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Sample records for dystrophin-deficient mdx heart

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

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    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.

  2. Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart.

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    Meyers, Tatyana A; Townsend, DeWayne

    2015-02-15

    Duchenne muscular dystrophy (DMD) is a progressive disease of striated muscle deterioration. Respiratory and cardiac muscle dysfunction are particularly clinically relevant because they result in the leading causes of death in DMD patients. Despite the clinical and physiological significance of these systems, little has been done to understand the cardiorespiratory interaction in DMD. We show here that prior to the onset of global cardiac dysfunction, dystrophin-deficient mdx mice have increased cardiac fibrosis with the right ventricle being particularly affected. Using a novel biventricular cardiac catheterization technique coupled with cardiac stress testing, we demonstrate that both the right and left ventricles have significant reductions in both systolic and diastolic function in response to dobutamine. Unstimulated cardiac function is relatively normal except for a significant reduction in the ventricular pressure transient duration compared with controls. These biventricular analyses also reveal the absence of a dobutamine-induced increase in isovolumic relaxation in the right ventricle of control hearts. Simultaneous assessment of biventricular pressure demonstrates a dobutamine-dependent enhancement of coupling between the ventricles in control mice, which is absent in mdx mice. Furthermore, studies probing the passive-extension properties of the left ventricle demonstrate that the mdx heart is significantly more compliant compared with age-matched C57BL/10 hearts, which have an age-dependent stiffening that is completely absent from dystrophic hearts. These new results indicate that right ventricular fibrosis is an early indicator of the development of dystrophic cardiomyopathy, suggesting a mechanism by which respiratory insufficiency may accelerate the development of heart failure in DMD.

  3. Laryngeal Muscles Are Spared in the Dystrophin Deficient "mdx" Mouse

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    Thomas, Lisa B.; Joseph, Gayle L.; Adkins, Tracey D.; Andrade, Francisco H.; Stemple, Joseph C.

    2008-01-01

    Purpose: "Duchenne muscular dystrophy (DMD)" is caused by the loss of the cytoskeletal protein, dystrophin. The disease leads to severe and progressive skeletal muscle wasting. Interestingly, the disease spares some muscles. The purpose of the study was to determine the effects of dystrophin deficiency on 2 intrinsic laryngeal muscles, the…

  4. Proteomic Profiling of the Dystrophin-Deficient mdx Phenocopy of Dystrophinopathy-Associated Cardiomyopathy

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    Ashling Holland

    2014-01-01

    Full Text Available Cardiorespiratory complications are frequent symptoms of Duchenne muscular dystrophy, a neuromuscular disorder caused by primary abnormalities in the dystrophin gene. Loss of cardiac dystrophin initially leads to changes in dystrophin-associated glycoproteins and subsequently triggers secondarily sarcolemmal disintegration, fibre necrosis, fibrosis, fatty tissue replacement, and interstitial inflammation. This results in progressive cardiac disease, which is the cause of death in a considerable number of patients afflicted with X-linked muscular dystrophy. In order to better define the molecular pathogenesis of this type of cardiomyopathy, several studies have applied mass spectrometry-based proteomics to determine proteome-wide alterations in dystrophinopathy-associated cardiomyopathy. Proteomic studies included both gel-based and label-free mass spectrometric surveys of dystrophin-deficient heart muscle from the established mdx animal model of dystrophinopathy. Comparative cardiac proteomics revealed novel changes in proteins associated with mitochondrial energy metabolism, glycolysis, signaling, iron binding, antibody response, fibre contraction, basal lamina stabilisation, and cytoskeletal organisation. This review summarizes the importance of studying cardiomyopathy within the field of muscular dystrophy research, outlines key features of the mdx heart and its suitability as a model system for studying cardiac pathogenesis, and discusses the impact of recent proteomic findings for exploring molecular and cellular aspects of cardiac abnormalities in inherited muscular dystrophies.

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

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    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.

  6. Ex vivo stretch reveals altered mechanical properties of isolated dystrophin-deficient hearts.

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    Barnabei, Matthew S; Metzger, Joseph M

    2012-01-01

    Duchenne muscular dystrophy (DMD) is a progressive and fatal disease of muscle wasting caused by loss of the cytoskeletal protein dystrophin. In the heart, DMD results in progressive cardiomyopathy and dilation of the left ventricle through mechanisms that are not fully understood. Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes. To expand upon these findings, here we have subjected the left ventricles of dystrophin-deficient mdx hearts to mechanical stretch. Unexpectedly, isolated mdx hearts showed increased left ventricular (LV) compliance compared to controls during stretch as LV volume was increased above normal end diastolic volume. During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts. This suggests that the mechanical properties of the intact heart cannot be modeled as a simple extrapolation of findings in single cardiac myocytes. To explain these findings, a model is proposed in which disruption of the dystrophin-glycoprotein complex perturbs cell-extracellular matrix contacts and promotes the apparent slippage of myocytes past each other during LV distension. In comparison, similar increases in LV compliance were obtained in isolated hearts from β-sarcoglycan-null and laminin-α(2) mutant mice, but not in dysferlin-null mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes. Collectively, these findings suggest a novel and cell-death independent mechanism for the progressive pathological LV dilation that occurs in DMD.

  7. Ex vivo stretch reveals altered mechanical properties of isolated dystrophin-deficient hearts.

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    Matthew S Barnabei

    Full Text Available Duchenne muscular dystrophy (DMD is a progressive and fatal disease of muscle wasting caused by loss of the cytoskeletal protein dystrophin. In the heart, DMD results in progressive cardiomyopathy and dilation of the left ventricle through mechanisms that are not fully understood. Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes. To expand upon these findings, here we have subjected the left ventricles of dystrophin-deficient mdx hearts to mechanical stretch. Unexpectedly, isolated mdx hearts showed increased left ventricular (LV compliance compared to controls during stretch as LV volume was increased above normal end diastolic volume. During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts. This suggests that the mechanical properties of the intact heart cannot be modeled as a simple extrapolation of findings in single cardiac myocytes. To explain these findings, a model is proposed in which disruption of the dystrophin-glycoprotein complex perturbs cell-extracellular matrix contacts and promotes the apparent slippage of myocytes past each other during LV distension. In comparison, similar increases in LV compliance were obtained in isolated hearts from β-sarcoglycan-null and laminin-α(2 mutant mice, but not in dysferlin-null mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes. Collectively, these findings suggest a novel and cell-death independent mechanism for the progressive pathological LV dilation that occurs in DMD.

  8. Functional rescue of dystrophin-deficient mdx mice by a chimeric peptide-PMO.

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    Yin, Haifang; Moulton, Hong M; Betts, Corinne; Merritt, Thomas; Seow, Yiqi; Ashraf, Shirin; Wang, Qingsong; Boutilier, Jordan; Wood, Matthew Ja

    2010-10-01

    Splice modulation using antisense oligonucleotides (AOs) has been shown to yield targeted exon exclusion to restore the open reading frame and generate truncated but partially functional dystrophin protein. This has been successfully demonstrated in dystrophin-deficient mdx mice and in Duchenne muscular dystrophy (DMD) patients. However, DMD is a systemic disease; successful therapeutic exploitation of this approach will therefore depend on effective systemic delivery of AOs to all affected tissues. We have previously shown the potential of a muscle-specific/arginine-rich chimeric peptide-phosphorodiamidate morpholino (PMO) conjugate, but its long-term activity, optimized dosing regimen, capacity for functional correction and safety profile remain to be established. Here, we report the results of this chimeric peptide-PMO conjugate in the mdx mouse using low doses (3 and 6 mg/kg) administered via a 6 biweekly systemic intravenous injection protocol. We show 100% dystrophin-positive fibers and near complete correction of the dystrophin transcript defect in all peripheral muscle groups, with restoration of 50% dystrophin protein over 12 weeks, leading to correction of the DMD pathological phenotype and restoration of muscle function in the absence of detectable toxicity or immune response. Chimeric muscle-specific/cell-penetrating peptides therefore represent highly promising agents for systemic delivery of splice-correcting PMO oligomers for DMD therapy.

  9. Matrix metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces angiogenesis resulting in impaired growth of regenerated muscle fibers.

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    Miyazaki, Daigo; Nakamura, Akinori; Fukushima, Kazuhiro; Yoshida, Kunihiro; Takeda, Shin'ichi; Ikeda, Shu-ichi

    2011-05-01

    Matrix metalloproteases (MMPs) are a family of endopeptidases classified into subgroups based on substrate preference in normal physiological processes such as embryonic development and tissue remodeling, as well as in various disease processes via degradation of extracellular matrix components. Among the MMPs, MMP-9 and MMP-2 have been reported to be up-regulated in skeletal muscles in the lethal X-linked muscle disorder Duchenne muscular dystrophy (DMD), which is caused by loss of dystrophin. A recent study showed that deletion of the MMP9 gene in mdx, a mouse model for DMD, improved skeletal muscle pathology and function; however, the role of MMP-2 in the dystrophin-deficient muscle is not well known. In this study, we aimed at verifying the role of MMP-2 in the dystrophin-deficient muscle by using mdx mice with genetic ablation of MMP-2 (mdx/MMP-2(-/-)). We found impairment of regenerated muscle fiber growth with reduction of angiogenesis in mdx/MMP-2(-/-) mice at 3 months of age. Expression of vascular endothelial growth factor-A (VEGF-A), an important angiogenesis-related factor, decreased in mdx/MMP-2(-/-) mice at 3 months of age. MMP-2 had not a critical role in the degradation of dystrophin-glycoprotein complex (DGC) components such as β-dystroglycan and β-sarcoglycan in the regeneration process of the dystrophic muscle. Accordingly, MMP-2 may be essential for growth of regenerated muscle fibers through VEGF-associated angiogenesis in the dystrophin-deficient skeletal muscle.

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

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    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

  11. Nestin expression in end-stage disease in dystrophin-deficient heart: implications for regeneration from endogenous cardiac stem cells.

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    Berry, Suzanne E; Andruszkiewicz, Peter; Chun, Ju Lan; Hong, Jun

    2013-11-01

    Nestin(+) cardiac stem cells differentiate into striated cells following myocardial infarct. Transplantation of exogenous stem cells into myocardium of a murine model for Duchenne muscular dystrophy (DMD) increased proliferation of endogenous nestin(+) stem cells and resulted in the appearance of nestin(+) striated cells. This correlated with, and may be responsible for, prevention of dilated cardiomyopathy. We examined nestin(+) stem cells in the myocardium of dystrophin/utrophin-deficient (mdx/utrn(-/-)) mice, a model for DMD. We found that 92% of nestin(+) interstitial cells expressed Flk-1, a marker present on cardiac progenitor cells that differentiate into the cardiac lineage, and that a subset expressed Sca-1, present on adult cardiac cells that become cardiomyocytes. Nestin(+) interstitial cells maintained expression of Flk-1 but lost Sca-1 expression with age and were present in lower numbers in dystrophin-deficient heart than in wild-type heart. Unexpectedly, large clusters of nestin(+) striated cells ranging in size from 20 to 250 cells and extending up to 500 μm were present in mdx/utrn(-/-) heart near the end stage of disease. These cells were also present in dystrophin-deficient mdx/utrn(+/-) and mdx heart but not wild-type heart. Nestin(+) striated cells expressed cardiac troponin I, desmin, and Connexin 43 and correlated with proinflammatory CD68(+) macrophages. Elongated nestin(+) interstitial cells with striations were observed that did not express Flk-1 or the late cardiac marker cardiac troponin I but strongly expressed the early cardiac marker desmin. Nestin was also detected in endothelial and smooth muscle cells. These data indicate that new cardiomyocytes form in dystrophic heart, and nestin(+) interstitial cells may generate them in addition to other cells of the cardiac lineage.

  12. Proteasome inhibitor (MG132 rescues Nav1.5 protein content and the cardiac sodium current in dystrophin-deficient mdx5cv mice

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    Jean-Sebastien eRougier

    2013-03-01

    Full Text Available The cardiac voltage-gated sodium channel, Nav1.5, plays a central role in cardiac excitability and impulse propagation and associates with the dystrophin multiprotein complex (DMC at the lateral membrane of cardiomyocytes. It was previously shown that Nav1.5 protein content and the sodium current (INa were both decreased in cardiomyocytes of dystrophin-deficient mdx5cv mice. In this study, wild-type (WT and mdx5cv mice were treated for 7 days with the proteasome inhibitor MG132 (10 µg/Kg/24 h using implanted osmotic mini pumps. MG132 rescued both the total amount of Nav1.5 protein and INa but, unlike in previous studies, de novo expression of dystrophin was not observed in skeletal or cardiac muscle. This study suggests that the reduced expression of Nav1.5 in dystrophin-deficient cells is dependent on proteasomal degradation.

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

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    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.

  14. Dietary phosphorus overload aggravates the phenotype of the dystrophin-deficient mdx mouse.

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    Wada, Eiji; Yoshida, Mizuko; Kojima, Yoriko; Nonaka, Ikuya; Ohashi, Kazuya; Nagata, Yosuke; Shiozuka, Masataka; Date, Munehiro; Higashi, Tetsuo; Nishino, Ichizo; Matsuda, Ryoichi

    2014-11-01

    Duchenne muscular dystrophy is a lethal X-linked disease with no effective treatment. Progressive muscle degeneration, increased macrophage infiltration, and ectopic calcification are characteristic features of the mdx mouse, a murine model of Duchenne muscular dystrophy. Because dietary phosphorus/phosphate consumption is increasing and adverse effects of phosphate overloading have been reported in several disease conditions, we examined the effects of dietary phosphorus intake in mdx mice phenotypes. On weaning, control and mdx mice were fed diets containing 0.7, 1.0, or 2.0 g phosphorus per 100 g until they were 90 days old. Dystrophic phenotypes were evaluated in cryosections of quadriceps and tibialis anterior muscles, and maximal forces and voluntary activity were measured. Ectopic calcification was analyzed by electron microscopy to determine the cells initially responsible for calcium deposition in skeletal muscle. Dietary phosphorus overload dramatically exacerbated the dystrophic phenotypes of mdx mice by increasing inflammation associated with infiltration of M1 macrophages. In contrast, minimal muscle necrosis and inflammation were observed in exercised mdx mice fed a low-phosphorus diet, suggesting potential beneficial therapeutic effects of lowering dietary phosphorus intake on disease progression. To our knowledge, this is the first report showing that dietary phosphorus intake directly affects muscle pathological characteristics of mdx mice. Dietary phosphorus overloading promoted dystrophic disease progression in mdx mice, whereas restricting dietary phosphorus intake improved muscle pathological characteristics and function.

  15. Early manifestation of alteration in cardiac function in dystrophin deficient mdx mouse using 3D CMR tagging

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    Zhong Jia

    2009-10-01

    Full Text Available Abstract Background Duchenne muscular dystrophy (DMD is caused by the absence of the cytoskeletal protein, dystrophin. In DMD patients, dilated cardiomyopathy leading to heart failure may occur during adolescence. However, early cardiac dysfunction is frequently undetected due to physical inactivity and generalized debilitation. The objective of this study is to determine the time course of cardiac functional alterations in mdx mouse, a mouse model of DMD, by evaluating regional ventricular function with CMR tagging. Methods In vivo myocardial function was evaluated by 3D CMR tagging in mdx mice at early (2 months, middle (7 months and late (10 months stages of disease development. Global cardiac function, regional myocardial wall strains, and ventricular torsion were quantified. Myocardial lesions were assessed with Masson's trichrome staining. Results Global contractile indexes were similar between mdx and C57BL/6 mice in each age group. Histology analysis showed that young mdx mice were free of myocardial lesions. Interstitial fibrosis was present in 7 month mdx mice, with further development into patches or transmural lesions at 10 months of age. As a result, 10 month mdx mice showed significantly reduced regional strain and torsion. However, young mdx mice showed an unexpected increase in regional strain and torsion, while 7 month mdx mice displayed similar regional ventricular function as the controls. Conclusion Despite normal global ventricular function, CMR tagging detected a biphasic change in myocardial wall strain and torsion, with an initial increase at young age followed by progressive decrease at older ages. These results suggest that CMR tagging can provide more sensitive measures of functional alterations than global functional indexes in dystrophin-related cardiomyopathies.

  16. Influence of Botulinumtoxin A on the Expression of Adult MyHC Isoforms in the Masticatory Muscles in Dystrophin-Deficient Mice (Mdx-Mice

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    Ute Ulrike Botzenhart

    2016-01-01

    Full Text Available The most widespread animal model to investigate Duchenne muscular dystrophy is the mdx-mouse. In contrast to humans, phases of muscle degeneration are replaced by regeneration processes; hence there is only a restricted time slot for research. The aim of the study was to investigate if an intramuscular injection of BTX-A is able to break down muscle regeneration and has direct implications on the gene expression of myosin heavy chains in the corresponding treated and untreated muscles. Therefore, paralysis of the right masseter muscle was induced in adult healthy and dystrophic mice by a specific intramuscular injection of BTX-A. After 21 days the mRNA expression and protein content of MyHC isoforms of the right and left masseter, temporal, and the tongue muscle were determined using quantitative RT-PCR and Western blot technique. MyHC-IIa and MyHC-I-mRNA expression significantly increased in the paralyzed masseter muscle of control-mice, whereas MyHC-IIb and MyHC-IIx/d-mRNA were decreased. In dystrophic muscles no effect of BTX-A could be detected at the level of MyHC. This study suggests that BTX-A injection is a suitable method to simulate DMD-pathogenesis in healthy mice but further investigations are necessary to fully analyse the BTX-A effect and to generate sustained muscular atrophy in mdx-mice.

  17. Influence of Botulinumtoxin A on the Expression of Adult MyHC Isoforms in the Masticatory Muscles in Dystrophin-Deficient Mice (Mdx-Mice)

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    Todorov, Teodor

    2016-01-01

    The most widespread animal model to investigate Duchenne muscular dystrophy is the mdx-mouse. In contrast to humans, phases of muscle degeneration are replaced by regeneration processes; hence there is only a restricted time slot for research. The aim of the study was to investigate if an intramuscular injection of BTX-A is able to break down muscle regeneration and has direct implications on the gene expression of myosin heavy chains in the corresponding treated and untreated muscles. Therefore, paralysis of the right masseter muscle was induced in adult healthy and dystrophic mice by a specific intramuscular injection of BTX-A. After 21 days the mRNA expression and protein content of MyHC isoforms of the right and left masseter, temporal, and the tongue muscle were determined using quantitative RT-PCR and Western blot technique. MyHC-IIa and MyHC-I-mRNA expression significantly increased in the paralyzed masseter muscle of control-mice, whereas MyHC-IIb and MyHC-IIx/d-mRNA were decreased. In dystrophic muscles no effect of BTX-A could be detected at the level of MyHC. This study suggests that BTX-A injection is a suitable method to simulate DMD-pathogenesis in healthy mice but further investigations are necessary to fully analyse the BTX-A effect and to generate sustained muscular atrophy in mdx-mice. PMID:27689088

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

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    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.

  19. Disodium cromoglycate protects dystrophin-deficient muscle fibers from leakiness.

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    Marques, Maria Julia; Ventura Machado, Rafael; Minatel, Elaine; Santo Neto, Humberto

    2008-01-01

    In dystrophin-deficient fibers of mdx mice and in Duchenne dystrophy, the lack of dystrophin leads to sarcolemma breakdown and muscle degeneration. We verified that cromolyn, a mast-cell stabilizer agent, stabilized dystrophic muscle fibers using Evans blue dye as a marker of sarcolemma leakiness. Mdx mice (n=8; 14 days of age) received daily intraperitoneal injections of cromolyn (50 mg/kg body weight) for 15 days. Untreated mdx mice (n=8) were injected with saline. Cryostat cross-sections of the sternomastoid, tibialis anterior, and diaphragm muscles were stained with hematoxylin and eosin. Cromolyn dramatically reduced Evans blue dye-positive fibers in all muscles (P<0.05; Student's t-test) and led to a significant increase in the percentage of fibers with peripheral nuclei. This study supports the protective effects of cromolyn in dystrophic muscles and further indicates its action against muscle fiber leakiness in muscles that are differently affected by the lack of dystrophin.

  20. Dystrophin-Deficient Cardiomyopathy.

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    Kamdar, Forum; Garry, Daniel J

    2016-05-31

    Dystrophinopathies are a group of distinct neuromuscular diseases that result from mutations in the structural cytoskeletal Dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy, as well as DMD and BMD female carriers. The primary presenting symptom in most dystrophinopathies is skeletal muscle weakness. However, cardiac muscle is also a subtype of striated muscle and is similarly affected in many of the muscular dystrophies. Cardiomyopathies associated with dystrophinopathies are an increasingly recognized manifestation of these neuromuscular disorders and contribute significantly to their morbidity and mortality. Recent studies suggest that these patient populations would benefit from cardiovascular therapies, annual cardiovascular imaging studies, and close follow-up with cardiovascular specialists. Moreover, patients with DMD and BMD who develop end-stage heart failure may benefit from the use of advanced therapies. This review focuses on the pathophysiology, cardiac involvement, and treatment of cardiomyopathy in the dystrophic patient. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  1. Deletion of Galgt2 (B4Galnt2) Reduces Muscle Growth in Response to Acute Injury and Increases Muscle Inflammation and Pathology in Dystrophin-Deficient Mice

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    Xu, Rui; Singhal, Neha; Serinagaoglu, Yelda; Chandrasekharan, Kumaran; Joshi, Mandar; Bauer, John A.; Janssen, Paulus M.L.; Martin, Paul T.

