoes an editing process that results in a Q to R substitution, a key factor in the regulation of AMPAR Ca2+-permeability. AMPARs lacking GluA2 or containing the unedited subunit are permeable to Ca2+ and Zn2+. The phenomenon physiologically modulates synaptic plasticity while, in pathologic conditions, leads to increased vulnerability to excitotoxic neuronal death. Given the importance of these subunits, we have therefore evaluated possible associations between changes in expression levels of AMPAR subunits and development of cognitive deficits in 3xTg-AD mice, a widely investigated transgenic mouse model of Alzheimer’s disease. With qRT-PCR, we assayed hippocampal mRNA expression levels of GluA1-4 subunits occurring in young [3 months of age (m.o.a.] and old (12 m.o.a Tg-AD mice and made comparisons with levels found in age-matched wild type (WT mice. Efficiency of GluA2 RNA editing was also analyzed. All animals were cognitively tested for short- and long-term spatial memory with the Morris Water Maze (MWM navigation task. 3xTg-AD mice showed age-dependent decreases of mRNA levels for all the AMPAR subunits, with the exception of GluA2. Editing remained fully efficient with aging in 3xTg-AD and WT mice. A one-to-one correlation analysis between MWM performances and GluA1-4 mRNA expression profiles showed negative correlations between GluA2 levels and MWM performances in young 3xTg-AD mice. On the contrary, positive correlations between GluA2 mRNA and MWM performances were found in young WT mice. Our data suggest that increases of AMPARs that contain GluA1, GluA3, and GluA4 subunits may help in maintaining cognition in pre-symptomatic 3xTg-AD mice.

  11. Spatial learning and memory deficits in young adult mice exposed to a brief intense noise at postnatal age

    Institute of Scientific and Technical Information of China (English)

    Shan Tao; Lijie Liu; Lijuan Shi; Xiaowei Li; Pei Shen; Qingying Xun; Xiaojing Guo; Zhiping Yu; Jian Wang

    2015-01-01

    Noise pollution is a major hazardous factor to human health and is likely harmful for vulnerable groups such as pre-term infants under life-support system in an intensive care unit. Previous studies have suggested that noise exposure impairs children's learning ability and cognitive performance and cognitive functions in animal models in which the effect is mainly attributed to the oxidant stress of noise on the cognitive brain. The potential role of noise induced hearing loss (NIHL), rather than the oxidant stress, has also been indicated by a depression of neurogenesis in the hippocampus long after a brief noise exposure, which produces only a tentative oxidant stress. It is not clear if noise exposure and NIHL during early development exerts a long term impact on cognitive function and neurogenesis towards adulthood. In the present study, a brief noise exposure at high sound level was performed in neonatal C57BL/6J mice (15 days after birth) to produce a significant amount of permanent hearing loss as proved 2 months after the noise. At this age, the noise-exposed animals showed deteriorated spatial learning and memory abilities and a reduction of hippocampal neurogenesis as compared with the control. The averaged hearing threshold was found to be strongly correlated with the scores for spatial learning and memory. We consider the effects observed are largely due to the loss of hearing sensitivity, rather than the oxidant stress, due to the long interval between noise exposure and the observations.

  12. Mouse ECG findings in aging, with conduction system affecting drugs and in cardiac pathologies: Development and validation of ECG analysis algorithm in mice.

    Science.gov (United States)

    Merentie, Mari; Lipponen, Jukka A; Hedman, Marja; Hedman, Antti; Hartikainen, Juha; Huusko, Jenni; Lottonen-Raikaslehto, Line; Parviainen, Viktor; Laidinen, Svetlana; Karjalainen, Pasi A; Ylä-Herttuala, Seppo

    2015-12-01

    Mouse models are extremely important in studying cardiac pathologies and related electrophysiology, but very few mouse ECG analysis programs are readily available. Therefore, a mouse ECG analysis algorithm was developed and validated. Surface ECG (lead II) was acquired during transthoracic echocardiography from C57Bl/6J mice under isoflurane anesthesia. The effect of aging was studied in young (2-3 months), middle-aged (14 months) and old (20-24 months) mice. The ECG changes associated with pharmacological interventions and common cardiac pathologies, that is, acute myocardial infarction (AMI) and progressive left ventricular hypertrophy (LVH), were studied. The ECG raw data were analyzed with an in-house ECG analysis program, modified specially for mouse ECG. Aging led to increases in P-wave duration, atrioventricular conduction time (PQ interval), and intraventricular conduction time (QRS complex width), while the R-wave amplitude decreased. In addition, the prevalence of arrhythmias increased during aging. Anticholinergic atropine shortened PQ time, and beta blocker metoprolol and calcium-channel blocker verapamil increased PQ interval and decreased heart rate. The ECG changes after AMI included early JT elevation, development of Q waves, decreased R-wave amplitude, and later changes in JT/T segment. In progressive LVH model, QRS complex width was increased at 2 and especially 4 weeks timepoint, and also repolarization abnormalities were seen. Aging, drugs, AMI, and LVH led to similar ECG changes in mice as seen in humans, which could be reliably detected with this new algorithm. The developed method will be very useful for studies on cardiovascular diseases in mice. PMID:26660552

  13. The Effects of Glucocorticoid and Voluntary Exercise Treatment on the Development of Thoracolumbar Kyphosis in Dystrophin-Deficient Mice

    OpenAIRE

    Brereton, Daniel; Plochocki, Jeffrey; An, Daniel; Costas, Jeffrey; Simons, Erin

    2012-01-01

    The development of spinal curvature deformities is a hallmark of muscular dystrophy. While glucocorticoid treatment has been shown to prolong muscle function in dystrophic mice, its effects on the development of dystrophinopathic spinal deformation are poorly understood. In this study, we test the effects of glucocorticoid treatment on the onset of thoracolumbar kyphosis in the dystrophin-deficient mdx mouse using voluntary running exercise to exacerbate muscle fibrosis. We measure the kyphot...

  14. Cardiac structure and function during ageing in energetically compromised Guanidinoacetate N-methyltransferase (GAMT-knockout mice – a one year longitudinal MRI study

    Directory of Open Access Journals (Sweden)

    Clarke Kieran

    2008-02-01

    Full Text Available Abstract Background High-resolution magnetic resonance imaging (cine-MRI is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female guanidinoacetate N-methyltransferase (GAMT knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Methods Measurements of cardiac structure (left ventricular mass and volumes and function (ejection fraction, stroke volume, cardiac output were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. Results There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT: 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively. Conclusion These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cine-MRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and