    2016-01-01

    Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of α dystroglycan (αDG) and the up-regulation of laminin α2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2−/−mdx). Galgt2−/− mdx mice had increased heart and skeletal muscle pathology and inflammation, and also worsened cardiac function, relative to age-matched mdx mice. Deletion of Galgt2 in wild-type mice also slowed skeletal muscle growth in response to acute muscle injury. In each instance where Galgt2 expression was elevated (developing muscle, regenerating muscle, and dystrophic muscle), Galgt2-dependent glycosylation of αDG was also increased. Overexpression of Galgt2 failed to inhibit skeletal muscle pathology in dystroglycan-deficient muscles, in contrast to previous studies in dystrophin-deficient mdx muscles. This study demonstrates that Galgt2 gene expression and glycosylation of αDG are dynamically regulated in muscle and that endogenous Galgt2 gene expression can ameliorate the extent of muscle pathology, inflammation, and dysfunction in mdx mice. PMID:26435413

  2. Evaluation of skeletal and cardiac muscle function after chronic administration of thymosin beta-4 in the dystrophin deficient mouse.

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    Christopher F Spurney

    Full Text Available Thymosin beta-4 (Tbeta4 is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. We studied the effects of chronic administration of Tbeta4 on the skeletal and cardiac muscle of dystrophin deficient mdx mice, the mouse model of Duchenne muscular dystrophy. Female wild type (C57BL10/ScSnJ and mdx mice, 8-10 weeks old, were treated with 150 microg of Tbeta4 twice a week for 6 months. To promote muscle pathology, mice were exercised for 30 minutes twice a week. Skeletal and cardiac muscle function were assessed via grip strength and high frequency echocardiography. Localization of Tbeta4 and amount of fibrosis were quantified using immunohistochemistry and Gomori's tri-chrome staining, respectively. Mdx mice treated with Tbeta4 showed a significant increase in skeletal muscle regenerating fibers compared to untreated mdx mice. Tbeta4 stained exclusively in the regenerating fibers of mdx mice. Although untreated mdx mice had significantly decreased skeletal muscle strength compared to untreated wild type, there were no significant improvements in mdx mice after treatment. Systolic cardiac function, measured as percent shortening fraction, was decreased in untreated mdx mice compared to untreated wild type and there was no significant difference after treatment in mdx mice. Skeletal and cardiac muscle fibrosis were also significantly increased in untreated mdx mice compared to wild type, but there was no significant improvement in treated mdx mice. In exercised dystrophin deficient mice, chronic administration of Tbeta4 increased the number of regenerating fibers in skeletal muscle and could have a potential role in treatment of skeletal muscle disease in Duchenne muscular dystrophy.

  3. Compensation for dystrophin-deficiency: ADAM12 overexpression in skeletal muscle results in increased alpha 7 integrin, utrophin and associated glycoproteins

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    Moghadaszadeh, Behzad; Albrechtsen, Reidar; Guo, Ling T;

    2003-01-01

    , and suggested that significant changes in mdx/ADAM12 muscle might occur post-transcriptionally. Indeed, by immunostaining and immunoblotting we found an approximately 2-fold increase in expression, and distinct extrasynaptic localization, of alpha 7B integrin and utrophin, the functional homolog of dystrophin....... The expression of the dystrophin-associated glycoproteins was also increased. In conclusion, these results demonstrate a novel way to alleviate dystrophin deficiency in mice, and may stimulate the development of new approaches to compensate for dystrophin deficiency in animals and humans....

  4. Decreased inward rectifier potassium current IK1 in dystrophin-deficient ventricular cardiomyocytes.

    Science.gov (United States)

    Rubi, Lena; Koenig, Xaver; Kubista, Helmut; Todt, Hannes; Hilber, Karlheinz

    2017-03-04

    Kir2.x channels in ventricular cardiomyocytes (most prominently Kir2.1) account for the inward rectifier potassium current IK1, which controls the resting membrane potential and the final phase of action potential repolarization. Recently it was hypothesized that the dystrophin-associated protein complex (DAPC) is important in the regulation of Kir2.x channels. To test this hypothesis, we investigated potential IK1 abnormalities in dystrophin-deficient ventricular cardiomyocytes derived from the hearts of Duchenne muscular dystrophy mouse models. We found that IK1 was substantially diminished in dystrophin-deficient cardiomyocytes when compared to wild type myocytes. This finding represents the first functional evidence for a significant role of the DAPC in the regulation of Kir2.x channels.

  5. Differential expression of myosin heavy chain isoforms in the masticatory muscles of dystrophin-deficient mice.

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    Spassov, Alexander; Gredes, Tomasz; Gedrange, Tomasz; Lucke, Silke; Morgenstern, Sven; Pavlovic, Dragan; Kunert-Keil, Christiane

    2011-12-01

    The dystrophin-deficient mouse (mdx) is a homologue animal model of Duchenne muscular dystrophy (DMD) and is characterized by slowly progressive muscle weakness accompanied by changes in myosin heavy chain (MyHC) composition. It is likely that the masticatory muscles undergo similar changes. The aim of this study was to examine the masticatory muscles (masseter, temporal, tongue, and soleus) of 100-day-old mdx and control mice (n = 8-10), and the fibre type distribution (by immunohistochemistry) as well as the expression of the corresponding MyHC messenger RNA (mRNA) (protein and mRNA expression, using Western blot or quantitative real-time polymerase chain reaction (RT-PCR)). Immunohistochemistry and western blot analysis revealed that the masticatory muscles in the control and mdx mice consisted mainly of type 2 fibres, whereas soleus muscle consisted of both type 1 and 2 fibres. In the masseter muscle, the mRNA in mdx mice was not different from that found in the controls. However, the mRNA content of the MyHC-2b isoform in mdx mice was lower in comparison with the controls in the temporal muscle [11.9 versus 36.9 per cent; P muscle (65.7 versus 73.8 per cent; P muscle was lower than in the controls (25.9 versus 30.8 per cent; P muscles of mdx mice may lead to changed fibre type composition. The different MyHC gene expression in mdx mice masticatory muscles may be seen as an adaptive mechanism to muscular dystrophy.

  6. Dystrophin deficiency exacerbates skeletal muscle pathology in dysferlin-null mice

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    Han Renzhi

    2011-12-01

    Full Text Available Abstract Background Mutations in the genes coding for either dystrophin or dysferlin cause distinct forms of muscular dystrophy. Dystrophin links the cytoskeleton to the sarcolemma through direct interaction with β-dystroglycan. This link extends to the extracellular matrix by β-dystroglycan's interaction with α-dystroglycan, which binds extracellular matrix proteins, including laminin α2, agrin and perlecan, that possess laminin globular domains. The absence of dystrophin disrupts this link, leading to compromised muscle sarcolemmal integrity. Dysferlin, on the other hand, plays an important role in the Ca2+-dependent membrane repair of damaged sarcolemma in skeletal muscle. Because dysferlin and dystrophin play different roles in maintaining muscle cell integrity, we hypothesized that disrupting sarcolemmal integrity with dystrophin deficiency would exacerbate the pathology in dysferlin-null mice and allow further characterization of the role of dysferlin in skeletal muscle. Methods To test our hypothesis, we generated dystrophin/dysferlin double-knockout (DKO mice by breeding mdx mice with dysferlin-null mice and analyzed the effects of a combined deficiency of dysferlin and dystrophin on muscle pathology and sarcolemmal integrity. Results The DKO mice exhibited more severe muscle pathology than either mdx mice or dysferlin-null mice, and, importantly, the onset of the muscle pathology occurred much earlier than it did in dysferlin-deficient mice. The DKO mice showed muscle pathology of various skeletal muscles, including the mandible muscles, as well as a greater number of regenerating muscle fibers, higher serum creatine kinase levels and elevated Evans blue dye uptake into skeletal muscles. Lengthening contractions caused similar force deficits, regardless of dysferlin expression. However, the rate of force recovery within 45 minutes following lengthening contractions was hampered in DKO muscles compared to mdx muscles or dysferlin

  7. Low-Level Laser Therapy (LLLT) in Dystrophin-Deficient Muscle Cells: Effects on Regeneration Capacity, Inflammation Response and Oxidative Stress.

    Science.gov (United States)

    Macedo, Aline Barbosa; Moraes, Luis Henrique Rapucci; Mizobuti, Daniela Sayuri; Fogaça, Aline Reis; Moraes, Fernanda Dos Santos Rapucci; Hermes, Tulio de Almeida; Pertille, Adriana; Minatel, Elaine

    2015-01-01

    The present study evaluated low-level laser therapy (LLLT) effects on some physiological pathways that may lead to muscle damage or regeneration capacity in dystrophin-deficient muscle cells of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD). Primary cultures of mdx skeletal muscle cells were irradiated only one time with laser and analyzed after 24 and 48 hours. The LLLT parameter used was 830 nm wavelengths at 5 J/cm² fluence. The following groups were set up: Ctrl (untreated C57BL/10 primary muscle cells), mdx (untreated mdx primary muscle cells), mdx LA 24 (mdx primary muscle cells - LLLT irradiated and analyzed after 24 h), and mdx LA 48 (mdx primary muscle cells - LLLT irradiated and analyzed after 48 h). The mdx LA 24 and mdx LA 48 groups showed significant increase in cell proliferation, higher diameter in muscle cells and decreased MyoD levels compared to the mdx group. The mdx LA 48 group showed significant increase in Myosin Heavy Chain levels compared to the untreated mdx and mdx LA 24 groups. The mdx LA 24 and mdx LA 48 groups showed significant increase in [Ca2+]i. The mdx group showed significant increase in H2O2 production and 4-HNE levels compared to the Ctrl group and LLLT treatment reduced this increase. GSH levels and GPx, GR and SOD activities increased in the mdx group. Laser treatment reduced the GSH levels and GR and SOD activities in dystrophic muscle cells. The mdx group showed significant increase in the TNF-α and NF-κB levels, which in turn was reduced by the LLLT treatment. Together, these results suggest that the laser treatment improved regenerative capacity and decreased inflammatory response and oxidative stress in dystrophic muscle cells, indicating that LLLT could be a helpful alternative therapy to be associated with other treatment for dystrophinopathies.

  8. Low-Level Laser Therapy (LLLT in Dystrophin-Deficient Muscle Cells: Effects on Regeneration Capacity, Inflammation Response and Oxidative Stress.

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    Aline Barbosa Macedo

    Full Text Available The present study evaluated low-level laser therapy (LLLT effects on some physiological pathways that may lead to muscle damage or regeneration capacity in dystrophin-deficient muscle cells of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD. Primary cultures of mdx skeletal muscle cells were irradiated only one time with laser and analyzed after 24 and 48 hours. The LLLT parameter used was 830 nm wavelengths at 5 J/cm² fluence. The following groups were set up: Ctrl (untreated C57BL/10 primary muscle cells, mdx (untreated mdx primary muscle cells, mdx LA 24 (mdx primary muscle cells - LLLT irradiated and analyzed after 24 h, and mdx LA 48 (mdx primary muscle cells - LLLT irradiated and analyzed after 48 h. The mdx LA 24 and mdx LA 48 groups showed significant increase in cell proliferation, higher diameter in muscle cells and decreased MyoD levels compared to the mdx group. The mdx LA 48 group showed significant increase in Myosin Heavy Chain levels compared to the untreated mdx and mdx LA 24 groups. The mdx LA 24 and mdx LA 48 groups showed significant increase in [Ca2+]i. The mdx group showed significant increase in H2O2 production and 4-HNE levels compared to the Ctrl group and LLLT treatment reduced this increase. GSH levels and GPx, GR and SOD activities increased in the mdx group. Laser treatment reduced the GSH levels and GR and SOD activities in dystrophic muscle cells. The mdx group showed significant increase in the TNF-α and NF-κB levels, which in turn was reduced by the LLLT treatment. Together, these results suggest that the laser treatment improved regenerative capacity and decreased inflammatory response and oxidative stress in dystrophic muscle cells, indicating that LLLT could be a helpful alternative therapy to be associated with other treatment for dystrophinopathies.

  9. Increased constitutive nitric oxide production by whole body periodic acceleration ameliorates alterations in cardiomyocytes associated with utrophin/dystrophin deficiency.

    Science.gov (United States)

    Lopez, Jose R; Kolster, Juan; Zhang, Rui; Adams, Jose

    2017-07-01

    Duchenne Muscular Dystrophy (DMD) cardiomyopathy is a progressive lethal disease caused by the lack of the dystrophin protein in the heart. The most widely used animal model of DMD is the dystrophin-deficient mdx mouse; however, these mice exhibit a mild dystrophic phenotype with heart failure only late in life. In contrast, mice deficient for both dystrophin and utrophin (mdx/utrn(-/-), or dKO) can be used to model severe DMD cardiomyopathy where pathophysiological indicators of heart failure are detectable by 8-10weeks of age. Nitric oxide (NO) is an important signaling molecule involved in vital functions of regulating rhythm, contractility, and microcirculation of the heart, and constitutive NO production affects the function of proteins involved in excitation-contraction coupling. In this study, we explored the efficacy of enhancing NO production as a therapeutic strategy for treating DMD cardiomyopathy using the dKO mouse model of DMD. Specifically, NO production was induced via whole body periodic acceleration (pGz), a novel non-pharmacologic intervention which enhances NO synthase (NOS) activity through sinusoidal motion of the body in a headward-footward direction, introducing pulsatile shear stress to the vascular endothelium and cardiomyocyte plasma membrane. Male dKO mice were randomized at 8weeks of age to receive daily pGz (480cpm, Gz±3.0m/s(2), 1h/d) for 4weeks or no treatment, and a separate age-matched group of WT animals (pGz-treated and untreated) served as non-diseased controls. At the conclusion of the protocol, cardiomyocytes from untreated dKO animals had, respectively, 4.3-fold and 3.5-fold higher diastolic resting concentration of Ca(2+) ([Ca(2+)]d) and Na(+) ([Na(+)]d) compared to WT, while pGz treatment significantly reduced these levels. For dKO cardiomyocytes, pGz treatment also improved the depressed contractile function, decreased oxidative stress, blunted the elevation in calpain activity, and mitigated the abnormal increase in [Ca

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

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    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.

  11. Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures.

    Science.gov (United States)

    Kornegay, Joe N; Bogan, Daniel J; Bogan, Janet R; Dow, Jennifer L; Wang, Jiahui; Fan, Zheng; Liu, Naili; Warsing, Leigh C; Grange, Robert W; Ahn, Mihye; Balog-Alvarez, Cynthia J; Cotten, Steven W; Willis, Monte S; Brinkmeyer-Langford, Candice; Zhu, Hongtu; Palandra, Joe; Morris, Carl A; Styner, Martin A; Wagner, Kathryn R

    2016-01-01

    Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn (+/-)) whippets. A total of four GRippets (dystrophic and Mstn (+/-)), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, there was no

  12. Improvement of cardiac contractile function by peptide-based inhibition of NF-κB in the utrophin/dystrophin-deficient murine model of muscular dystrophy

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    Guttridge Denis C

    2011-05-01

    Full Text Available Abstract Background Duchenne muscular dystrophy (DMD is an inherited and progressive disease causing striated muscle deterioration. Patients in their twenties generally die from either respiratory or cardiac failure. In order to improve the lifespan and quality of life of DMD patients, it is important to prevent or reverse the progressive loss of contractile function of the heart. Recent studies by our labs have shown that the peptide NBD (Nemo Binding Domain, targeted at blunting Nuclear Factor κB (NF-κB signaling, reduces inflammation, enhances myofiber regeneration, and improves contractile deficits in the diaphragm in dystrophin-deficient mdx mice. Methods To assess whether cardiac function in addition to diaphragm function can be improved, we investigated physiological and histological parameters of cardiac muscle in mice deficient for both dystrophin and its homolog utrophin (double knockout = dko mice treated with NBD peptide. These dko mice show classic pathophysiological hallmarks of heart failure, including myocyte degeneration, an impaired force-frequency response and a severely blunted β-adrenergic response. Cardiac contractile function at baseline and frequencies and pre-loads throughout the in vivo range as well as β-adrenergic reserve was measured in isolated cardiac muscle preparations. In addition, we studied histopathological and inflammatory markers in these mice. Results At baseline conditions, active force development in cardiac muscles from NBD treated dko mice was more than double that of vehicle-treated dko mice. NBD treatment also significantly improved frequency-dependent behavior of the muscles. The increase in force in NBD-treated dko muscles to β-adrenergic stimulation was robustly restored compared to vehicle-treated mice. However, histological features, including collagen content and inflammatory markers were not significantly different between NBD-treated and vehicle-treated dko mice. Conclusions We conclude

  13. Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice.

    Science.gov (United States)

    Gray, Sarah K; McGee-Lawrence, Meghan E; Sanders, Jennifer L; Condon, Keith W; Tsai, Chung-Jui; Donahue, Seth W

    2012-09-01

    Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6 weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic

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

    DEFF Research Database (Denmark)

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

    2002-01-01

    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...

  15. Morphological changes in the trigemino-rubral pathway in dystrophic (mdx) mice.

    Science.gov (United States)

    Pinto, Magali Luci; Tokunaga, Heloisa Helena Vieira Olyntho; Souccar, Caden; Schoorlemmer, Guus H M; Lapa, Rita de Cássia Ribeiro da Silva

    2007-04-12

    The lack of dystrophin that causes Duchenne muscle disease affects not only the muscles but also the central nervous system. Dystrophin-deficient mdx mice present changes in several brain fiber systems. We compared the projections from the trigeminal sensory nuclear complex to the red nucleus in control and mdx mice using retrograde tracers. Injection of 200 nL 2% fluorogold into the red nucleus caused labeling in the mesencephalic trigeminal nucleus, the principal sensory nucleus and the oral, interpolar, and caudal subnuclei of the spinal trigeminal nucleus in both control and mdx mice. Injection of latex microbeads labeled with rhodamine and fluorescein gave results similar to those seen with fluorogold. The number of labeled neurons in the trigeminal sensory nuclear complex was significantly reduced in mdx mice. In the oral subnucleus of the spinal trigeminal nucleus this reduction was 50%. These results indicate that the trigemino-rubral pathway is reduced in dystrophin-deficient mice.

  16. Diaphragm degeneration and cardiac structure in mdx mouse: potential clinical implications for Duchenne muscular dystrophy.

    Science.gov (United States)

    Barbin, Isabel Cristina Chagas; Pereira, Juliano Alves; Bersan Rovere, Matheus; de Oliveira Moreira, Drielen; Marques, Maria Julia; Santo Neto, Humberto

    2016-05-01

    We examined the effects of exercise on diaphragm degeneration and cardiomyopathy in dystrophin-deficient mdx mice. Mdx mice (11 months of age) were exercised (swimming) for 2 months to worsen diaphragm degeneration. Control mdx mice were kept sedentary. Morphological evaluation demonstrated increased fibrosis in the diaphragm of exercised mdx mice (33.3 ± 6.0% area of fibrosis) compared with control mdx mice (20.9 ± 1.7% area of fibrosis). Increased (26%) activity of MMP-2, a marker of fibrosis, was detected in the diaphragms from exercised mdx mice. Morphological evaluation of the heart demonstrated a 45% increase in fibrosis in the right ventricle (8.3 ± 0.6% in sedentary vs. 12.0 ± 0.6% of fibrosis in exercised) and in the left ventricle (35% increase) in the exercised mdx mice. The density of inflammatory cells-degenerating cardiomyocytes increased 95% in the right ventricle (2.3 ± 0.6 in sedentary vs. 4.5 ± 0.8 in exercised) and 71% in the left ventricle (1.4 ± 0.6 sedentary vs. 2.4 ± 0.5 exercised). The levels of both active MMP-2 and the pro-fibrotic factor transforming growth factor beta were elevated in the hearts of exercised compared with sedentary mdx mice. The wall thickness to lumen diameter ratio of the pulmonary trunk was significantly increased in the exercised mdx mice (0.11 ± 0.04 in sedentary vs. 0.28 ± 0.12 in exercised), as was the thickness of the right ventricle wall, which suggests the occurrence of pulmonary hypertension in those animals. It is suggested that diaphragm degeneration is a main contributor to right ventricle dystrophic pathology. These findings may be relevant for future interventional studies for Duchenne muscular dystrophy-associated cardiomyopathy.

  17. Effect of Dystrophin Deficiency on Selected Intrinsic Laryngeal Muscles of the "mdx" Mouse

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    Fry, Lisa T.; Stemple, Joseph C.; Andreatta, Richard D.; Harrison, Anne L.; Andrade, Francisco H.

    2010-01-01

    Background: Intrinsic laryngeal muscles (ILM) show biological differences from the broader class of skeletal muscles. Yet most research regarding ILM specialization has been completed on a few muscles, most notably the thyroarytenoid and posterior cricoarytenoid. Little information exists regarding the biology of other ILM. Early evidence suggests…

  18. Fetal skeletal muscle progenitors have regenerative capacity after intramuscular engraftment in dystrophin deficient mice.

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    Hiroshi Sakai

    Full Text Available Muscle satellite cells (SCs are stem cells that reside in skeletal muscles and contribute to regeneration upon muscle injury. SCs arise from skeletal muscle progenitors expressing transcription factors Pax3 and/or Pax7 during embryogenesis in mice. However, it is unclear whether these fetal progenitors possess regenerative ability when transplanted in adult muscle. Here we address this question by investigating whether fetal skeletal muscle progenitors (FMPs isolated from Pax3(GFP/+ embryos have the capacity to regenerate muscle after engraftment into Dystrophin-deficient mice, a model of Duchenne muscular dystrophy. The capacity of FMPs to engraft and enter the myogenic program in regenerating muscle was compared with that of SCs derived from adult Pax3(GFP/+ mice. Transplanted FMPs contributed to the reconstitution of damaged myofibers in Dystrophin-deficient mice. However, despite FMPs and SCs having similar myogenic ability in culture, the regenerative ability of FMPs was less than that of SCs in vivo. FMPs that had activated MyoD engrafted more efficiently to regenerate myofibers than MyoD-negative FMPs. Transcriptome and surface marker analyses of these cells suggest the importance of myogenic priming for the efficient myogenic engraftment. Our findings suggest the regenerative capability of FMPs in the context of muscle repair and cell therapy for degenerative muscle disease.

  19. 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

    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...... in 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...

  20. A comparative study of N-glycolylneuraminic acid (Neu5Gc and cytotoxic T cell (CT carbohydrate expression in normal and dystrophin-deficient dog and human skeletal muscle.

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    Paul T Martin

    Full Text Available The expression of N-glycolylneuraminic acid (Neu5Gc and the cytotoxic T cell (CT carbohydrate can impact the severity of muscular dystrophy arising from the loss of dystrophin in mdx mice. Here, we describe the expression of these two glycans in skeletal muscles of dogs and humans with or without dystrophin-deficiency. Neu5Gc expression was highly reduced (>95% in muscle from normal golden retriever crosses (GR, n = 3 and from golden retriever with muscular dystrophy (GRMD, n = 5 dogs at multiple ages (3, 6 and 13 months when compared to mouse muscle, however, overall sialic acid expression in GR and GRMD muscles remained high at all ages. Neu5Gc was expressed on only a minority of GRMD satellite cells, CD8⁺ T lymphocytes and macrophages. Human muscle from normal (no evident disease, n = 3, Becker (BMD, n = 3 and Duchenne (DMD, n = 3 muscular dystrophy individuals had absent to very low Neu5Gc staining, but some punctate intracellular muscle staining was present in BMD and DMD muscles. The CT carbohydrate was localized to the neuromuscular junction in GR muscle, while GRMD muscles had increased expression on a subset of myofibers and macrophages. In humans, the CT carbohydrate was ectopically expressed on the sarcolemmal membrane of some BMD muscles, but not normal human or DMD muscles. These data are consistent with the notion that altered Neu5Gc and CT carbohydrate expression may modify disease severity resulting from dystrophin deficiency in dogs and humans.

  1. A comparative study of N-glycolylneuraminic acid (Neu5Gc) and cytotoxic T cell (CT) carbohydrate expression in normal and dystrophin-deficient dog and human skeletal muscle.

    Science.gov (United States)

    Martin, Paul T; Golden, Bethannie; Okerblom, Jonathan; Camboni, Marybeth; Chandrasekharan, Kumaran; Xu, Rui; Varki, Ajit; Flanigan, Kevin M; Kornegay, Joe N

    2014-01-01

    The expression of N-glycolylneuraminic acid (Neu5Gc) and the cytotoxic T cell (CT) carbohydrate can impact the severity of muscular dystrophy arising from the loss of dystrophin in mdx mice. Here, we describe the expression of these two glycans in skeletal muscles of dogs and humans with or without dystrophin-deficiency. Neu5Gc expression was highly reduced (>95%) in muscle from normal golden retriever crosses (GR, n = 3) and from golden retriever with muscular dystrophy (GRMD, n = 5) dogs at multiple ages (3, 6 and 13 months) when compared to mouse muscle, however, overall sialic acid expression in GR and GRMD muscles remained high at all ages. Neu5Gc was expressed on only a minority of GRMD satellite cells, CD8⁺ T lymphocytes and macrophages. Human muscle from normal (no evident disease, n = 3), Becker (BMD, n = 3) and Duchenne (DMD, n = 3) muscular dystrophy individuals had absent to very low Neu5Gc staining, but some punctate intracellular muscle staining was present in BMD and DMD muscles. The CT carbohydrate was localized to the neuromuscular junction in GR muscle, while GRMD muscles had increased expression on a subset of myofibers and macrophages. In humans, the CT carbohydrate was ectopically expressed on the sarcolemmal membrane of some BMD muscles, but not normal human or DMD muscles. These data are consistent with the notion that altered Neu5Gc and CT carbohydrate expression may modify disease severity resulting from dystrophin deficiency in dogs and humans.

  2. A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping.

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    Gemma L Walmsley

    Full Text Available BACKGROUND: Duchenne muscular dystrophy (DMD, which afflicts 1 in 3500 boys, is one of the most common genetic disorders of children. This fatal degenerative condition is caused by an absence or deficiency of dystrophin in striated muscle. Most affected patients have inherited or spontaneous deletions in the dystrophin gene that disrupt the reading frame resulting in unstable truncated products. For these patients, restoration of the reading frame via antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach. The major DMD deletion "hot spot" is found between exons 45 and 53, and skipping exon 51 in particular is predicted to ameliorate the dystrophic phenotype in the greatest number of patients. Currently the mdx mouse is the most widely used animal model of DMD, although its mild phenotype limits its suitability in clinical trials. The Golden Retriever muscular dystrophy (GRMD model has a severe phenotype, but due to its large size, is expensive to use. Both these models have mutations in regions of the dystrophin gene distant from the commonly mutated DMD "hot spot". METHODOLOGY/PRINCIPAL FINDINGS: Here we describe the severe phenotype, histopathological findings, and molecular analysis of Cavalier King Charles Spaniels with dystrophin-deficient muscular dystrophy (CKCS-MD. The dogs harbour a missense mutation in the 5' donor splice site of exon 50 that results in deletion of exon 50 in mRNA transcripts and a predicted premature truncation of the translated protein. Antisense oligonucleotide-mediated skipping of exon 51 in cultured myoblasts from an affected dog restored the reading frame and protein expression. CONCLUSIONS/SIGNIFICANCE: Given the small size of the breed, the amiable temperament and the nature of the mutation, we propose that CKCS-MD is a valuable new model for clinical trials of antisense oligonucleotide-induced exon skipping and other therapeutic approaches for DMD.

  3. Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy.

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    Thibaut Larcher

    Full Text Available A few animal models of Duchenne muscular dystrophy (DMD are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD.

  4. Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Larcher, Thibaut; Lafoux, Aude; Tesson, Laurent; Remy, Séverine; Thepenier, Virginie; François, Virginie; Le Guiner, Caroline; Goubin, Helicia; Dutilleul, Maéva; Guigand, Lydie; Toumaniantz, Gilles; De Cian, Anne; Boix, Charlotte; Renaud, Jean-Baptiste; Cherel, Yan; Giovannangeli, Carine; Concordet, Jean-Paul; Anegon, Ignacio; Huchet, Corinne

    2014-01-01

    A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD.

  5. Voltage-gated ion channel dysfunction precedes cardiomyopathy development in the dystrophic heart.

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    Xaver Koenig

    Full Text Available Duchenne muscular dystrophy (DMD, caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology.To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged.Ion channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers.

  6. Dystrophin-deficient cardiomyocytes derived from human urine: New biologic reagents for drug discovery

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    Xuan Guan

    2014-03-01

    Full Text Available The ability to extract somatic cells from a patient and reprogram them to pluripotency opens up new possibilities for personalized medicine. Induced pluripotent stem cells (iPSCs have been employed to generate beating cardiomyocytes from a patient's skin or blood cells. Here, iPSC methods were used to generate cardiomyocytes starting from the urine of a patient with Duchenne muscular dystrophy (DMD. Urine was chosen as a starting material because it contains adult stem cells called urine-derived stem cells (USCs. USCs express the canonical reprogramming factors c-myc and klf4, and possess high telomerase activity. Pluripotency of urine-derived iPSC clones was confirmed by immunocytochemistry, RT-PCR and teratoma formation. Urine-derived iPSC clones generated from healthy volunteers and a DMD patient were differentiated into beating cardiomyocytes using a series of small molecules in monolayer culture. Results indicate that cardiomyocytes retain the DMD patient's dystrophin mutation. Physiological assays suggest that dystrophin-deficient cardiomyocytes possess phenotypic differences from normal cardiomyocytes. These results demonstrate the feasibility of generating cardiomyocytes from a urine sample and that urine-derived cardiomyocytes retain characteristic features that might be further exploited for mechanistic studies and drug discovery.

  7. Longitudinal ambulatory measurements of gait abnormality in dystrophin-deficient dogs

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    Voit Thomas

    2011-04-01

    Full Text Available Abstract Background This study aimed to measure the gait abnormalities in GRMD (Golden retriever muscular dystrophy dogs during growth and disease progression using an ambulatory gait analyzer (3D-accelerometers as a possible tool to assess the effects of a therapeutic intervention. Methods Six healthy and twelve GRMD dogs were evaluated twice monthly, from the age of two to nine months. The evolution of each gait variable previously shown to be modified in control and dystrophin-deficient adults was assessed using two-ways variance analysis (age, clinical status with repeated measurements. A principal component analysis (PCA was applied to perfect multivariate data interpretation. Results Speed, stride length, total power and force significantly already decreased (p Conclusion The gait variables measured by the accelerometers were sensitive to early detect and follow the gait disorders and mirrored the heterogeneity of clinical presentations, giving sense to monitor gait in GRMD dogs during progression of the disease and pre-clinical therapeutic trials.

  8. Lengthening-contractions in isolated myocardium impact force development and worsen cardiac contractile function in the mdx mouse model of muscular dystrophy.

    Science.gov (United States)

    Xu, Ying; Delfín, Dawn A; Rafael-Fortney, Jill A; Janssen, Paul M L

    2011-02-01

    Lengthening-contractions exert eccentric stress on myofibers in normal myocardium. In congestive heart failure caused by a variety of diseases, the impact of lengthening-contractions of myocardium likely becomes more prevalent and severe. The present study introduces a method to investigate the role of stretching imposed by repetitive lengthening-contractions in myocardium under near-physiological conditions. By exerting various stretch-release ramps while the muscle is contracting, consecutive lengthening-contractions and their potential detrimental effect on cardiac function can be studied. We tested our model and hypothesis in age-matched (young and adult) mdx and wild-type mouse right ventricular trabeculae. These linear and ultrathin muscles possess all major cardiac cell types, and their contractile behavior very closely mimics that of the whole myocardium. In the first group of experiments, 10 lengthening-contractions at various magnitudes of stretch were performed in trabeculae from 10-wk-old mdx and wild-type mice. In the second group, 100 lengthening-contractions at various magnitudes were conducted in trabeculae from 10- and 20-wk-old mice. The peak isometric active developed tension (F(dev), in mN/mm(2)) and kinetic parameters time to peak tension (TTP, in ms) and time from peak tension to half-relaxation (RT50, in ms) were measured. Our results indicate lengthening-contractions significantly impact contractile behavior, and that dystrophin-deficient myocardium in mdx mice is significantly more susceptible to these damaging lengthening-contractions. The results indicate that lengthening-contractions in intact myocardium can be used in vitro to study this emerging contributor to cardiomyopathy.

  9. Disruption of action potential and calcium signaling properties in malformed myofibers from dystrophin-deficient mice.

    Science.gov (United States)

    Hernández-Ochoa, Erick O; Pratt, Stephen J P; Garcia-Pelagio, Karla P; Schneider, Martin F; Lovering, Richard M

    2015-04-01

    Duchenne muscular dystrophy (DMD), the most common and severe muscular dystrophy, is caused by the absence of dystrophin. Muscle weakness and fragility (i.e., increased susceptibility to damage) are presumably due to structural instability of the myofiber cytoskeleton, but recent studies suggest that the increased presence of malformed/branched myofibers in dystrophic muscle may also play a role. We have previously studied myofiber morphology in healthy wild-type (WT) and dystrophic (MDX) skeletal muscle. Here, we examined myofiber excitability using high-speed confocal microscopy and the voltage-sensitive indicator di-8-butyl-amino-naphthyl-ethylene-pyridinium-propyl-sulfonate (di-8-ANEPPS) to assess the action potential (AP) properties. We also examined AP-induced Ca(2+) transients using high-speed confocal microscopy with rhod-2, and assessed sarcolemma fragility using elastimetry. AP recordings showed an increased width and time to peak in malformed MDX myofibers compared to normal myofibers from both WT and MDX, but no significant change in AP amplitude. Malformed MDX myofibers also exhibited reduced AP-induced Ca(2+) transients, with a further Ca(2+) transient reduction in the branches of malformed MDX myofibers. Mechanical studies indicated an increased sarcolemma deformability and instability in malformed MDX myofibers. The data suggest that malformed myofibers are functionally different from myofibers with normal morphology. The differences seen in AP properties and Ca(2+) signals suggest changes in excitability and remodeling of the global Ca(2+) signal, both of which could underlie reported weakness in dystrophic muscle. The biomechanical changes in the sarcolemma support the notion that malformed myofibers are more susceptible to damage. The high prevalence of malformed myofibers in dystrophic muscle may contribute to the progressive strength loss and fragility seen in dystrophic muscles. © 2015 The Authors. Physiological Reports published by Wiley

  10. Loss of nNOS inhibits compensatory muscle hypertrophy and exacerbates inflammation and eccentric contraction-induced damage in mdx mice

    Science.gov (United States)

    Froehner, Stanley C.; Reed, Sarah M.; Anderson, Kendra N.; Huang, Paul L.; Percival, Justin M.

    2015-01-01

    Approaches targeting nitric oxide (NO) signaling show promise as therapies for Duchenne and Becker muscular dystrophies. However, the mechanisms by which NO benefits dystrophin-deficient muscle remain unclear, but may involve nNOSβ, a newly discovered enzymatic source of NO in skeletal muscle. Here we investigate the impact of dystrophin deficiency on nNOSβ and use mdx mice engineered to lack nNOSμ and nNOSβ to discern how the loss of nNOS impacts dystrophic skeletal muscle pathology. In mdx muscle, nNOSβ was mislocalized and its association with the Golgi complex was reduced. nNOS depletion from mdx mice prevented compensatory skeletal muscle cell hypertrophy, decreased myofiber central nucleation and increased focal macrophage cell infiltration, indicating exacerbated dystrophic muscle damage. Reductions in muscle integrity in nNOS-null mdx mice were accompanied by decreases in specific force and increased susceptibility to eccentric contraction-induced muscle damage compared with mdx controls. Unexpectedly, muscle fatigue was unaffected by nNOS depletion, revealing a novel latent compensatory mechanism for the loss of nNOS in mdx mice. Together with previous studies, these data suggest that localization of both nNOSμ and nNOSβ is disrupted by dystrophin deficiency. They also indicate that nNOS has a more complex role as a modifier of dystrophic pathology and broader therapeutic potential than previously recognized. Importantly, these findings also suggest nNOSβ as a new drug target and provide a new conceptual framework for understanding nNOS signaling and the benefits of NO therapies in dystrophinopathies. PMID:25214536

  11. Upregulation of the creatine synthetic pathway in skeletal muscles of mature mdx mice.

    Science.gov (United States)

    McClure, Warren C; Rabon, Rick E; Ogawa, Hirofumi; Tseng, Brian S

    2007-08-01

    Duchenne muscular dystrophy (DMD) is a fatal neuromuscular human disease caused by dystrophin deficiency. The mdx mouse lacks dystrophin protein, yet does not exhibit the debilitating DMD phenotype. Investigating compensatory mechanisms in the mdx mouse may shed new insights into modifying DMD pathogenesis. This study targets two metabolic genes, guanidinoacetate methyltransferase (GAMT) and arginine:glycine amidinotransferase (AGAT) which are required for creatine synthesis. We show that GAMT and AGAT mRNA are up-regulated 5.4- and 1.9-fold respectively in adult mdx muscle compared to C57. In addition, GAMT protein expression is up-regulated at least 2.5-fold in five different muscles of mdx vs. control. Furthermore, we find GAMT immunoreactivity in up to 80% of mature mdx muscle fibers in addition to small regenerating fibers and rare revertants; while GAMT immunoreactivity is equal to background levels in all muscle fibers of mature C57 mice. The up-regulation of the creatine synthetic pathway may help maintain muscle creatine levels and limit cellular energy failure in leaky mdx skeletal muscles. These results may help better understand the mild phenotype of the mdx mouse and may offer new treatment horizons for DMD.

  12. Skeletal muscle-specific ablation of gamma(cyto-actin does not exacerbate the mdx phenotype.

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    Kurt W Prins

    Full Text Available We previously documented a ten-fold increase in gamma(cyto-actin expression in dystrophin-deficient skeletal muscle and hypothesized that increased gamma(cyto-actin expression may participate in an adaptive cytoskeletal remodeling response. To explore whether increased gamma(cyto-actin fortifies the cortical cytoskeleton in dystrophic skeletal muscle, we generated double knockout mice lacking both dystrophin and gamma(cyto-actin specifically in skeletal muscle (ms-DKO. Surprisingly, dystrophin-deficient mdx and ms-DKO mice presented with comparable levels of myofiber necrosis, membrane instability, and deficits in muscle function. The lack of an exacerbated phenotype in ms-DKO mice suggests gamma(cyto-actin and dystrophin function in a common pathway. Finally, because both mdx and ms-DKO skeletal muscle showed similar levels of utrophin expression and presented with identical dystrophies, we conclude utrophin can partially compensate for the loss of dystrophin independent of a gamma(cyto-actin-utrophin interaction.

  13. Comparative Label-Free Mass Spectrometric Analysis of Mildly versus Severely Affected mdx Mouse Skeletal Muscles Identifies Annexin, Lamin, and Vimentin as Universal Dystrophic Markers

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    Ashling Holland

    2015-06-01

    Full Text Available The primary deficiency in the membrane cytoskeletal protein dystrophin results in complex changes in dystrophic muscles. In order to compare the degree of secondary alterations in differently affected subtypes of skeletal muscles, we have conducted a global analysis of proteome-wide changes in various dystrophin-deficient muscles. In contrast to the highly degenerative mdx diaphragm muscle, which showed considerable alterations in 35 distinct proteins, the spectrum of mildly to moderately dystrophic skeletal muscles, including interosseus, flexor digitorum brevis, soleus, and extensor digitorum longus muscle, exhibited a smaller number of changed proteins. Compensatory mechanisms and/or cellular variances may be responsible for differing secondary changes in individual mdx muscles. Label-free mass spectrometry established altered expression levels for diaphragm proteins associated with contraction, energy metabolism, the cytoskeleton, the extracellular matrix and the cellular stress response. Comparative immunoblotting verified the differences in the degree of secondary changes in dystrophin-deficient muscles and showed that the up-regulation of molecular chaperones, the compensatory increase in proteins of the intermediate filaments, the fibrosis-related increase in collagen levels and the pathophysiological decrease in calcium binding proteins is more pronounced in mdx diaphragm as compared to the less severely affected mdx leg muscles. Annexin, lamin, and vimentin were identified as universal dystrophic markers.

  14. Mechanical, biochemical and morphometric alterations in the femur of mdx mice.

    Science.gov (United States)

    Nakagaki, Wilson Romero; Bertran, Celso Aparecido; Matsumura, Cintia Yuri; Santo-Neto, Humberto; Camilli, José Angelo

    2011-02-01

    probably due to genetic factors that are directly or indirectly related to dystrophin deficiency. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Enhanced currents through L-type calcium channels in cardiomyocytes disturb the electrophysiology of the dystrophic heart.

    Science.gov (United States)

    Koenig, Xaver; Rubi, Lena; Obermair, Gerald J; Cervenka, Rene; Dang, Xuan B; Lukacs, Peter; Kummer, Stefan; Bittner, Reginald E; Kubista, Helmut; Todt, Hannes; Hilber, Karlheinz

    2014-02-15

    Duchenne muscular dystrophy (DMD), induced by mutations in the gene encoding for the cytoskeletal protein dystrophin, is an inherited disease characterized by progressive muscle weakness. Besides the relatively well characterized skeletal muscle degenerative processes, DMD is also associated with cardiac complications. These include cardiomyopathy development and cardiac arrhythmias. The current understanding of the pathomechanisms in the heart is very limited, but recent research indicates that dysfunctional ion channels in dystrophic cardiomyocytes play a role. The aim of the present study was to characterize abnormalities in L-type calcium channel function in adult dystrophic ventricular cardiomyocytes. By using the whole cell patch-clamp technique, the properties of currents through calcium channels in ventricular cardiomyocytes isolated from the hearts of normal and dystrophic adult mice were compared. Besides the commonly used dystrophin-deficient mdx mouse model for human DMD, we also used mdx-utr mice, which are both dystrophin- and utrophin-deficient. We found that calcium channel currents were significantly increased, and channel inactivation was reduced in dystrophic cardiomyocytes. Both effects enhance the calcium influx during an action potential (AP). Whereas the AP in dystrophic mouse cardiomyocytes was nearly normal, implementation of the enhanced dystrophic calcium conductance in a computer model of a human ventricular cardiomyocyte considerably prolonged the AP. Finally, the described dystrophic calcium channel abnormalities entailed alterations in the electrocardiograms of dystrophic mice. We conclude that gain of function in cardiac L-type calcium channels may disturb the electrophysiology of the dystrophic heart and thereby cause arrhythmias.

  16. The artificial gene Jazz, a transcriptional regulator of utrophin, corrects the dystrophic pathology in mdx mice.

    Science.gov (United States)

    Di Certo, Maria Grazia; Corbi, Nicoletta; Strimpakos, Georgios; Onori, Annalisa; Luvisetto, Siro; Severini, Cinzia; Guglielmotti, Angelo; Batassa, Enrico Maria; Pisani, Cinzia; Floridi, Aristide; Benassi, Barbara; Fanciulli, Maurizio; Magrelli, Armando; Mattei, Elisabetta; Passananti, Claudio

    2010-03-01

    The absence of the cytoskeletal protein dystrophin results in Duchenne muscular dystrophy (DMD). The utrophin protein is the best candidate for dystrophin replacement in DMD patients. To obtain therapeutic levels of utrophin expression in dystrophic muscle, we developed an alternative strategy based on the use of artificial zinc finger transcription factors (ZF ATFs). The ZF ATF 'Jazz' was recently engineered and tested in vivo by generating a transgenic mouse specifically expressing Jazz at the muscular level. To validate the ZF ATF technology for DMD treatment we generated a second mouse model by crossing Jazz-transgenic mice with dystrophin-deficient mdx mice. Here, we show that the artificial Jazz protein restores sarcolemmal integrity and prevents the development of the dystrophic disease in mdx mice. This exclusive animal model establishes the notion that utrophin-based therapy for DMD can be efficiently developed using ZF ATF technology and candidates Jazz as a novel therapeutic molecule for DMD therapy.

  17. 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

    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, alpha7B integrin, and dystroglycans. Ectopic ADAM12 expression in normal mouse skeletal muscle also improved regeneration after freeze injury, presumably by the same mechanism. Hence, it was suggested...... overexpressing ADAM12 (ADAM12(+)/mdx mice), even though their utrophin levels were mildly elevated compared with age-matched controls. Thus, membrane stabilization was not sufficient to provide protection during prolonged disease. Consequently, we reinvestigated skeletal muscle regeneration in ADAM12 transgenic...

  18. Eosinophilia of dystrophin-deficient muscle is promoted by perforin-mediated cytotoxicity by T cell effectors

    Science.gov (United States)

    Cai, B.; Spencer, M. J.; Nakamura, G.; Tseng-Ong, L.; Tidball, J. G.

    2000-01-01

    Previous investigations have shown that cytotoxic T lymphocytes (CTLs) contribute to muscle pathology in the dystrophin-null mutant mouse (mdx) model of Duchenne muscular dystrophy through perforin-dependent and perforin-independent mechanisms. We have assessed whether the CTL-mediated pathology includes the promotion of eosinophilia in dystrophic muscle, and thereby provides a secondary mechanism through which CTLs contribute to muscular dystrophy. Quantitative immunohistochemistry confirmed that eosinophilia is a component of the mdx dystrophy. In addition, electron microscopic observations show that eosinophils traverse the basement membrane of mdx muscle fibers and display sites of close apposition of eosinophil and muscle membranes. The close membrane apposition is characterized by impingement of eosinophilic rods of major basic protein into the muscle cell membrane. Transfer of mdx splenocytes and mdx muscle extracts to irradiated C57 mice by intraperitoneal injection resulted in muscle eosinophilia in the recipient mice. Double-mutant mice lacking dystrophin and perforin showed less eosinophilia than was displayed by mdx mice that expressed perforin. Finally, administration of prednisolone, which has been shown previously to reduce the concentration of CTLs in dystrophic muscle, produced a significant reduction in eosinophilia. These findings indicate that eosinophilia is a component of the mdx pathology that is promoted by perforin-dependent cytotoxicity of effector T cells. However, some eosinophilia of mdx muscle is independent of perforin-mediated processes.

  19. Motor physical therapy affects muscle collagen type I and decreases gait speed in dystrophin-deficient dogs.

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    Thaís P Gaiad

    Full Text Available Golden Retriever Muscular Dystrophy (GRMD is a dystrophin-deficient canine model genetically homologous to Duchenne Muscular Dystrophy (DMD in humans. Muscular fibrosis secondary to cycles of degeneration/regeneration of dystrophic muscle tissue and muscular weakness leads to biomechanical adaptation that impairs the quality of gait. Physical therapy (PT is one of the supportive therapies available for DMD, however, motor PT approaches have controversial recommendations and there is no consensus regarding the type and intensity of physical therapy. In this study we investigated the effect of physical therapy on gait biomechanics and muscular collagen deposition types I and III in dystrophin-deficient dogs. Two dystrophic dogs (treated dogs-TD underwent a PT protocol of active walking exercise, 3×/week, 40 minutes/day, 12 weeks. Two dystrophic control dogs (CD maintained their routine of activities of daily living. At t0 (pre and t1 (post-physical therapy, collagen type I and III were assessed by immunohistochemistry and gait biomechanics were analyzed. Angular displacement of shoulder, elbow, carpal, hip, stifle and tarsal joint and vertical (Fy, mediolateral (Fz and craniocaudal (Fx ground reaction forces (GRF were assessed. Wilcoxon test was used to verify the difference of biomechanical variables between t0 and t1, considering p<.05. Type I collagen of endomysium suffered the influence of PT, as well as gait speed that had decreased from t0 to t1 (p<.000. The PT protocol employed accelerates morphological alterations on dystrophic muscle and promotes a slower velocity of gait. Control dogs which maintained their routine of activities of daily living seem to have found a better balance between movement and preservation of motor function.

  20. Sparing of the dystrophin-deficient cranial sartorius muscle is associated with classical and novel hypertrophy pathways in GRMD dogs.

    Science.gov (United States)

    Nghiem, Peter P; Hoffman, Eric P; Mittal, Priya; Brown, Kristy J; Schatzberg, Scott J; Ghimbovschi, Svetlana; Wang, Zuyi; Kornegay, Joe N

    2013-11-01

    Both Duchenne and golden retriever muscular dystrophy (GRMD) are caused by dystrophin deficiency. The Duchenne muscular dystrophy sartorius muscle and orthologous GRMD cranial sartorius (CS) are relatively spared/hypertrophied. We completed hierarchical clustering studies to define molecular mechanisms contributing to this differential involvement and their role in the GRMD phenotype. GRMD dogs with larger CS muscles had more severe deficits, suggesting that selective hypertrophy could be detrimental. Serial biopsies from the hypertrophied CS and other atrophied muscles were studied in a subset of these dogs. Myostatin showed an age-dependent decrease and an inverse correlation with the degree of GRMD CS hypertrophy. Regulators of myostatin at the protein (AKT1) and miRNA (miR-539 and miR-208b targeting myostatin mRNA) levels were altered in GRMD CS, consistent with down-regulation of myostatin signaling, CS hypertrophy, and functional rescue of this muscle. mRNA and proteomic profiling was used to identify additional candidate genes associated with CS hypertrophy. The top-ranked network included α-dystroglycan and like-acetylglucosaminyltransferase. Proteomics demonstrated increases in myotrophin and spectrin that could promote hypertrophy and cytoskeletal stability, respectively. Our results suggest that multiple pathways, including decreased myostatin and up-regulated miRNAs, α-dystroglycan/like-acetylglucosaminyltransferase, spectrin, and myotrophin, contribute to hypertrophy and functional sparing of the CS. These data also underscore the muscle-specific responses to dystrophin deficiency and the potential deleterious effects of differential muscle involvement. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  1. Profiling of Age-Related Changes in the Tibialis Anterior Muscle Proteome of the mdx Mouse Model of Dystrophinopathy

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    Steven Carberry

    2012-01-01

    Full Text Available X-linked muscular dystrophy is a highly progressive disease of childhood and characterized by primary genetic abnormalities in the dystrophin gene. Senescent mdx specimens were used for a large-scale survey of potential age-related alterations in the dystrophic phenotype, because the established mdx animal model of dystrophinopathy exhibits progressive deterioration of muscle tissue with age. Since the mdx tibialis anterior muscle is a frequently used model system in muscular dystrophy research, we employed this particular muscle to determine global changes in the dystrophic skeletal muscle proteome. The comparison of mdx mice aged 8 weeks versus 22 months by mass-spectrometry-based proteomics revealed altered expression levels in 8 distinct protein species. Increased levels were shown for carbonic anhydrase, aldolase, and electron transferring flavoprotein, while the expressions of pyruvate kinase, myosin, tropomyosin, and the small heat shock protein Hsp27 were found to be reduced in aged muscle. Immunoblotting confirmed age-dependent changes in the density of key muscle proteins in mdx muscle. Thus, segmental necrosis in mdx tibialis anterior muscle appears to trigger age-related protein perturbations due to dystrophin deficiency. The identification of novel indicators of progressive muscular dystrophy might be useful for the establishment of a muscle subtype-specific biomarker signature of dystrophinopathy.

  2. Non-Invasive MRI and Spectroscopy of mdx Mice Reveal Temporal Changes in Dystrophic Muscle Imaging and in Energy Deficits

    Science.gov (United States)

    Heier, Christopher R.; Guerron, Alfredo D.; Korotcov, Alexandru; Lin, Stephen; Gordish-Dressman, Heather; Fricke, Stanley; Sze, Raymond W.; Hoffman, Eric P.; Wang, Paul; Nagaraju, Kanneboyina

    2014-01-01

    In Duchenne muscular dystrophy (DMD), a genetic disruption of dystrophin protein expression results in repeated muscle injury and chronic inflammation. Magnetic resonance imaging shows promise as a surrogate outcome measure in both DMD and rehabilitation medicine that is capable of predicting clinical benefit years in advance of functional outcome measures. The mdx mouse reproduces the dystrophin deficiency that causes DMD and is routinely used for preclinical drug testing. There is a need to develop sensitive, non-invasive outcome measures in the mdx model that can be readily translatable to human clinical trials. Here we report the use of magnetic resonance imaging and spectroscopy techniques for the non-invasive monitoring of muscle damage in mdx mice. Using these techniques, we studied dystrophic mdx muscle in mice from 6 to 12 weeks of age, examining both the peak disease phase and natural recovery phase of the mdx disease course. T2 and fat-suppressed imaging revealed significant levels of tissue with elevated signal intensity in mdx hindlimb muscles at all ages; spectroscopy revealed a significant deficiency of energy metabolites in 6-week-old mdx mice. As the mdx mice progressed from the peak disease stage to the recovery stage of disease, each of these phenotypes was either eliminated or reduced, and the cross-sectional area of the mdx muscle was significantly increased when compared to that of wild-type mice. Histology indicates that hyper-intense MRI foci correspond to areas of dystrophic lesions containing inflammation as well as regenerating, degenerating and hypertrophied myofibers. Statistical sample size calculations provide several robust measures with the ability to detect intervention effects using small numbers of animals. These data establish a framework for further imaging or preclinical studies, and they support the development of MRI as a sensitive, non-invasive outcome measure for muscular dystrophy. PMID:25390038

  3. Metabolic dysfunction and altered mitochondrial dynamics in the utrophin-dystrophin deficient mouse model of duchenne muscular dystrophy.

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    Meghna Pant

    Full Text Available The utrophin-dystrophin deficient (DKO mouse model has been widely used to understand the progression of Duchenne muscular dystrophy (DMD. However, it is unclear as to what extent muscle pathology affects metabolism. Therefore, the present study was focused on understanding energy expenditure in the whole animal and in isolated extensor digitorum longus (EDL muscle and to determine changes in metabolic enzymes. Our results show that the 8 week-old DKO mice consume higher oxygen relative to activity levels. Interestingly the EDL muscle from DKO mouse consumes higher oxygen per unit integral force, generates less force and performs better in the presence of pyruvate thus mimicking a slow twitch muscle. We also found that the expression of hexokinase 1 and pyruvate kinase M2 was upregulated several fold suggesting increased glycolytic flux. Additionally, there is a dramatic increase in dynamin-related protein 1 (Drp 1 and mitofusin 2 protein levels suggesting increased mitochondrial fission and fusion, a feature associated with increased energy demand and altered mitochondrial dynamics. Collectively our studies point out that the dystrophic disease has caused significant changes in muscle metabolism. To meet the increased energetic demand, upregulation of metabolic enzymes and regulators of mitochondrial fusion and fission is observed in the dystrophic muscle. A better understanding of the metabolic demands and the accompanied alterations in the dystrophic muscle can help us design improved intervention therapies along with existing drug treatments for the DMD patients.

  4. Expression of full-length utrophin prevents muscular dystrophy in mdx mice.

    Science.gov (United States)

    Tinsley, J; Deconinck, N; Fisher, R; Kahn, D; Phelps, S; Gillis, J M; Davies, K

    1998-12-01

    Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fiber leading to the gradual depletion of skeletal muscle. The molecular structure of dystrophin is very similar to that of the related protein utrophin. Utrophin is found in all tissues and is confined to the neuromuscular and myotendinous junctions in mature muscle. Sarcolemmal localization of a truncated utrophin transgene in the dystrophin-deficient mdx mouse significantly improves the dystrophic muscle phenotype. Therefore, up-regulation of utrophin by drug therapy is a plausible therapeutic approach in the treatment of DMD. Here we demonstrate that expression of full-length utrophin in mdx mice prevents the development of muscular dystrophy. We assessed muscle morphology, fiber regeneration and mechanical properties (force development and resistance to stretch) of mdx and transgenic mdx skeletal and diaphragm muscle. The utrophin levels required in muscle are significantly less than the normal endogenous utrophin levels seen in lung and kidney, and we provide evidence that the pathology depends on the amount of utrophin expression. These results also have important implications for DMD therapies in which utrophin replacement is achieved by delivery using exogenous vectors.

  5. 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

  6. The passive mechanical properties of the extensor digitorum longus muscle are compromised in 2- to 20-mo-old mdx mice.

    Science.gov (United States)

    Hakim, Chady H; Grange, Robert W; Duan, Dongsheng

    2011-06-01

    Muscle rigidity and myotendinous junction (MTJ) deficiency contribute to immobilization in Duchenne muscular dystrophy (DMD), a lethal disease caused by the absence of dystrophin. However, little is known about the muscle passive properties and MTJ strength in a diseased muscle. Here, we hypothesize that dystrophin-deficient muscle pathology renders skeletal muscle stiffer and MTJ weaker. To test our hypothesis, we examined the passive properties of an intact noncontracting muscle-tendon unit in mdx mice, a mouse model for DMD. The extensor digitorum longus (EDL) muscle-tendon preparations of 2-, 6-, 14-, and 20-mo-old mdx and normal control mice were strained stepwisely from 110% to 160% of the muscle optimal length. The stress-strain response and failure position were analyzed. In support of our hypothesis, the mdx EDL preparation consistently developed higher stress before muscle failure. Postfailure stresses decreased dramatically in mdx but not normal preparations. Further, mdx showed a significantly faster stress relaxation rate. Consistent with stress-strain assay results, we observed significantly higher fibrosis in mdx muscle. In 2- and 6-mo-old mdx and 20-mo-old BL10 mice failure occurred within the muscle (2- to 14-mo-old BL10 preparations did not fail). Interestingly, in ≥14-mo-old mdx mice the failure site shifted toward the MTJ. Electron microscopy revealed substantial MTJ degeneration in aged but not young mdx mice. In summary, our results suggest that the passive properties of the EDL muscle and the strength of MTJ are compromised in mdx in an age-dependent manner. These findings offer new insights in studying DMD pathogenesis and developing novel therapies.

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

    DEFF Research Database (Denmark)

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

    2002-01-01

    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......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......, as 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....

  8. Levels of α7 integrin and laminin-α2 are increased following prednisone treatment in the mdx mouse and GRMD dog models of Duchenne muscular dystrophy.

    Science.gov (United States)

    Wuebbles, Ryan D; Sarathy, Apurva; Kornegay, Joe N; Burkin, Dean J

    2013-09-01

    Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease for which there is no cure and limited treatment options. Prednisone is currently the first line treatment option for DMD and studies have demonstrated that it improves muscle strength. Although prednisone has been used for the treatment of DMD for decades, the mechanism of action of this drug remains unclear. Recent studies have shown that the α7β1 integrin is a major modifier of disease progression in mouse models of DMD and is therefore a target for drug-based therapies. In this study we examined whether prednisone increased α7β1 integrin levels in mdx mouse and GRMD dog models and myogenic cells from humans with DMD. Our results show that prednisone promotes an increase in α7 integrin protein in cultured myogenic cells and in the muscle of mdx and GRMD animal models of DMD. The prednisone-mediated increase in α7 integrin was associated with increased laminin-α2 in prednisone-treated dystrophin-deficient muscle. Together, our results suggest that prednisone acts in part through increased merosin in the muscle basal lamina and through sarcolemmal stabilization of α7β1 integrin in dystrophin-deficient muscle. These results indicate that therapies that target an increase in muscle α7β1 integrin, its signaling pathways and/or laminin could be therapeutic in DMD.

  9. Levels of α7 integrin and laminin-α2 are increased following prednisone treatment in the mdx mouse and GRMD dog models of Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Ryan D. Wuebbles

    2013-09-01

    Duchenne muscular dystrophy (DMD is a fatal neuromuscular disease for which there is no cure and limited treatment options. Prednisone is currently the first line treatment option for DMD and studies have demonstrated that it improves muscle strength. Although prednisone has been used for the treatment of DMD for decades, the mechanism of action of this drug remains unclear. Recent studies have shown that the α7β1 integrin is a major modifier of disease progression in mouse models of DMD and is therefore a target for drug-based therapies. In this study we examined whether prednisone increased α7β1 integrin levels in mdx mouse and GRMD dog models and myogenic cells from humans with DMD. Our results show that prednisone promotes an increase in α7 integrin protein in cultured myogenic cells and in the muscle of mdx and GRMD animal models of DMD. The prednisone-mediated increase in α7 integrin was associated with increased laminin-α2 in prednisone-treated dystrophin-deficient muscle. Together, our results suggest that prednisone acts in part through increased merosin in the muscle basal lamina and through sarcolemmal stabilization of α7β1 integrin in dystrophin-deficient muscle. These results indicate that therapies that target an increase in muscle α7β1 integrin, its signaling pathways and/or laminin could be therapeutic in DMD.

  10. Effective exon skipping and dystrophin restoration by 2'-o-methoxyethyl antisense oligonucleotide in dystrophin-deficient mice.

    Directory of Open Access Journals (Sweden)

    Lu Yang

    Full Text Available Antisense oligonucleotide (AO-mediated exon-skipping therapy is one of the most promising therapeutic strategies for Duchenne Muscular Dystrophy (DMD and several AO chemistries have been rigorously investigated. In this report, we focused on the effect of 2'-O-methoxyethyl oligonucleotides (MOE on exon skipping in cultured mdx myoblasts and mice. Efficient dose-dependent skipping of targeted exon 23 was achieved in myoblasts with MOE AOs of different lengths and backbone chemistries. Furthermore, we established that 25-mer MOE phosphorothioate (PS AOs provided the greatest exon-skipping efficacy. When compared with 2'O methyl phosphorothioate (2'OmePS AOs, 25-mer MOE (PS AOs also showed higher exon-skipping activity in vitro and in mdx mice after intramuscular injections. Characterization of uptake in vitro corroborated with exon-skipping results, suggesting that increased uptake of 25-mer MOE PS AOs might partly contribute to the difference in exon-skipping activity observed in vitro and in mdx mice. Our findings demonstrate the substantial potential for MOE PS AOs as an alternative option for the treatment of DMD.

  11. Differential expression of genes involved in the calcium homeostasis in masticatory muscles of MDX mice.

    Science.gov (United States)

    Kunert-Keil, C H; Gredes, T; Lucke, S; Botzenhart, U; Dominiak, M; Gedrange, T

    2014-04-01

    Duchenne Muscular Dystrophy (DMD) and its murine model, mdx, are characterized by Ca(2+) induced muscle damage and muscle weakness followed by distorted dentofacial morphology. In both, DMD patients and in mdx mice, could be proven so far that only the extraocular muscles (EOM) are not affected by muscular dystrophy. The EOMs are protected against calcium overload by enhanced expression of genes involved in the Ca(2+) homeostasis. We could recently demonstrate that masticatory muscles of mdx mice are differentially affected by muscle dystrophy. The dystrophic masseter and temporalis shows muscle histology comparable to all other skeletal muscles in this animal model, whereas dystrophic tongue muscles seem to develop a milder phenotype. Due to this fact it is to hypothesize that an altered Ca(2+) homeostasis seems to underlie the mdx masticatory muscle pathology. Aim of this study was to examine the mRNA and protein levels of the sarcoplasmic reticulum Ca(2+) ATPases SERCA1 and SERCA2, the plasma membrane Ca(2+) ATPases Atp2b1 and Atp2b4, the sodium/calcium exchanger NCX1, the ryanodine receptor 1, parvalbumin, sarcolipin, phospholamban and the L-type Ca(2+) channel alpha-1 subunit (Cacna1s) in Musculus masseter, temporalis, and tongue of 100 day old control and mdx mice. In mdx masseter muscle significant increased mRNA levels of NCX1 and Cacna1s were found compared to control mice. In contrast, the mRNA amount of RYR1 was significant reduced in mdx temporalis muscle, whereas ATP2b4 was significant increased. In mdx tongue a down-regulation of the ATP2b1, sarcolipin and parvalbumin mRNA expression was found, whereas the phospholamban mRNA level was significantly increased compared to controls. These data were verified by western blot analyses. Our findings revealed that mdx masticatory muscles showed an unequally altered expression of genes involved in the Ca(2+) homeostasis that can support the differences in masticatory muscles response to dystrophin deficiency.

  12. Fetal microchimeric cells in a fetus-treats-its-mother paradigm do not contribute to dystrophin production in serially parous mdx females.

    Science.gov (United States)

    Seppanen, Elke Jane; Hodgson, Samantha Susan; Khosrotehrani, Kiarash; Bou-Gharios, George; Fisk, Nicholas M

    2012-10-10

    Throughout every pregnancy, genetically distinct fetal microchimeric stem/progenitor cells (FMCs) engraft in the mother, persist long after delivery, and may home to damaged maternal tissues. Phenotypically normal fetal lymphoid progenitors have been described to develop in immunodeficient mothers in a fetus-treats-its-mother paradigm. Since stem cells contribute to muscle repair, we assessed this paradigm in the mdx mouse model of Duchenne muscular dystrophy. mdx females were bred serially to either ROSAeGFP males or mdx males to obtain postpartum microchimeras that received either wild-type FMCs or dystrophin-deficient FMCs through serial gestations. To enhance regeneration, notexin was injected into the tibialis anterior of postpartum mice. FMCs were detected by qPCR at a higher frequency in injected compared to noninjected side muscle (P=0.02). However, the number of dystrophin-positive fibers was similar in mothers delivering wild-type compared to mdx pups. In addition, there was no correlation between FMC detection and percentage dystrophin, and no GFP+ve FMCs were identified that expressed dystrophin. In 10/11 animals, GFP+ve FMCs were detected by immunohistochemistry, of which 60% expressed CD45 with 96% outside the basal lamina defining myofiber contours. Finally we confirmed lack of FMC contribution to statellite cells in postpartum mdx females mated with Myf5-LacZ males. We conclude that the FMC contribution to regenerating muscles is insufficient to have a functional impact.

  13. Proteomics reveals drastic increase of extracellular matrix proteins collagen and dermatopontin in the aged mdx diaphragm model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Carberry, Steven; Zweyer, Margit; Swandulla, Dieter; Ohlendieck, Kay

    2012-08-01

    Duchenne muscular dystrophy is a lethal genetic disease of childhood caused by primary abnormalities in the gene coding for the membrane cytoskeletal protein dystrophin. The mdx mouse is an established animal model of various aspects of X-linked muscular dystrophy and is widely used for studying fundamental mechanisms of dystrophinopathy and testing novel therapeutic approaches to treat one of the most frequent gender-specific diseases in humans. In order to determine global changes in the muscle proteome with the progressive deterioration of mdx tissue with age, we have characterized diaphragm muscle from mdx mice at three ages (8-weeks, 12-months and 22-months) using mass spectrometry-based proteomics. Altered expression levels in diaphragm of 8-week vs. 22-month mice were shown to occur in 11 muscle-associated proteins. Aging in the mdx diaphragm seems to be associated with a drastic increase in the extracellular matrix proteins, collagen and dermatopontin, the molecular chaperone αB-crystallin, and the intermediate filament protein vimentin, suggesting increased accumulation of connective tissue, an enhanced cellular stress response and compensatory stabilization of the weakened membrane cytoskeleton. These proteomic findings establish the aged mdx diaphragm as an excellent model system for studying secondary effects of dystrophin deficiency in skeletal muscle tissue.

  14. Aberrant location of inhibitory synaptic marker proteins in the hippocampus of dystrophin-deficient mice: implications for cognitive impairment in duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Elżbieta Krasowska

    Full Text Available Duchenne muscular dystrophy (DMD is a neuromuscular disease that arises from mutations in the dystrophin-encoding gene. Apart from muscle pathology, cognitive impairment, primarily of developmental origin, is also a significant component of the disorder. Convergent lines of evidence point to an important role for dystrophin in regulating the molecular machinery of central synapses. The clustering of neurotransmitter receptors at inhibitory synapses, thus impacting on synaptic transmission, is of particular significance. However, less is known about the role of dystrophin in influencing the precise expression patterns of proteins located within the pre- and postsynaptic elements of inhibitory synapses. To this end, we exploited molecular markers of inhibitory synapses, interneurons and dystrophin-deficient mouse models to explore the role of dystrophin in determining the stereotypical patterning of inhibitory connectivity within the cellular networks of the hippocampus CA1 region. In tissue from wild-type (WT mice, immunoreactivity of neuroligin2 (NL2, an adhesion molecule expressed exclusively in postsynaptic elements of inhibitory synapses, and the vesicular GABA transporter (VGAT, a marker of GABAergic presynaptic elements, were predictably enriched in strata pyramidale and lacunosum moleculare. In acute contrast, NL2 and VGAT immunoreactivity was relatively evenly distributed across all CA1 layers in dystrophin-deficient mice. Similar changes were evident with the cannabinoid receptor 1, vesicular glutamate transporter 3, parvalbumin, somatostatin and the GABAA receptor alpha1 subunit. The data show that in the absence of dystrophin, there is a rearrangement of the molecular machinery, which underlies the precise spatio-temporal pattern of GABAergic synaptic transmission within the CA1 sub-field of the hippocampus.

  15. Low intensity training of mdx mice reduces carbonylation and increases expression levels of proteins involved in energy metabolism and muscle contraction.

    Science.gov (United States)

    Hyzewicz, Janek; Tanihata, Jun; Kuraoka, Mutsuki; Ito, Naoki; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi

    2015-05-01

    High intensity training induces muscle damage in dystrophin-deficient mdx mice, an animal model for Duchenne muscular dystrophy. However, low intensity training (LIT) rescues the mdx phenotype and even reduces the level of protein carbonylation, a marker of oxidative damage. Until now, beneficial effects of LIT were mainly assessed at the physiological level. We investigated the effects of LIT at the molecular level on 8-week-old wild-type and mdx muscle using 2D Western blot and protein-protein interaction analysis. We found that the fast isoforms of troponin T and myosin binding protein C as well as glycogen phosphorylase were overcarbonylated and downregulated in mdx muscle. Some of the mitochondrial enzymes of the citric acid cycle were overcarbonylated, whereas some proteins of the respiratory chain were downregulated. Of functional importance, ATP synthase was only partially assembled, as revealed by Blue Native PAGE analysis. LIT decreased the carbonylation level and increased the expression of fast isoforms of troponin T and of myosin binding protein C, and glycogen phosphorylase. In addition, it increased the expression of aconitate hydratase and NADH dehydrogenase, and fully restored the ATP synthase complex. Our study demonstrates that the benefits of LIT are associated with lowered oxidative damage as revealed by carbonylation and higher expression of proteins involved in energy metabolism and muscle contraction. Potentially, these results will help to design therapies for DMD based on exercise mimicking drugs.

  16. The Dietary Supplement Protandim® Decreases Plasma Osteopontin and Improves Markers of Oxidative Stress in Muscular Dystrophy Mdx Mice

    Science.gov (United States)

    Qureshi, Muhammad Muddasir; McClure, Warren C.; Arevalo, Nicole L.; Rabon, Rick E.; Mohr, Benjamin; Bose, Swapan K.; McCord, Joe M.; Tseng, Brian S.

    2010-01-01

    Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscular disorder in children, remain elusive. Oxidative damage is implicated as a pertinent factor involved in its pathogenesis. Protandim® is an over-the-counter supplement with the ability to induce antioxidant enzymes. In this study we investigated whether Protandim® provided benefit using surrogate markers and functional measures in the dystrophin-deficient (mdx)mouse model of DMD. Male 3-week-old mdx mice were randomized into two treatment groups: control (receiving standard rodent chow) and Protandim®-supplemented standard rodent chow. The diets were continued for 6-week and 6-month studies. The endpoints included the oxidative stress marker thiobarbituric acid-reactive substances (TBARS), plasma osteopontin (OPN), plasma paraoxonase (PON1) activity, H&E histology, gadolinium-enhanced magnetic resonance imaging (MRI) of leg muscle and motor functional measurements. The Protandim® chow diet in mdx mice for 6 months was safe and well tolerated. After 6 months of Protandim®, a 48% average decrease in plasma TBARS was seen; 0.92 nmol/mg protein in controls versus 0.48 nmol/mg protein in the Protandim® group (p = .006). At 6 months, plasma OPN was decreased by 57% (p = .001) in the Protandim®-treated mice. Protandim® increased the plasma antioxidant enzyme PON1 activity by 35% (p = .018). After 6 months, the mdx mice with Protandim® showed 38% less MRI signal abnormality (p = .07) than mice on control diet. In this 6-month mdx mouse study, Protandim® did not significantly alter motor function nor histological criteria. PMID:20740052

  17. The Dietary Supplement Protandim Decreases Plasma Osteopontin and Improves Markers of Oxidative Stress in Muscular Dystrophy Mdx Mice.

    Science.gov (United States)

    Qureshi, Muhammad Muddasir; McClure, Warren C; Arevalo, Nicole L; Rabon, Rick E; Mohr, Benjamin; Bose, Swapan K; McCord, Joe M; Tseng, Brian S

    2010-06-01

    Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscular disorder in children, remain elusive. Oxidative damage is implicated as a pertinent factor involved in its pathogenesis. Protandim((R)) is an over-the-counter supplement with the ability to induce antioxidant enzymes. In this study we investigated whether Protandim((R)) provided benefit using surrogate markers and functional measures in the dystrophin-deficient (mdx)mouse model of DMD. Male 3-week-old mdx mice were randomized into two treatment groups: control (receiving standard rodent chow) and Protandim((R))-supplemented standard rodent chow. The diets were continued for 6-week and 6-month studies. The endpoints included the oxidative stress marker thiobarbituric acid-reactive substances (TBARS), plasma osteopontin (OPN), plasma paraoxonase (PON1) activity, H&E histology, gadolinium-enhanced magnetic resonance imaging (MRI) of leg muscle and motor functional measurements. The Protandim((R)) chow diet in mdx mice for 6 months was safe and well tolerated. After 6 months of Protandim((R)), a 48% average decrease in plasma TBARS was seen; 0.92 nmol/mg protein in controls versus 0.48 nmol/mg protein in the Protandim((R)) group (p = .006). At 6 months, plasma OPN was decreased by 57% (p = .001) in the Protandim((R))-treated mice. Protandim((R)) increased the plasma antioxidant enzyme PON1 activity by 35% (p = .018). After 6 months, the mdx mice with Protandim((R)) showed 38% less MRI signal abnormality (p = .07) than mice on control diet. In this 6-month mdx mouse study, Protandim((R)) did not significantly alter motor function nor histological criteria.

  18. Evaluation of the therapeutic potential of carbonic anhydrase inhibitors in two animal models of dystrophin deficient muscular dystrophy.

    Science.gov (United States)

    Giacomotto, Jean; Pertl, Cordula; Borrel, Caroline; Walter, Maggie C; Bulst, Stefanie; Johnsen, Bob; Baillie, David L; Lochmüller, Hanns; Thirion, Christian; Ségalat, Laurent

    2009-11-01

    Duchenne Muscular Dystrophy is an inherited muscle degeneration disease for which there is still no efficient treatment. However, compounds active on the disease may already exist among approved drugs but are difficult to identify in the absence of cellular models. We used the Caenorhabditis elegans animal model to screen a collection of 1000 already approved compounds. Two of the most active hits obtained were methazolamide and dichlorphenamide, carbonic anhydrase inhibitors widely used in human therapy. In C. elegans, these drugs were shown to interact with CAH-4, a putative carbonic anhydrase. The therapeutic efficacy of these compounds was further validated in long-term experiments on mdx mice, the mouse model of Duchenne Muscular Dystrophy. Mice were treated for 120 days with food containing methazolamide or dichlorphenamide at two doses each. Musculus tibialis anterior and diaphragm muscles were histologically analyzed and isometric muscle force was measured in M. extensor digitorum longus. Both substances increased the tetanic muscle force in the treated M. extensor digitorum longus muscle group, dichlorphenamide increased the force significantly by 30%, but both drugs failed to increase resistance of muscle fibres to eccentric contractions. Histological analysis revealed a reduction of centrally nucleated fibers in M. tibialis anterior and diaphragm in the treated groups. These studies further demonstrated that a C. elegans-based screen coupled with a mouse model validation strategy can lead to the identification of potential pharmacological agents for rare diseases.

  19. Comparative proteomic profiling of soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscles from the mdx mouse model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Carberry, Steven; Brinkmeier, Heinrich; Zhang, Yaxin; Winkler, Claudia K; Ohlendieck, Kay

    2013-09-01

    Duchenne muscular dystrophy is due to genetic abnormalities in the dystrophin gene and represents one of the most frequent genetic childhood diseases. In the X-linked muscular dystrophy (mdx) mouse model of dystrophinopathy, different subtypes of skeletal muscles are affected to a varying degree albeit the same single base substitution within exon 23 of the dystrophin gene. Thus, to determine potential muscle subtype-specific differences in secondary alterations due to a deficiency in dystrophin, in this study, we carried out a comparative histological and proteomic survey of mdx muscles. We intentionally included the skeletal muscles that are often used for studying the pathomechanism of muscular dystrophy. Histological examinations revealed a significantly higher degree of central nucleation in the soleus and extensor digitorum longus muscles compared with the flexor digitorum brevis and interosseus muscles. Muscular hypertrophy of 20-25% was likewise only observed in the soleus and extensor digitorum longus muscles from mdx mice, but not in the flexor digitorum brevis and interosseus muscles. For proteomic analysis, muscle protein extracts were separated by fluorescence two-dimensional (2D) gel electrophoresis. Proteins with a significant change in their expression were identified by mass spectrometry. Proteomic profiling established an altered abundance of 24, 17, 19 and 5 protein species in the dystrophin-deficient soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscle, respectively. The key proteomic findings were verified by immunoblot analysis. The identified proteins are involved in the contraction-relaxation cycle, metabolite transport, muscle metabolism and the cellular stress response. Thus, histological and proteomic profiling of muscle subtypes from mdx mice indicated that distinct skeletal muscles are differentially affected by the loss of the membrane cytoskeletal protein, dystrophin. Varying degrees of perturbed protein

  20. Taurine deficiency, synthesis and transport in the mdx mouse model for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Terrill, Jessica R; Grounds, Miranda D; Arthur, Peter G

    2015-09-01

    The amino acid taurine is essential for the function of skeletal muscle and administration is proposed as a treatment for Duchenne Muscular Dystrophy (DMD). Taurine homeostasis is dependent on multiple processes including absorption of taurine from food, endogenous synthesis from cysteine and reabsorption in the kidney. This study investigates the cause of reported taurine deficiency in the dystrophic mdx mouse model of DMD. Levels of metabolites (taurine, cysteine, cysteine sulfinate and hypotaurine) and proteins (taurine transporter [TauT], cysteine deoxygenase and cysteine sulfinate dehydrogenase) were quantified in juvenile control C57 and dystrophic mdx mice aged 18 days, 4 and 6 weeks. In C57 mice, taurine content was much higher in both liver and plasma at 18 days, and both cysteine and cysteine deoxygenase were increased. As taurine levels decreased in maturing C57 mice, there was increased transport (reabsorption) of taurine in the kidney and muscle. In mdx mice, taurine and cysteine levels were much lower in liver and plasma at 18 days, and in muscle cysteine was low at 18 days, whereas taurine was lower at 4: these changes were associated with perturbations in taurine transport in liver, kidney and muscle and altered metabolism in liver and kidney. These data suggest that the maintenance of adequate body taurine relies on sufficient dietary intake of taurine and cysteine availability and metabolism, as well as retention of taurine by the kidney. This research indicates dystrophin deficiency not only perturbs taurine metabolism in the muscle but also affects taurine metabolism in the liver and kidney, and supports targeting cysteine and taurine deficiency as a potential therapy for DMD. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

  1. Quantification of the mechanical behavior of carotid arteries from wild-type, dystrophin-deficient, and sarcoglycan-δ knockout mice

    Science.gov (United States)

    Gleason, Rudolph L.; Dye, Wendy W.; Wilson, Emily; Humphrey, Jay D.

    2008-01-01

    As patients with muscular dystrophy live longer because of improved clinical care, they will become increasingly susceptible to many of the cardiovascular diseases that affect the general population. There is, therefore, a pressing need to better understand both the biology and the mechanics of the arterial wall in these patients. In this paper, we use nonlinear constitutive relations to model, for the first time, the biaxial mechanical behavior of carotid arteries from two common mouse models of muscular dystrophy (dystrophin deficient and sarcoglycan-delta null) and wild-type controls. It is shown that a structurally motivated four-fiber family stress-strain relation describes the passive behavior of all three genotypes better than does a commonly used phenomenological exponential model, and that a Rachev-Hayashi model describes the mechanical contribution of smooth muscle contraction under basal tone. Because structurally motivated constitutive relations can be extended easily to model adaptations to altered hemodynamics, results from this study represent an important step toward the ultimate goal of understanding better the mechanobiology and pathophysiology of arteries in muscular dystrophy. PMID:18842267

  2. Concurrent Label-Free Mass Spectrometric Analysis of Dystrophin Isoform Dp427 and the Myofibrosis Marker Collagen in Crude Extracts from mdx-4cv Skeletal Muscles

    Directory of Open Access Journals (Sweden)

    Sandra Murphy

    2015-09-01

    Full Text Available The full-length dystrophin protein isoform of 427 kDa (Dp427, the absence of which represents the principal abnormality in X-linked muscular dystrophy, is difficult to identify and characterize by routine proteomic screening approaches of crude tissue extracts. This is probably related to its large molecular size, its close association with the sarcolemmal membrane, and its existence within a heterogeneous glycoprotein complex. Here, we used a careful extraction procedure to isolate the total protein repertoire from normal versus dystrophic mdx-4cv skeletal muscles, in conjunction with label-free mass spectrometry, and successfully identified Dp427 by proteomic means. In contrast to a considerable number of previous comparative studies of the total skeletal muscle proteome, using whole tissue proteomics we show here for the first time that the reduced expression of this membrane cytoskeletal protein is the most significant alteration in dystrophinopathy. This agrees with the pathobiochemical concept that the almost complete absence of dystrophin is the main defect in Duchenne muscular dystrophy and that the mdx-4cv mouse model of dystrophinopathy exhibits only very few revertant fibers. Significant increases in collagens and associated fibrotic marker proteins, such as fibronectin, biglycan, asporin, decorin, prolargin, mimecan, and lumican were identified in dystrophin-deficient muscles. The up-regulation of collagen in mdx-4cv muscles was confirmed by immunofluorescence microscopy and immunoblotting. Thus, this is the first mass spectrometric study of crude tissue extracts that puts the proteomic identification of dystrophin in its proper pathophysiological context.

  3. The use of urinary and kidney SILAM proteomics to monitor kidney response to high dose morpholino oligonucleotides in the mdx mouse

    Directory of Open Access Journals (Sweden)

    Aiping Zhang

    2015-01-01

    Full Text Available Phosphorodiamidate morpholino oligonucleotides (PMO are used as a promising exon-skipping gene therapy for Duchenne muscular dystrophy (DMD. One potential complication of high dose PMO therapy is its transient accumulation in the kidneys. Therefore new urinary biomarkers are needed to monitor this treatment. Here, we carried out a pilot proteomic profiling study using stable isotope labeling in mammals (SILAM strategy to identify new biomarkers to monitor the effect of PMO on the kidneys of the dystrophin deficient mouse model for DMD (mdx-23. We first assessed the baseline renal status of the mdx-23 mouse compared to the wild type (C57BL10 mouse, and then followed the renal outcome of mdx-23 mouse treated with a single high dose intravenous PMO injection (800 mg/kg. Surprisingly, untreated mdx-23 mice showed evidence of renal injury at baseline, which was manifested by albuminuria, increased urine output, and changes in established urinary biomarker of acute kidney injury (AKI. The PMO treatment induced further transient renal injury, which peaked at 7 days, and returned to almost the baseline status at 30 days post-treatment. In the kidney, the SILAM approach followed by western blot validation identified changes in Meprin A subunit alpha at day 2, then returned to normal levels at days 7 and 30 after PMO injection. In the urine, SILAM approach identified an increase in Clusterin and γ-glutamyl transpeptidase 1 as potential candidates to monitor the transient renal accumulation of PMO. These results, which were confirmed by Western blots or ELISA, demonstrate the value of the SILAM approach to identify new candidate biomarkers of renal injury in mdx-23 mice treated with high dose PMO.

  4. 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

  5. Rescue of dystrophic skeletal muscle by PGC-1α involves a fast to slow fiber type shift in the mdx mouse.

    Directory of Open Access Journals (Sweden)

    Joshua T Selsby

    Full Text Available Increased utrophin expression is known to reduce pathology in dystrophin-deficient skeletal muscles. Transgenic over-expression of PGC-1α has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1α signaling can lead to increased oxidative capacity and a fast to slow fiber type shift. Given that it has been shown that slow fibers produce and maintain more utrophin than fast skeletal muscle fibers, we hypothesized that over-expression of PGC-1α in post-natal mdx mice would increase utrophin levels via a fiber type shift, resulting in more slow, oxidative fibers that are also more resistant to contraction-induced damage. To test this hypothesis, neonatal mdx mice were injected with recombinant adeno-associated virus (AAV driving expression of PGC-1α. PGC-1α over-expression resulted in increased utrophin and type I myosin heavy chain expression as well as elevated mitochondrial protein expression. Muscles were shown to be more resistant to contraction-induced damage and more fatigue resistant. Sirt-1 was increased while p38 activation and NRF-1 were reduced in PGC-1α over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1α pathway activator, resveratrol, could drive the same physiological changes. Resveratrol administration (100 mg/kg/day resulted in improved fatigue resistance, but did not achieve significant increases in utrophin expression. These data suggest that the PGC-1α pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle.

  6. Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

    Science.gov (United States)

    Church, Jarrod E; Trieu, Jennifer; Chee, Annabel; Naim, Timur; Gehrig, Stefan M; Lamon, Séverine; Angelini, Corrado; Russell, Aaron P; Lynch, Gordon S

    2014-04-01

    New Findings What is the central question of this study? The Notch signalling pathway plays an important role in muscle regeneration, and activation of the pathway has been shown to enhance muscle regeneration in aged mice. It is unknown whether Notch activation will have a similarly beneficial effect on muscle regeneration in the context of Duchenne muscular dystrophy (DMD). What is the main finding and its importance? Although expression of Notch signalling components is altered in both mouse models of DMD and in human DMD patients, activation of the Notch signalling pathway does not confer any functional benefit on muscles from dystrophic mice, suggesting that other signalling pathways may be more fruitful targets for manipulation in treating DMD. Abstract In Duchenne muscular dystrophy (DMD), muscle damage and impaired regeneration lead to progressive muscle wasting, weakness and premature death. The Notch signalling pathway represents a central regulator of gene expression and is critical for cellular proliferation, differentiation and apoptotic signalling during all stages of embryonic muscle development. Notch activation improves muscle regeneration in aged mice, but its potential to restore regeneration and function in muscular dystrophy is unknown. We performed a comprehensive examination of several genes involved in Notch signalling in muscles from dystrophin-deficient mdx and dko (utrophin- and dystrophin-null) mice and DMD patients. A reduction of Notch1 and Hes1 mRNA in tibialis anterior muscles of dko mice and quadriceps muscles of DMD patients and a reduction of Hes1 mRNA in the diaphragm of the mdx mice were observed, with other targets being inconsistent across species. Activation and inhibition of Notch signalling, followed by measures of muscle regeneration and function, were performed in the mouse models of DMD. Notch activation had no effect on functional regeneration in C57BL/10, mdx or dko mice. Notch inhibition significantly depressed the

  7. In vivo MRI characterization of progressive cardiac dysfunction in the mdx mouse model of muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Daniel J Stuckey

    Full Text Available AIMS: The mdx mouse has proven to be useful in understanding the cardiomyopathy that frequently occurs in muscular dystrophy patients. Here we employed a comprehensive array of clinically relevant in vivo MRI techniques to identify early markers of cardiac dysfunction and follow disease progression in the hearts of mdx mice. METHODS AND RESULTS: Serial measurements of cardiac morphology and function were made in the same group of mdx mice and controls (housed in a non-SPF facility using MRI at 1, 3, 6, 9 and 12 months after birth. Left ventricular (LV and right ventricular (RV systolic and diastolic function, response to dobutamine stress and myocardial fibrosis were assessed. RV dysfunction preceded LV dysfunction, with RV end systolic volumes increased and RV ejection fractions reduced at 3 months of age. LV ejection fractions were reduced at 12 months, compared with controls. An abnormal response to dobutamine stress was identified in the RV of mdx mice as early as 1 month. Late-gadolinium-enhanced MRI identified increased levels of myocardial fibrosis in 6, 9 and 12-month-old mdx mice, the extent of fibrosis correlating with the degree of cardiac remodeling and hypertrophy. CONCLUSIONS: MRI could identify cardiac abnormalities in the RV of mdx mice as young as 1 month, and detected myocardial fibrosis at 6 months. We believe these to be the earliest MRI measurements of cardiac function reported for any mice, and the first use of late-gadolinium-enhancement in a mouse model of congenital cardiomyopathy. These techniques offer a sensitive and clinically relevant in vivo method for assessment of cardiomyopathy caused by muscular dystrophy and other diseases.

  8. Plantarflexion Contracture in the mdx Mouse

    Science.gov (United States)

    Garlich, Michael W.; Baltgalvis, Kristen A.; Call, Jarrod A.; Dorsey, Lisa L.; Lowe, Dawn A.

    2012-01-01

    Objective Contractures are a major clinical issue for patients with muscular dystrophies. However, it is unknown whether contractures are present in the widely used mdx mouse model of Duchenne muscular dystrophy. Therefore, the objectives of this study were to develop methods to measure muscle contractures in mice, to determine whether plantarflexion contractures are present in mdx mice, and to analyze the composition of the major muscles involved. Design Hindlimbs of eight wild type and six mdx mice were assessed every 2 wks during the course of a 12-wk study. Assessments included range of motion and in vivo torques about the ankle. At the end of the study, mice were euthanized, and muscles were analyzed for composition. Results The mdx mice had ~10 degrees less dorsiflexion, increased passive torque moving the ankle into dorsiflexion, and an increased passive-to-active torque ratio relative to wild type mice. Gastrocnemius muscle composition alterations included increased wet mass, decreased protein content, and increased collagen. Conclusions The results indicate that mdx mice have plantarflexion contractures similar to those seen in children with Duchenne muscular dystrophy. In future studies, these measures can be used to assess strategies to slow the progression of contractures that occur with muscular dystrophies. PMID:21403594

  9. 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.

  10. 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

  11. Severe mechanical dysfunction in pharyngeal muscle from adult mdx mice.

    Science.gov (United States)

    Attal, P; Lambert, F; Marchand-Adam, S; Bobin, S; Pourny, J C; Chemla, D; Lecarpentier, Y; Coirault, C

    2000-07-01

    The mdx mouse is a widely used animal model of human muscular dystrophy. Although diaphragm muscle exhibits severe muscle weakness throughout the life of the animal, the limb muscle function of mdx mice spontaneously recovers by 6 mo of age. Pharyngeal dilator muscles such as sternohyoid (SH) contribute to upper airway patency during breathing. We hypothesized that SH muscle function was impaired in 6-mo-old mdx mice. Mechanical properties and myosin heavy chain (MHC) composition were investigated in isolated SH from 6-mo-old control (C, n = 10) and mdx (n = 10) mice. As compared with C, peak tetanic tension (Pmax) and maximum shortening velocity were 50% and 16% lower in mdx mice (p mechanical power was lower in mdx than in C (19.0 +/- 3.2 versus 57.4 +/- 5.1 mW g(-)(1), p muscular dystrophy.

  12. Muscle development in mdx mutant mice.

    Science.gov (United States)

    Dangain, J; Vrbova, G

    1984-01-01

    Mechanical and contractile properties of tibialis anterior (TA) muscles from X-linked muscular dystrophic (mdx) mutant mice at different stages of development are compared to those of muscles from normal control animals. There is no difference between the tension output, speeds of contraction and relaxation, and weight of TA muscles from mutant adults and normal control animals. However, it is found that in 3-4-week-old mutant animals, tension output and muscle weight are very much reduced, and half relaxation time is prolonged. Thus, during this stage of development, muscles from mdx mice do not function properly. Histological examination of these muscles provides further evidence that, in these animals, rapid muscle destruction occurs at a particular time of development and that it is followed by complete recovery. This new mutant therefore presents an interesting case of muscle destruction and rapid regeneration. However, it is not an adequate model for Duchenne muscular dystrophy.

  13. 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.

  14. Activity of Krebs cycle enzymes in mdx mice.

    Science.gov (United States)

    Comim, Clarissa M; Hoepers, Andreza; Ventura, Letícia; Freiberger, Viviane; Dominguini, Diogo; Mina, Francielle; Mendonça, Bruna P; Scaini, Giselli; Vainzof, Mariz; Streck, Emílio L; Quevedo, João

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a degenerative disease of skeletal, respiratory, and cardiac muscles caused by defects in the dystrophin gene. More recently, brain involvement has been verified. Mitochondrial dysfunction and oxidative stress may underlie the pathophysiology of DMD. In this study we evaluate Krebs cycle enzymes activity in the cerebral cortex, diaphragm, and quadriceps muscles of mdx mice. Cortex, diaphragm, and quadriceps tissues from male dystrophic mdx and control mice were used. We observed increased malate dehydrogenase activity in the cortex; increased malate dehydrogenase and succinate dehydrogenase activities in the diaphragm; and increased citrate synthase, isocitrate dehydrogenase, and malate dehydrogenase activities in the quadriceps of mdx mice. This study showed increased activity of Krebs cycle enzymes in cortex, quadriceps, and diaphragm in mdx mice. © 2015 Wiley Periodicals, Inc.

  15. Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Hori, Yusuke S; Kuno, Atsushi; Hosoda, Ryusuke; Tanno, Masaya; Miura, Tetsuji; Shimamoto, Kazuaki; Horio, Yoshiyuki

    2011-09-01

    Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. We previously showed that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant and activator of the NAD(+)-dependent protein deacetylase SIRT1, delays the progression of heart failure and prolongs the lifespan of δ-sarcoglycan-deficient hamsters. Because a defect of dystroglycan complex causes muscular dystrophies, and δ-sarcoglycan is a component of this complex, we hypothesized that resveratrol might be a new therapeutic tool for muscular dystrophies. Here, we examined resveratrol's effect in mdx mice, an animal model of Duchenne muscular dystrophy. mdx mice that received resveratrol in the diet for 32 weeks (4 g/kg diet) showed significantly less muscle mass loss and nonmuscle interstitial tissue in the biceps femoris compared with mdx mice fed a control diet. In the muscles of these mice, resveratrol significantly decreased oxidative damage shown by the immunostaining of nitrotyrosine and 8-hydroxy-2'-deoxyguanosine and suppressed the up-regulation of NADPH oxidase subunits Nox4, Duox1, and p47(phox). Resveratrol also reduced the number of α-smooth muscle actin (α-SMA)(+) myofibroblast cells and endomysial fibrosis in the biceps femoris, although the infiltration of CD45(+) inflammatory cells and increase in transforming growth factor-β1 (TGF-β1) were still observed. In C2C12 myoblast cells, resveratrol pretreatment suppressed the TGF-β1-induced increase in reactive oxygen species, fibronectin production, and expression of α-SMA, and SIRT1 knockdown blocked these inhibitory effects. SIRT1 small interfering RNA also increased the expression of Nox4, p47(phox), and α-SMA in C2C12 cells. Taken together, these findings indicate that SIRT1 activation may be a useful strategy for treating muscular dystrophies.

  16. 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

    2015-03-11

    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.

  17. Lack of dystrophin leads to the selective loss of superior cervical ganglion neurons projecting to muscular targets in genetically dystrophic mdx mice.

    Science.gov (United States)

    De Stefano, M Egle; Leone, Lucia; Lombardi, Loredana; Paggi, Paola

    2005-12-01

    Autonomic imbalance is a pathological aspect of Duchenne muscular dystrophy. Here, we show that the sympathetic superior cervical ganglion (SCG) of mdx mice, which lack dystrophin (Dp427), has 36% fewer neurons than that of wild-type animals. Cell loss occurs around P10 and affects those neurons innervating muscular targets (heart and iris), which, differently from the submandibular gland (non-muscular target), are precociously damaged by the lack of Dp427. In addition, although we reveal altered axonal defasciculation in the submandibular gland and reduced terminal sprouting in all SCG target organs, poor adrenergic innervation is observed only in the heart and iris. These alterations, detected as early as P5, when neuronal loss has not yet occurred, suggest that in mdx mice the absence of Dp427 directly impairs the axonal growth and terminal sprouting of sympathetic neurons. However, when these intrinsic alterations combine with structural and/or functional damages of muscular targets, neuronal death occurs.

  18. 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.

  19. Gender differences in contractile and passive properties of mdx extensor digitorum longus muscle.

    Science.gov (United States)

    Hakim, Chady H; Duan, Dongsheng

    2012-02-01

    Duchenne muscular dystrophy (DMD) is a severe, muscle-wasting disease caused by mutations in the dystrophin gene. The mdx mouse is the first and perhaps the most commonly used animal model for study of DMD. Both male and female mdx mice are used. However, it is not completely clear whether gender influences contraction and the passive mechanical properties of mdx skeletal muscle. We compared isometric tetanic forces and passive forces of the extensor digitorum longus muscle between male and female mdx mice. At age 6 months, female mdx mice showed better-preserved specific tetanic force. Interestingly, at 20 months of age, female mdx muscle appeared stiffer. Our results suggest that gender may profoundly influence physiological measurement outcomes in mdx mice. Copyright © 2011 Wiley Periodicals, Inc.

  20. 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)

  1. Dystrophin deficiency-induced changes in porcine skeletal muscle

    Science.gov (United States)

    A novel porcine stress syndrome was detected in the U.S. Meat Animal Research Center’s swine research population when two sibling barrows died of apparent stress symptoms (open mouth breathing, vocalization, and refusal to move or stand) after transport at 12 weeks of age. At eight weeks of age, the...

  2. Gait analysis using accelerometry in dystrophin-deficient dogs.

    Science.gov (United States)

    Barthélémy, Inès; Barrey, Eric; Thibaud, Jean-Laurent; Uriarte, Ane; Voit, Thomas; Blot, Stéphane; Hogrel, Jean-Yves

    2009-11-01

    Dogs affected with Golden Retriever Muscular Dystrophy (GRMD) exhibit striking clinical similarities with patients suffering from Duchenne muscular dystrophy (DMD), particularly gait impairments. The purpose of this study was to describe the use and reliability of accelerometry in gait assessment of dogs with muscular dystrophy. Eight healthy and 11 GRMD adult dogs underwent three gait assessment sessions, using accelerometry. Three-axial recordings of accelerations were performed, and gait variables calculated. Total power, force and regularity of accelerations, stride length and speed, normalized by height at withers, stride frequency, and cranio-caudal power were significantly decreased, whereas medio-lateral power was significantly increased in GRMD dogs. Moreover, these variables were repeatable within and between sessions. Accelerometry provides reliable variables which highlight specific gait patterns of GRMD dogs, describing objectively and quantitatively their slow, short-stepped, and swaying gait. As it is easy to set-up, quick to perform and inexpensive, accelerometry represents a useful tool, to assess locomotion during pre-clinical trials.

  3. Myogenic reprogramming of bone marrow derived cells in a W⁴¹Dmd(mdx deficient mouse model.

    Directory of Open Access Journals (Sweden)

    Stuart Walsh

    Full Text Available Lack of expression of dystrophin leads to degeneration of muscle fibers and infiltration of connective and adipose tissue. Cell transplantation therapy has been proposed as a treatment for intractable muscle degenerative disorders. Several reports have demonstrated the ability of bone-marrow derived cells (BMDC to contribute to non-haematopoietic tissues including epithelium, heart, liver, skeletal muscle and brain following transplantation by means of fusion and reprogramming. A key issue is the extent to which fusion and reprogramming can occur in vivo, particularly under conditions of myogenic deterioration.To investigate the therapeutic potential of bone marrow transplantation in monogenetic myopathy, green fluorescent protein-positive (GFP+ bone marrow cells were transplanted into non-irradiated c-kit receptor-deficient (W⁴¹ mdx mice. This model allows BMDC reconstitution in the absence of irradiation induced myeloablation. We provide the first report of BMDC fusion in a W⁴¹Dmd(mdx deficient mouse model.In the absence of irradiation induced injury, few GFP+ cardiomyocytes and muscle fibres were detected 24 weeks post BMT. It was expected that the frequency of fusion in the hearts of W⁴¹Dmd(mdx mice would be similar to frequencies observed in infarcted mice. Although, it is clear from this study that individual cardiomyocytes with monogenetic deficiencies can be rescued by fusion, it is as clear that in the absence of irradiation, the formation of stable and reprogrammed fusion hybrids occurs, with the current techniques, at very low levels in non-irradiated recipients.

  4. EXPRESSION OF INTERCELLULAR ADHESION MOLECULE-1 BY MYOFIBERS IN mdx MICE

    Science.gov (United States)

    TORRES-PALSA, MARIA J.; KOZIOL, MATTHEW V.; GOH, QINGNIAN; CICINELLI, PETER A.; PETERSON, JENNIFER M.; PIZZA, FRANCIS X.

    2017-01-01

    Introduction We investigated the extent to which intercellular adhesion molecule-1 (ICAM-1), a critical protein of the inflammatory response, is expressed in skeletal muscles of mdx mice (a murine model of Duchenne muscular dystrophy). Methods Muscles were collected from control and mdx mice at 2–24 weeks of age and analyzed for ICAM-1 expression by means of Western blot and immunofluorescence. Results Western blot revealed higher expression of ICAM-1 in mdx compared with control muscles through 24 weeks of age. In contrast to control muscles, ICAM-1 was expressed on the membrane of damaged, regenerating, and normal myofibers of mdx mice. CD11b+ myeloid cells also expressed ICAM-1 in mdx muscles, and CD11b+ cells were closely associated with the membrane of myofibers expressing ICAM-1. Conclusions These findings support a paradigm in which ICAM-1 and its localization to myofibers in muscles of mdx mice contributes to the dystrophic pathology. PMID:25728314

  5. 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)

  6. Peptide conjugation of 2'-O-methyl phosphorothioate antisense oligonucleotides enhances cardiac uptake and exon skipping in mdx mice.

    Science.gov (United States)

    Jirka, Silvana M G; Heemskerk, Hans; Tanganyika-de Winter, Christa L; Muilwijk, Daan; Pang, Kar Him; de Visser, Peter C; Janson, Anneke; Karnaoukh, Tatyana G; Vermue, Rick; 't Hoen, Peter A C; van Deutekom, Judith C T; Aguilera, Begoña; Aartsma-Rus, Annemieke

    2014-02-01

    Antisense oligonucleotide (AON)-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy that is currently being tested in various clinical trials. This approach is based on restoring the open reading frame of dystrophin transcripts resulting in shorter but partially functional dystrophin proteins as found in patients with Becker muscular dystrophy. After systemic administration, a large proportion of AONs ends up in the liver and kidneys. Therefore, enhancing AON uptake by skeletal and cardiac muscle would improve the AONs' therapeutic effect. For phosphorodiamidate morpholino oligomer, AONs use nonspecific positively charged cell penetrating peptides to enhance efficacy. However, this is challenging for negatively charged 2'-O-methyl phosphorothioate oligomer. Therefore, we screened a 7-mer phage display peptide library to identify muscle and heart homing peptides in vivo in the mdx mouse model and found a promising candidate peptide capable of binding muscle cells in vitro and in vivo. Upon systemic administration in dystrophic mdx mice, conjugation of a 2'-O-methyl phosphorothioate AON to this peptide indeed improved uptake in skeletal and cardiac muscle, and resulted in higher exon skipping levels with a significant difference in heart and diaphragm. Based on these results, peptide conjugation represents an interesting strategy to enhance the therapeutic effect of exon skipping with 2'-O-methyl phosphorothioate AONs for Duchenne muscular dystrophy.

  7. 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

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

    OpenAIRE

    D Feder; Rugollini, M.; Santomauro Jr,A.; de Oliveira, L. P.; Lioi,V.P.; R. dos Santos; Ferreira, L.G.; Nunes,M.T.; M.H. Carvalho; P.O. Delgado; A.A.S. Carvalho; Fonseca, F.L.A.

    2014-01-01

    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 ...

  9. Tachykinergic neurotransmission is enhanced in duodenum from dystrophic (mdx) mice

    OpenAIRE

    Zizzo, Maria Grazia; Mulè, Flavia; Serio, Rosa

    2005-01-01

    Duodenal longitudinal muscle of mdx mice, an animal model for Duchenne muscular dystrophy, showed a decrease in the electrically evoked nonadrenergic, noncholinergic (NANC) inhibitory responses associated with a reduction of the participation of nitric oxide (NO). In this study, we investigated whether the impairment of NO could also lead to alterations in the NANC excitatory transmission.Nerve-evoked responses consisted of an inhibitory phase followed, at the end of stimulation, by an excita...

  10. Fibrosis and inflammation are greater in muscles of beta-sarcoglycan-null mouse than mdx mouse.

    Science.gov (United States)

    Gibertini, Sara; Zanotti, Simona; Savadori, Paolo; Curcio, Maurizio; Saredi, Simona; Salerno, Franco; Andreetta, Francesca; Bernasconi, Pia; Mantegazza, Renato; Mora, Marina

    2014-05-01

    The Sgcb-null mouse, with knocked-down β-sarcoglycan, develops severe muscular dystrophy as in type 2E human limb girdle muscular dystrophy. The mdx mouse, lacking dystrophin, is the most used model for Duchenne muscular dystrophy (DMD). Unlike DMD, the mdx mouse has mild clinical features and shows little fibrosis in limb muscles. To characterize ECM protein deposition and the progression of muscle fibrosis, we evaluated protein and transcript levels of collagens I, III and VI, decorin, and TGF-β1, in quadriceps and diaphragm, at 2, 4, 8, 12, 26, and 52 weeks in Sgcb-null mice, and protein levels at 12, 26, and 52 weeks in mdx mice. In Sgcb-null mice, severe morphological disruption was present from 4 weeks in both quadriceps and diaphragm, and included conspicuous deposition of extracellular matrix components. Histopathological features of Sgcb-null mouse muscles were similar to those of age-matched mdx muscles at all ages examined, but, in the Sgcb-null mouse, the extent of connective tissue deposition was generally greater than mdx. Furthermore, in the Sgcb-null mouse, the amount of all three collagen isoforms increased steadily, while, in the mdx, they remained stable. We also found that, at 12 weeks, macrophages were significantly more numerous in mildly inflamed areas of Sgcb-null quadriceps compared to mdx quadriceps (but not in highly inflamed regions), while, in the diaphragm, macrophages did not differ significantly between the two models, in either region. Osteopontin mRNA was also significantly greater at 12 weeks in laser-dissected highly inflamed areas of the Sgcb-null quadriceps compared to the mdx quadriceps. TGF-β1 was present in areas of degeneration-regeneration, but levels were highly variable and in general did not differ significantly between the two models and controls. The roles of the various subtypes of macrophages in muscle repair and fibrosis in the two models require further study. The Sgcb-null mouse, which develops early fibrosis

  11. Muscle Structure Influences Utrophin Expression in mdx Mice

    Science.gov (United States)

    Banks, Glen B.; Combs, Ariana C.; Odom, Guy L.; Bloch, Robert J.; Chamberlain, Jeffrey S.

    2014-01-01

    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. PMID:24922526

  12. 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

  13. Effect of omega-3 in dystrophic muscle of mdx mice

    OpenAIRE

    Adriana Fogagnolo Maurício

    2012-01-01

    Resumo: Na Distrofia Muscular de Duchenne (DMD) e no camundongo mdx, modelo experimental da DMD, a ausência de distrofina promove instabilidade do sarcolema e degeneração muscular progressiva. O processo inflamatório que se instala contribui de forma significativa para a fisiopatologia da doença, sendo que antiinflamatórios esteroides são amplamente utilizados para a terapia da DMD. Entretanto, em decorrência da sua ação pouco efetiva e dos efeitos colaterais outras drogas são investigadas co...

  14. Mechanical and morphological aspects of the calcaneal tendon of mdx mice at 21 days of age.

    Science.gov (United States)

    Nakagaki, Wilson Romero; Tomiosso, Tatiana Carla; Pimentel, Edson Rosa; Camilli, José Angelo

    2013-10-01

    A relationship between compromised muscles and other tissues has been demonstrated in mdx mouse, an animal model studied for understanding of Duchenne muscular dystrophy. The hypothesis is that changes in the calcaneal tendon of mdx mice occur previous to the onset of rigorous and most marked episodes of muscle degeneration, which start suddenly after 21 days of life. Thus, this study aimed to identify possible alterations in the calcaneal tendon of mdx mouse at 21 days of age. Control and mdx tendons were submitted to mechanical tensile testing, quantification of hydroxyproline, and staining with toluidine blue and picrosirius red. Hydroxyproline content was similar between mdx and control groups. The control tendon presented higher mechanical strength (load, stress, and elastic modulus) and its morphological analysis showed a larger number of round fibroblasts, nuclei with well-decondensed chromatin, and slightly metachromatic well-stained cytoplasmic material, different from that observed in mdx tendons. The results suggest that the absence of dystrophin in mdx mouse can provoke directly or indirectly alterations in the mechanical properties and morphology of the calcaneal tendon. Copyright © 2013 Wiley Periodicals, Inc.

  15. 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.

  16. 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.

  17. Skeletal muscle fibrosis in the mdx/utrn+/- mouse validates its suitability as a murine model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Gutpell, Kelly M; Hrinivich, William T; Hoffman, Lisa M

    2015-01-01

    Various therapeutic approaches have been studied for the treatment of Duchenne muscular dystrophy (DMD), but none of these approaches have led to significant long-term effects in patients. One reason for this observed inefficacy may be the use of inappropriate animal models for the testing of therapeutic agents. The mdx mouse is the most widely used murine model of DMD, yet it does not model the fibrotic progression observed in patients. Other murine models of DMD are available that lack one or both alleles of utrophin, a functional analog of dystrophin. The aim of this study was to compare fibrosis and myofiber damage in the mdx, mdx/utrn+/- and double knockout (dko) mouse models. We used Masson's trichrome stain and percentage of centrally-nucleated myofibers as indicators of fibrosis and myofiber regeneration, respectively, to assess disease progression in diaphragm and gastrocnemius muscles harvested from young and aged wild-type, mdx, mdx/utrn+/- and dko mice. Our results indicated that eight week-old gastrocnemius muscles of both mdx/utrn+/- and dko hind limb developed fibrosis whereas age-matched mdx gastrocnemius muscle did not (p = 0.002). The amount of collagen found in the mdx/utrn+/- diaphragm was significantly higher than that found in the corresponding diaphragm muscles of wild-type animals, but not of mdx animals (p = 0.0003). Aged mdx/utrn+/- mice developed fibrosis in both diaphragm and gastrocnemius muscles compared to wild-type controls (p = 0.003). Mdx diaphragm was fibrotic in aged mice as well (p = 0.0235), whereas the gastrocnemius muscle in these animals was not fibrotic. We did not measure a significant difference in collagen staining between wild-type and mdx gastrocnemius muscles. The results of this study support previous reports that the moderately-affected mdx/utrn+/- mouse is a better model of DMD, and we show here that this difference is apparent by 2 months of age.

  18. Overexpression of dystrophin in transgenic mdx mice eliminates dystrophic symptoms without toxicity.

    Science.gov (United States)

    Cox, G A; Cole, N M; Matsumura, K; Phelps, S F; Hauschka, S D; Campbell, K P; Faulkner, J A; Chamberlain, J S

    1993-08-19

    Duchenne and Becker muscular dystrophy (DMD and BMD) are X-linked recessive diseases caused by defective expression of dystrophin. The mdx mouse, an animal model for DMD, has a mutation that eliminates expression of the 427K muscle and brain isoforms of dystrophin. Although these animals do not display overt muscle weakness or impaired movement, the diaphragm muscle of the mdx mouse is severely affected and shows progressive myofibre degeneration and fibrosis which closely resembles the human disease. Here we explore the feasibility of gene therapy for DMD by examining the potential of a full-length dystrophin transgene to correct dystrophic symptoms in mdx mice. We find that expression of dystrophin in muscles of transgenic mdx mice eliminates the morphological and immunohistological symptoms of muscular dystrophy. In addition, overexpression of dystrophin prevents the development of the abnormal mechanical properties associated with dystrophic muscle without causing deleterious side effects. Our results provide functional evidence for the feasibility of gene therapy for DMD.

  19. Skeletal muscle NADPH oxidase is increased and triggers stretch-induced damage in the mdx mouse.

    Science.gov (United States)

    Whitehead, Nicholas P; Yeung, Ella W; Froehner, Stanley C; Allen, David G

    2010-12-20

    Recent studies have shown that oxidative stress contributes to the pathogenesis of muscle damage in dystrophic (mdx) mice. In this study we have investigated the role of NADPH oxidase as a source of the oxidative stress in these mice. The NADPH oxidase subunits gp91(phox), p67(phox) and rac 1 were increased 2-3 fold in tibilais anterior muscles from mdx mice compared to wild type. Importantly, this increase occurred in 19 day old mice, before the onset of muscle necrosis and inflammation, suggesting that NADPH oxidase is an important source of oxidative stress in mdx muscle. In muscles from 9 week old mdx mice, gp91(phox) and p67(phox) were increased 3-4 fold and NADPH oxidase superoxide production was 2 times greater than wild type. In single fibers from mdx muscle NADPH oxidase subunits were all located on or near the sarcolemma, except for p67(phox),which was expressed in the cytosol. Pharmacological inhibition of NADPH oxidase significantly reduced the intracellular Ca(2+) rise following stretched contractions in mdx single fibers, and also attenuated the loss of muscle force. These results suggest that NADPH oxidase is a major source of reactive oxygen species in dystrophic muscle and its enhanced activity has a stimulatory effect on stretch-induced Ca(2+) entry, a key mechanism for muscle damage and functional impairment.

  20. Caveolin-1, caveolin-3 and VEGF expression in the masticatory muscles of mdx mice

    Directory of Open Access Journals (Sweden)

    Alexander Spassov

    2011-07-01

    Full Text Available Duchenne muscular dystrophy (DMD and murine X-linked muscular dystrophy (mdx, its murine model, are characterized by muscle damage and muscle weakness associated with inflammation and new vessel formation. Caveolins, dystrophin-associated proteins, are involved in the pathogenesis of DMD, because increased numbers of caveolae are found in DMD and mdx hindlimb muscles. Caveolae influence angiogenesis due to their content of vascular endothelial growth factor (VEGF receptors. Orofacial muscles in mdx mice undergo muscle necrosis followed by muscle regeneration. To ascertain the role of caveolins and VEGF in the pathogenesis of dystrophic masticatory muscles, we examined the expression of caveolin-1 (cav-1, caveolin-3 (cav-3 and VEGF in control and mdx mice. In mdx masticatory muscles, no changes in transcript and protein levels of VEGF were found, whereas cav-1 and cav-3 expression was increased. Using immunohistochemistry, a strong sarcolemmal staining of caveolin-3 in regenerated muscle fibers was found. Furthermore, immunohistochemistry with the caveolin-1 antibody showed an increase in the amount of blood vessels in areas with regenerating muscle fibers. Dystrophic masticatory muscles showed changes comparable to those of hindlimb muscles in the expression of cav-1 and cav-3. The angiogenesis seems to be unaffected in the jaw muscles of mdx mice. We speculate that the increased caveolin expression could cause extensive and efficient muscle regeneration. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 2, pp. 291–298

  1. Endogenous mesenchymal stromal cells in bone marrow are required to preserve muscle function in mdx mice.

    Science.gov (United States)

    Fujita, Ryo; Tamai, Katsuto; Aikawa, Eriko; Nimura, Keisuke; Ishino, Saki; Kikuchi, Yasushi; Kaneda, Yasufumi

    2015-03-01

    The physiological role of "endogenous" bone marrow (BM) mesenchymal stromal cells (MSCs) in tissue regeneration is poorly understood. Here, we show the significant contribution of unique endogenous BM-MSC populations to muscle regeneration in Duchenne muscular dystrophy (DMD) mice (mdx). Transplantation of BM cells (BMCs) from 10-week-old mdx into 3-4-week-old mdx mice increased inflammation and fibrosis and reduced muscle function compared with mdx mice that received BMCs from 10-week-old wild-type mice, suggesting that the alteration of BMC populations in mdx mice affects the progression of muscle pathology. Two distinct MSC populations in BM, that is, hematopoietic lineage (Lin)(-) /ckit(-) /CD106(+) /CD44(+) and Lin(-) /ckit(-) /CD106(+) /CD44(-) cells, were significantly reduced in 10-week-old mdx mice in disease progression. The results of a whole-transcriptome analysis indicated that these two MSC populations have distinct gene expression profiles, indicating that the Lin(-) /ckit(-) /CD106(+) /CD44(+) and Lin(-) /ckit(-) /CD106(+) /CD44(-) MSC populations are proliferative- and dormant-state populations in BM, respectively. BM-derived Lin(-) /CD106(+) /CD44(+) MSCs abundantly migrated to damaged muscles and highly expressed tumor necrosis factor-alpha-stimulated gene/protein-6 (TSG-6), an anti-inflammatory protein, in damaged muscles. We also demonstrated that TSG-6 stimulated myoblast proliferation. The injection of Lin(-) /ckit(-) /CD106(+) /CD44(+) MSCs into the muscle of mdx mice successfully ameliorated muscle dysfunction by decreasing inflammation and enhancing muscle regeneration through TSG-6-mediated activities. Thus, we propose a novel function of the unique endogenous BM-MSC population, which countered muscle pathology progression in a DMD model.

  2. Muscular dystrophy in the mdx mouse is a severe myopathy compounded by hypotrophy, hypertrophy and hyperplasia.

    Science.gov (United States)

    Duddy, William; Duguez, Stephanie; Johnston, Helen; Cohen, Tatiana V; Phadke, Aditi; Gordish-Dressman, Heather; Nagaraju, Kanneboyina; Gnocchi, Viola; Low, SiewHui; Partridge, Terence

    2015-01-01

    Preclinical testing of potential therapies for Duchenne muscular dystrophy (DMD) is conducted predominantly of the mdx mouse. But lack of a detailed quantitative description of the pathology of this animal limits our ability to evaluate the effectiveness of putative therapies or their relevance to DMD. Accordingly, we have measured the main cellular components of muscle growth and regeneration over the period of postnatal growth and early pathology in mdx and wild-type (WT) mice; phalloidin binding is used as a measure of fibre size, myonuclear counts and BrdU labelling as records of myogenic activity. We confirm a two-phase postnatal growth pattern in WT muscle: first, increase in myonuclear number over weeks 1 to 3, then expansion of myonuclear domain. Mdx muscle growth lags behind that of WT prior to overt signs of pathology. Fibres are smaller, with fewer myonuclei and smaller myonuclear domains. Moreover, satellite cells are more readily detached from mdx than WT muscle fibres. At 3 weeks, mdx muscles enter a phase of florid myonecrosis, accompanied by concurrent regeneration of an intensity that results in complete replacement of pre-existing muscle over the succeeding 3 to 4 weeks. Both WT and mdx muscles attain maximum size by 12 to 14 weeks, mdx muscle fibres being up to 50% larger than those of WT as they become increasingly branched. Mdx muscle fibres also become hypernucleated, containing twice as many myonuclei per sarcoplasmic volume, as those of WT, the excess corresponding to the number of centrally placed myonuclei. The best-known consequence of lack of dystrophin that is common to DMD and the mdx mouse is the conspicuous necrosis and regeneration of muscle fibres. We present protocols for measuring this in terms both of loss of muscle nuclei previously labelled with BrdU and of the intensity of myonuclear labelling with BrdU administered during the regeneration period. Both measurements can be used to assess the efficacy of putative

  3. Sparing of the extraocular muscles in mdx mice with absent or reduced utrophin expression: A life span analysis.

    Science.gov (United States)

    McDonald, Abby A; Hebert, Sadie L; McLoon, Linda K

    2015-11-01

    Sparing of the extraocular muscles in muscular dystrophy is controversial. To address the potential role of utrophin in this sparing, mdx:utrophin(+/-) and mdx:utrophin(-/-) mice were examined for changes in myofiber size, central nucleation, and Pax7-positive and MyoD-positive cell density at intervals over their life span. Known to be spared in the mdx mouse, and contrary to previous reports, the extraocular muscles from both the mdx:utrophin(+/-) and mdx:utrophin(-/-) mice were also morphologically spared. In the mdx:utrophin(+/)(-) mice, which have a normal life span compared to the mdx:utrophin(-/-) mice, the myofibers were larger at 3 and 12 months than the wild type age-matched eye muscles. While there was a significant increase in central nucleation in the extraocular muscles from all mdx:utrophin(+/)(-) mice, the levels were still very low compared to age-matched limb skeletal muscles. Pax7- and MyoD-positive myogenic precursor cell populations were retained and were similar to age-matched wild type controls. These results support the hypothesis that utrophin is not involved in extraocular muscle sparing in these genotypes. In addition, it appears that these muscles retain the myogenic precursors that would allow them to maintain their regenerative capacity and normal morphology over a lifetime even in these more severe models of muscular dystrophy.

  4. 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.

  5. Intrinsic laryngeal muscles are spared from myonecrosis in the mdx mouse model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Marques, Maria Julia; Ferretti, Renato; Vomero, Viviane Urbini; Minatel, Elaine; Neto, Humberto Santo

    2007-03-01

    Intrinsic laryngeal muscles share many anatomical and physiological properties with extraocular muscles, which are unaffected in both Duchenne muscular dystrophy and mdx mice. We hypothesized that intrinsic laryngeal muscles are spared from myonecrosis in mdx mice and may serve as an additional tool to understand the mechanisms of muscle sparing in dystrophinopathy. Intrinsic laryngeal muscles and tibialis anterior (TA) muscle of adult and aged mdx and control C57Bl/10 mice were investigated. The percentage of central nucleated fibers, as a sign of muscle fibers that had undergone injury and regeneration, and myofiber labeling with Evans blue dye, as a marker of myofiber damage, were studied. Except for the cricothyroid muscle, none of the intrinsic laryngeal muscles from adult and old mdx mice showed signs of myofiber damage or Evans blue dye labeling, and all appeared to be normal. Central nucleation was readily visible in the TA of the same mdx mice. A significant increase in the percentage of central nucleated fibers was observed in adult cricothyroid muscle compared to the other intrinsic laryngeal muscles, which worsened with age. Thus, we have shown that the intrinsic laryngeal muscles are spared from the lack of dystrophin and may serve as a useful model to study the mechanisms of muscle sparing in dystrophinopathy.

  6. The Dynamics of Compound, Transcript, and Protein Effects After Treatment With 2OMePS Antisense Oligonucleotides in mdx Mice

    Directory of Open Access Journals (Sweden)

    Ingrid E C Verhaart

    2014-01-01

    Full Text Available Antisense-mediated exon skipping is currently in clinical development for Duchenne muscular dystrophy (DMD to amend the consequences of the underlying genetic defect and restore dystrophin expression. Due to turnover of compound, transcript, and protein, chronic treatment with effector molecules (antisense oligonucleotides will be required. To investigate the dynamics and persistence of antisense 2′-O-methyl phosphorothioate oligonucleotides, exon skipping, and dystrophin expression after dosing was concluded, mdx mice were treated subcutaneously for 8 weeks with 100 mg/kg oligonucleotides twice weekly. Thereafter, mice were sacrificed at different time points after the final injection (36 hours–24 weeks. Oligonucleotide half-life was longer in heart (~65 days compared with that in skeletal muscle, liver, and kidney (~35 days. Exon skipping half-lives varied between 33 and 53 days, whereas dystrophin protein showed a long half-life (>100 days. Oligonucleotide and exon-skipping levels peaked in the first week and declined thereafter. By contrast, dystrophin expression peaked after 3–8 weeks and then slowly declined, remaining detectable after 24 weeks. Concordance between levels of oligonucleotides, exon skipping, and proteins was observed, except in heart, wherein high oligonucleotide levels but low exon skipping and dystrophin expression were seen. Overall, these results enhance our understanding of the pharmacokinetics and pharmacodynamics of 2′-O-methyl phosphorothioate oligos used for the treatment of DMD.

  7. Heregulin ameliorates the dystrophic phenotype in mdx mice.

    Science.gov (United States)

    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

    2004-09-21

    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, extracellular signal-related kinase-dependent activation of the GABP(alpha/beta) transcription factor complex. Therefore, this pathway offers a potential mechanism to modulate utrophin expression in muscle. We tested the ability of heregulin to improve the dystrophic phenotype in the mdx mouse model of DMD. Intraperitoneal injections of a small peptide encoding the epidermal growth factor-like region of heregulin ectodomain for 3 months in vivo resulted in up-regulation of utrophin, a marked improvement in the mechanical properties of muscle as evidenced by resistance to eccentric contraction mediated damage, and a reduction of muscle pathology. The amelioration of dystrophic phenotype by heregulin-mediated utrophin 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.

  8. Telomere shortening in diaphragm and tibialis anterior muscles of aged mdx mice.

    Science.gov (United States)

    Lund, Troy C; Grange, Robert W; Lowe, Dawn A

    2007-09-01

    The progression of Duchenne muscular dystrophy (DMD) is, in part, due to satellite cell senescence driven by high replicative pressure as these muscle stem cells repeatedly divide and fuse to damaged muscle fibers. We hypothesize that telomere shortening in satellite cells underlies their senescence. To test this hypothesis, we evaluated the diaphragm and a leg muscle from dystrophic mice of various ages for telomere dynamics. We found 30% telomere shortening in tibialis anterior muscles from 600-day-old mdx mice relative to age-matched wildtype mice. We also found a more severe shortening of telomere length in diaphragm muscles of old mdx mice. In those muscles, telomeres were shortened by approximately 15% and 40% in 100- and 600-day-old mdx mice, respectively. These findings indicate that satellite cells undergo telomere erosion, which may contribute to the inability of these cells to perpetually repair DMD muscle.

  9. 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.

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

    Science.gov (United States)

    Radley-Crabb, Hannah G; Marini, Juan C; Sosa, Horacio A; Castillo, Liliana I; Grounds, Miranda D; Fiorotto, Marta L

    2014-01-01

    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.

  11. Deficiency in Cardiac Dystrophin Affects the Abundance of the α-/β-Dystroglycan Complex

    Directory of Open Access Journals (Sweden)

    James Lohan

    2005-01-01

    Full Text Available Although Duchenne muscular dystrophy is primarily categorised as a skeletal muscle disease, deficiency in the membrane cytoskeletal protein dystrophin also affects the heart. The central transsarcolemmal linker between the actin membrane cytoskeleton and the extracellular matrix is represented by the dystrophin-associated dystroglycans. Chemical cross-linking analysis revealed no significant differences in the dimeric status of the α-/β-dystroglycan subcomplex in the dystrophic mdx heart as compared to normal cardiac tissue. In analogy to skeletal muscle fibres, heart muscle also exhibited a greatly reduced abundance of both dystroglycans in dystrophin-deficient cells. Immunoblotting demonstrated that the degree of reduction in α-dystroglycan is more pronounced in matured mdx skeletal muscle as contrasted to the mdx heart. The fact that the deficiency in dystrophin triggers a similar pathobiochemical response in both types of muscle suggests that the cardiomyopathic complications observed in x-linked muscular dystrophy might be initiated by the loss of the dystrophin-associated surface glycoprotein complex.

  12. Efecto del aceite esencial de Citrus aurantium l. en la regeneración muscular en ratones mdx

    OpenAIRE

    Tome de Souza, Paula Aiello [UNESP; Marques, Maria Julia; Hiruma-Lima, Clélia Akiko; Michelin Matheus, Selma Maria

    2011-01-01

    Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder characterized by the progressive loss of muscular strength. Mdx mutant mice show a marked deficiency in dystrophin, which was related to muscle membrane stability. The aim of this study was to verify the possible protective anti-inflammatory effect of citrus oil on mdx muscle fibers. Thus, adult male and female mdx mice (014/06-CEEA) were divided into control and citrus-treated. After 60 days of treatment, one ml of blo...

  13. Measuring tendon properties in mdx mice: cell viability and viscoelastic characteristics.

    Science.gov (United States)

    Rizzuto, E; Musarò, A; Catizone, A; Del Prete, Z

    2009-10-16

    Muscular dystrophy is a genetic disorder of skeletal muscle characterized by progressive muscle weakness. Here we assessed whether muscle wasting affects cell viability and mechanical properties of extensor digitorum longus (EDL) and of tibialis anterior (TA) tendons from mdx dystrophic mice compared to wild type (WT) mice. mdx mice represent the classical animal model for human Duchenne muscular dystrophy, and show several signs of the pathology, including a decrease in specific force and an increase of fibrotic index. Cell viability of tendons was evaluated by histological analysis, and viscoelastic properties have been assessed by a rapid measurement protocol that allowed us to compute, at the same time, tissue complex compliance for all the frequencies of interest. Confocal microscopy and mechanical properties measurements revealed that mdx tendons, compared to WT ones, have an increase in the number of dead cells and a significant reduction in tissue elasticity for all the frequencies that were tested. These findings indicate a reduced quality of the tissue. Moreover, mdx tendons have an increase in the viscous response, indicating that during dynamic loading, they dissipate more energy compared to WT. Our results demonstrate that muscular dystrophy involves not only muscle wasting, but also alteration in the viscoelastic properties of tendons, suggesting a paracrine effect of altered skeletal muscle on tendinous tissue.

  14. Parvalbumin-positive GABAergic interneurons are increased in the dorsal hippocampus of the dystrophic mdx mouse.

    Science.gov (United States)

    Del Tongo, Claudia; Carretta, Donatella; Fulgenzi, Gianluca; Catini, Claudio; Minciacchi, Diego

    2009-12-01

    Duchenne muscular dystrophy (DMD) is characterized by variable alterations of the dystrophin gene and by muscle weakness and cognitive impairment. We postulated an association between cognitive impairment and architectural changes of the hippocampal GABAergic system. We investigated a major subpopulation of GABAergic neurons, the parvalbumin-immunopositive (PV-I) cells, in the dorsal hippocampus of the mdx mouse, an acknowledged model of DMD. PV-I neurons were quantified and their distribution was compared in CA1, CA2, CA3, and dentate gyrus in wild-type and mdx mice. The cell morphology and topography of PV-I neurons were maintained. Conversely, the number of PV-I neurons was significantly increased in the mdx mouse. The percent increase of PV-I neurons was from 45% for CA2, up to 125% for the dentate gyrus. In addition, the increased parvalbumin content in the mdx hippocampus was confirmed by Western blot. A change in the hippocampus processing abilities is the expected functional counterpart of the modification displayed by PV-I GABAergic neurons. Altered hippocampal functionality can be responsible for part of the cognitive impairment in DMD.

  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. Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice

    Science.gov (United States)

    2013-01-01

    Background Presently, there is no effective treatment for the lethal muscle wasting disease Duchenne muscular dystrophy (DMD). Here we show that increased sphingosine-1-phoshate (S1P) through direct injection or via the administration of the small molecule 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, has beneficial effects in acutely injured dystrophic muscles of mdx mice. Methods We treated mdx mice with and without acute injury and characterized the histopathological and functional effects of increasing S1P levels. We also tested exogenous and direct administration of S1P on mdx muscles to examine the molecular pathways under which S1P promotes regeneration in dystrophic muscles. Results Short-term treatment with THI significantly increased muscle fiber size and extensor digitorum longus (EDL) muscle specific force in acutely injured mdx limb muscles. In addition, the accumulation of fibrosis and fat deposition, hallmarks of DMD pathology and impaired muscle regeneration, were lower in the injured muscles of THI-treated mdx mice. Furthermore, increased muscle force was observed in uninjured EDL muscles with a longer-term treatment of THI. Such regenerative effects were linked to the response of myogenic cells, since intramuscular injection of S1P increased the number of Myf5nlacz/+ positive myogenic cells and newly regenerated myofibers in injured mdx muscles. Intramuscular injection of biotinylated-S1P localized to muscle fibers, including newly regenerated fibers, which also stained positive for S1P receptor 1 (S1PR1). Importantly, plasma membrane and perinuclear localization of phosphorylated S1PR1 was observed in regenerating muscle fibers of mdx muscles. Intramuscular increases of S1P levels, S1PR1 and phosphorylated ribosomal protein S6 (P-rpS6), and elevated EDL muscle specific force, suggest S1P promoted the upregulation of anabolic pathways that mediate skeletal muscle mass and function. Conclusions These data show that S1P is

  17. 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

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

    Science.gov (United States)

    Altamirano, Francisco; Valladares, Denisse; Henríquez-Olguín, Carlos; Casas, Mariana; López, Jose R; Allen, Paul D; Jaimovich, Enrique

    2013-01-01

    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 perspectives

  19. 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

  20. 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.

  1. Preservation of Muscle Force in Mdx3cv Mice Correlates with Low-Level Expression of a Near Full-Length Dystrophin Protein

    OpenAIRE

    2008-01-01

    The complete absence of dystrophin causes Duchenne muscular dystrophy. Its restoration by greater than 20% is needed to reduce muscle pathology and improve muscle force. Dystrophin levels lower than 20% are considered therapeutically irrelevant but are associated with a less severe phenotype in certain Becker muscular dystrophy patients. To understand the role of low-level dystrophin expression, we compared muscle force and pathology in mdx3cv and mdx4cv mice. Dystrophin was eliminated in mdx...

  2. Pre-exercise low-level laser therapy improves performance and levels of oxidative stress markers in mdx mice subjected to muscle fatigue by high-intensity exercise.

    Science.gov (United States)

    Silva, Andreia Aparecida de Oliveira; Leal-Junior, Ernesto Cesar Pinto; D'Avila, Katia de Angelis Lobo; Serra, Andrey Jorge; Albertini, Regiane; França, Cristiane Miranda; Nishida, Joen Akemi; de Carvalho, Paulo de Tarso Camillo

    2015-08-01

    This study was designed to determine if the levels of oxidative stress markers are influenced by low-level laser therapy (LLLT) in mdx mice subjected to high-intensity exercise training on an electric treadmill. We used 21 C57BL/10ScSn-Dmdmdx/J mice and 7 C57BL/10ScSn mice, all aged 4 weeks. The mice were divided into four groups: a positive control group of normal, wild-type mice (WT); a negative control group of untreated mdx mice; a group of mdx mice that underwent forced high-intensity exercise on a treadmill (mdx fatigue); and another group of mdx mice with the same characteristics that were treated with LLLT at a single point on the gastrocnemius muscle of the hind paw and underwent forced high-intensity exercise on a treadmill. The mdx mice treated with LLLT showed significantly lower levels of creatine kinase (CK) and oxidative stress than mdx mice that underwent forced high-intensity exercise on a treadmill. The activities of the antioxidant enzyme superoxide dismutase (SOD) were higher in control mdx mice than in WT mice. LLLT also significantly reduced the level of this marker. LLLT had a beneficial effect also on the skeletal muscle performance of mdx mice. However, the single application of LLLT and the dose parameters used in this study were not able to change the morphology of a dystrophic muscle.

  3. Brain Function in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J. Gordon Millichap

    2002-02-01

    Full Text Available The role of dystrophin disorders in the CNS function of boys with Duchenne muscular dystrophy (DMD and the dystrophin-deficient mdx mouse, an animal model of DMD, is reviewed at the University of New South Wales, University of Sydney, Australia.

  4. Dystrophin insufficiency causes selective muscle histopathology and loss of dystrophin-glycoprotein complex assembly in pig skeletal muscle

    Science.gov (United States)

    Duchenne muscular dystrophy (DMD) is caused by a dystrophin deficiency while Becker muscular dystrophy (BMD) is caused by a dystrophin insufficiency or expression of a partially functional protein product. Both of these dystrophinopathies are most commonly studied using the mdx mouse and a golden r...

  5. 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...

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

    OpenAIRE

    Sandra Lopes Seixas; Jussara Lagrota-Cândido; Wilson Savino; Thereza Quirico-Santos

    1997-01-01

    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 nest...

  7. Collagen content does not alter the passive mechanical properties of fibrotic skeletal muscle in mdx mice.

    Science.gov (United States)

    Smith, Lucas R; Barton, Elisabeth R

    2014-05-15

    Many skeletal muscle diseases are associated with progressive fibrosis leading to impaired muscle function. Collagen within the extracellular matrix is the primary structural protein providing a mechanical scaffold for cells within tissues. During fibrosis collagen not only increases in amount but also undergoes posttranslational changes that alter its organization that is thought to contribute to tissue stiffness. Little, however, is known about collagen organization in fibrotic muscle and its consequences for function. To investigate the relationship between collagen content and organization with muscle mechanical properties, we studied mdx mice, a model for Duchenne muscular dystrophy (DMD) that undergoes skeletal muscle fibrosis, and age-matched control mice. We determined collagen content both histologically, with picosirius red staining, and biochemically, with hydroxyproline quantification. Collagen content increased in the mdx soleus and diaphragm muscles, which was exacerbated by age in the diaphragm. Collagen packing density, a parameter of collagen organization, was determined using circularly polarized light microscopy of picosirius red-stained sections. Extensor digitorum longus (EDL) and soleus muscle had proportionally less dense collagen in mdx muscle, while the diaphragm did not change packing density. The mdx muscles had compromised strength as expected, yet only the EDL had a significantly increased elastic stiffness. The EDL and diaphragm had increased dynamic stiffness and a change in relative viscosity. Unexpectedly, passive stiffness did not correlate with collagen content and only weakly correlated with collagen organization. We conclude that muscle fibrosis does not lead to increased passive stiffness and that collagen content is not predictive of muscle stiffness. Copyright © 2014 the American Physiological Society.

  8. Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice

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    Stevens Paula J

    2007-07-01

    Full Text Available Abstract Background Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy. Methods Using the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R agonist treatment has on diaphragm function, morphology and gene expression. Results We have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression. Conclusion Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.

  9. Molecular hydrogen alleviates motor deficits and muscle degeneration in mdx mice.

    Science.gov (United States)

    Hasegawa, Satoru; Ito, Mikako; Fukami, Mayu; Hashimoto, Miki; Hirayama, Masaaki; Ohno, Kinji

    2017-01-01

    Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by a mutation in DMD encoding dystrophin. Oxidative stress accounts for dystrophic muscle pathologies in DMD. We examined the effects of molecular hydrogen in mdx mice, a model animal for DMD. The pregnant mother started to take supersaturated hydrogen water (>5 ppm) ad libitum from E15.5 up to weaning of the offspring. The mdx mice took supersaturated hydrogen water from weaning until age 10 or 24 weeks when they were sacrificed. Hydrogen water prevented abnormal body mass gain that is commonly observed in mdx mice. Hydrogen improved the spontaneous running distance that was estimated by a counter-equipped running-wheel, and extended the duration on the rota-rod. Plasma creatine kinase activities were decreased by hydrogen at ages 10 and 24 weeks. Hydrogen also decreased the number of central nuclei of muscle fibers at ages 10 and 24 weeks, and immunostaining for nitrotyrosine in gastrocnemius muscle at age 24 weeks. Additionally, hydrogen tended to increase protein expressions of antioxidant glutathione peroxidase 1, as well as anti-apoptotic Bcl-2, in skeletal muscle at age 10 weeks. Although molecular mechanisms of the diverse effects of hydrogen remain to be elucidated, hydrogen potentially improves muscular dystrophy in DMD patients.

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

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    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.

  11. Utrophins compensate for Dp71 absence in mdx3cv in adhered platelets.

    Science.gov (United States)

    Cerecedo, Doris; Mondragón, Ricardo; Candelario, Aurora; García-Sierra, Francisco; Mornet, Dominique; Rendón, Alvaro; Martínez-Rojas, Dalila

    2008-01-01

    Platelet adhesion is a critical step due to its hemostatic role in stopping bleeding after vascular damage. Short dystrophins are the most abundant dmd gene products in nonmuscle tissues, and in association with cytoskeleton proteins contribute to their intrinsic function; while utrophins are dystrophin-homologous related family proteins with structural and functional similarities. We previously demonstrated the presence of Dp71 isoforms, utrophins, and various dystrophin-associated proteins and their participation in cytoskeleton re-organization, filopodia and lamellipodia extension, and in centralizing cytoplasmic granules during the adhesion process of human platelets. To evaluate the morphologic changes and actin-based structures of mdx(3cv) platelets during the adhesion process, we compared the topographic distribution of Dp71d/Dp71Delta110(m) and dystrophin-associated protein in adhered platelets from dystrophic mdx(3cv) mouse. By confocal microscopy, we showed that absence of Dp71 isoforms in platelets from this animal model disrupted dystrophin-associated protein expression and distribution without modifying the platelet morphology displayed during the glass-adhesion process. By immunoprecipitation assays, we proved that up-regulated utrophins were associated with dystrophin-associated proteins to conform the dystrophin-associated protein complex corresponding to utrophins, which might compensate for Dp71 absence in mdx(3cv) platelets.

  12. Chemical and mechanistic toxicology evaluation of exon skipping phosphorodiamidate morpholino oligomers in mdx mice.

    Science.gov (United States)

    Sazani, Peter; Ness, Kirk P Van; Weller, Doreen L; Poage, Duane; Nelson, Keith; Shrewsbury, And Stephen B

    2011-05-01

    AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) designed to induce skipping of dystrophin exon 51 and restore its expression in patients with Duchenne muscular dystrophy (DMD). Preclinically, restoration of dystrophin in the dystrophic mdx mouse model requires skipping of exon 23, achieved with the mouse-specific PMO, AVI-4225. Herein, we report the potential toxicological consequences of exon skipping and dystrophin restoration in mdx mice using AVI-4225. We also evaluated the toxicological effects of AVI-4658 in both mdx and wild-type mice. In both studies, animals were dosed once weekly for 12 weeks up to the maximum feasible dose of 960 mg/kg per injection. Both AVI-4658 and AVI-4225 were well-tolerated at all doses. Findings in AVI-4225-treated animals were generally limited to mild renal tubular basophilia/vacuolation, without any significant changes in renal function and with evidence of reversing. No toxicity associated with the mechanism of action of AVI-4225 in a dystrophic animal was observed.

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

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    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

  14. Quantitative T2 combined with texture analysis of nuclear magnetic resonance images identify different degrees of muscle involvement in three mouse models of muscle dystrophy: mdx, Largemyd and mdx/Largemyd.

    Directory of Open Access Journals (Sweden)

    Aurea B Martins-Bach

    Full Text Available Quantitative nuclear magnetic resonance imaging (MRI has been considered a promising non-invasive tool for monitoring therapeutic essays in small size mouse models of muscular dystrophies. Here, we combined MRI (anatomical images and transverse relaxation time constant-T2-measurements to texture analyses in the study of four mouse strains covering a wide range of dystrophic phenotypes. Two still unexplored mouse models of muscular dystrophies were analyzed: The severely affected Largemyd mouse and the recently generated and worst double mutant mdx/Largemyd mouse, as compared to the mildly affected mdx and normal mice. The results were compared to histopathological findings. MRI showed increased intermuscular fat and higher muscle T2 in the three dystrophic mouse models when compared to the wild-type mice (T2: mdx/Largemyd: 37.6±2.8 ms; mdx: 35.2±4.5 ms; Largemyd: 36.6±4.0 ms; wild-type: 29.1±1.8 ms, p<0.05, in addition to higher muscle T2 in the mdx/Largemyd mice when compared to mdx (p<0.05. The areas with increased muscle T2 in the MRI correlated spatially with the identified histopathological alterations such as necrosis, inflammation, degeneration and regeneration foci. Nevertheless, muscle T2 values were not correlated with the severity of the phenotype in the 3 dystrophic mouse strains, since the severely affected Largemyd showed similar values than both the mild mdx and worst mdx/Largemyd lineages. On the other hand, all studied mouse strains could be unambiguously identified with texture analysis, which reflected the observed differences in the distribution of signals in muscle MRI. Thus, combined T2 intensity maps and texture analysis is a powerful approach for the characterization and differentiation of dystrophic muscles with diverse genotypes and phenotypes. These new findings provide important noninvasive tools in the evaluation of the efficacy of new therapies, and most importantly, can be directly applied in human

  15. Quantitative T2 Combined with Texture Analysis of Nuclear Magnetic Resonance Images Identify Different Degrees of Muscle Involvement in Three Mouse Models of Muscle Dystrophy: mdx, Largemyd and mdx/Largemyd

    Science.gov (United States)

    Martins-Bach, Aurea B.; Malheiros, Jackeline; Matot, Béatrice; Martins, Poliana C. M.; Almeida, Camila F.; Caldeira, Waldir; Ribeiro, Alberto F.; Loureiro de Sousa, Paulo; Azzabou, Noura; Tannús, Alberto; Carlier, Pierre G.; Vainzof, Mariz

    2015-01-01

    Quantitative nuclear magnetic resonance imaging (MRI) has been considered a promising non-invasive tool for monitoring therapeutic essays in small size mouse models of muscular dystrophies. Here, we combined MRI (anatomical images and transverse relaxation time constant—T2—measurements) to texture analyses in the study of four mouse strains covering a wide range of dystrophic phenotypes. Two still unexplored mouse models of muscular dystrophies were analyzed: The severely affected Largemyd mouse and the recently generated and worst double mutant mdx/Largemyd mouse, as compared to the mildly affected mdx and normal mice. The results were compared to histopathological findings. MRI showed increased intermuscular fat and higher muscle T2 in the three dystrophic mouse models when compared to the wild-type mice (T2: mdx/Largemyd: 37.6±2.8 ms; mdx: 35.2±4.5 ms; Largemyd: 36.6±4.0 ms; wild-type: 29.1±1.8 ms, p<0.05), in addition to higher muscle T2 in the mdx/Largemyd mice when compared to mdx (p<0.05). The areas with increased muscle T2 in the MRI correlated spatially with the identified histopathological alterations such as necrosis, inflammation, degeneration and regeneration foci. Nevertheless, muscle T2 values were not correlated with the severity of the phenotype in the 3 dystrophic mouse strains, since the severely affected Largemyd showed similar values than both the mild mdx and worst mdx/Largemyd lineages. On the other hand, all studied mouse strains could be unambiguously identified with texture analysis, which reflected the observed differences in the distribution of signals in muscle MRI. Thus, combined T2 intensity maps and texture analysis is a powerful approach for the characterization and differentiation of dystrophic muscles with diverse genotypes and phenotypes. These new findings provide important noninvasive tools in the evaluation of the efficacy of new therapies, and most importantly, can be directly applied in human translational research

  16. Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice

    OpenAIRE

    2009-01-01

    Editors' Summary Background Muscular dystrophies are genetic (inherited) diseases in which the body's muscles gradually weaken and degenerate. The commonest and most severe muscular dystrophy—Duchenne muscular dystrophy—affects 1 in 3,500 boys (girls can be carriers of the disease but rarely have any symptoms). At birth, these boys seem normal but the symptoms of their disease begin to appear in early childhood. Affected children may initially have difficulty walking or find it to hard to sit...

  17. Dystrophin deficiency leads to disturbance of LAMP1-vesicle-associated protein secretion

    DEFF Research Database (Denmark)

    Duguez, S.; Duddy, W.; Johnston, H.

    2013-01-01

    Duchenne muscular dystrophy results from loss of the protein dystrophin, which links the intracellular cytoskeletal network with the extracellular matrix, but deficiency in this function does not fully explain the onset or progression of the disease. While some intracellular events involved...... of new potential therapeutic targets....

  18. Matrix metalloproteinase-9 inhibition improves proliferation and engraftment of myogenic cells in dystrophic muscle of mdx mice.

    Directory of Open Access Journals (Sweden)

    Sajedah M Hindi

    Full Text Available Duchenne muscular dystrophy (DMD caused by loss of cytoskeletal protein dystrophin is a devastating disorder of skeletal muscle. Primary deficiency of dystrophin leads to several secondary pathological changes including fiber degeneration and regeneration, extracellular matrix breakdown, inflammation, and fibrosis. Matrix metalloproteinases (MMPs are a group of extracellular proteases that are involved in tissue remodeling, inflammation, and development of interstitial fibrosis in many disease states. We have recently reported that the inhibition of MMP-9 improves myopathy and augments myofiber regeneration in mdx mice (a mouse model of DMD. However, the mechanisms by which MMP-9 regulates disease progression in mdx mice remain less understood. In this report, we demonstrate that the inhibition of MMP-9 augments the proliferation of satellite cells in dystrophic muscle. MMP-9 inhibition also causes significant reduction in percentage of M1 macrophages with concomitant increase in the proportion of promyogenic M2 macrophages in mdx mice. Moreover, inhibition of MMP-9 increases the expression of Notch ligands and receptors, and Notch target genes in skeletal muscle of mdx mice. Furthermore, our results show that while MMP-9 inhibition augments the expression of components of canonical Wnt signaling, it reduces the expression of genes whose products are involved in activation of non-canonical Wnt signaling in mdx mice. Finally, the inhibition of MMP-9 was found to dramatically improve the engraftment of transplanted myoblasts in skeletal muscle of mdx mice. Collectively, our study suggests that the inhibition of MMP-9 is a promising approach to stimulate myofiber regeneration and improving engraftment of muscle progenitor cells in dystrophic muscle.

  19. Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Terrill, Jessica R; Pinniger, Gavin J; Graves, Jamie A; Grounds, Miranda D; Arthur, Peter G

    2016-06-01

    Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation, oxidative stress and myofibre necrosis. Cysteine precursor antioxidants such as N-acetyl cysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) reduce dystropathology in the mdx mouse model for DMD, and we propose this is via increased synthesis of the amino acid taurine. We compared the capacity of OTC and taurine treatment to increase taurine content of mdx muscle, as well as effects on in vivo and ex vivo muscle function, inflammation and oxidative stress. Both treatments increased taurine in muscles, and improved many aspects of muscle function and reduced inflammation. Taurine treatment also reduced protein thiol oxidation and was overall more effective, as OTC treatment reduced body and muscle weight, suggesting some adverse effects of this drug. These data suggest that increasing dietary taurine is a better candidate for a therapeutic intervention for DMD. Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease for which there is no widely available cure. Whilst the mechanism of loss of muscle function in DMD and the mdx mouse model are not fully understood, disruptions in intracellular calcium homeostasis, inflammation and oxidative stress are implicated. We have shown that protein thiol oxidation is increased in mdx muscle, and that the indirect thiol antioxidant l-2-oxothiazolidine-4-carboxylate (OTC), which increases cysteine availability, decreases pathology and increases in vivo strength. We propose that the protective effects of OTC are a consequence of conversion of cysteine to taurine, which has itself been shown to be beneficial to mdx pathology. This study compares the efficacy of taurine with OTC in decreasing dystropathology in mdx mice by measuring in vivo and ex vivo contractile function and measurements of inflammation and protein thiol oxidation. Increasing the taurine content of mdx muscle improved both in vivo and ex

  20. Evaluation of Amphiphilic Peptide Modified Antisense Morpholino Oligonucleotides In Vitro and in Dystrophic mdx Mice

    OpenAIRE

    Mingxing Wang; Bo Wu; Peijuan Lu; Shah, Sapana N.; Jason D. Tucker; Lauren E. Bollinger; Qilong Lu

    2017-01-01

    A series of amphiphilic peptides modified PMO (Pt-PMO) were prepared, and their antisense effect and toxicity were evaluated both in vitro and in mdx mice. The results showed that the exon-skipping performance of Pt-PMO are relative to the structure of the conjugated peptide: the Pt3/Pt4 composed of six/seven arginines and one myristoylation modified PMO showed more efficacy and with less toxicity as compared to others, confirming that appropriate hydrophilic-lipophilic balance (HLB) and cati...

  1. Importância do camundongo mdx na fisiopatologia da distrofia muscular de Duchenne

    OpenAIRE

    Seixas,Sandra Lopes; Lagrota-Cândido,Jussara; Savino, Wilson; Quirico-Santos,Thereza

    1997-01-01

    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 nest...

  2. Granulocyte-colony stimulating factor improves MDX mouse response to peripheral nerve injury.

    Directory of Open Access Journals (Sweden)

    Gustavo Ferreira Simões

    Full Text Available BACKGROUND: G-CSF has been shown to increase neuronal survival, which may positively influence the spinal cord microenvironment during the course of muscular dystrophies. METHODOLOGY/PRINCIPAL FINDINGS: Male MDX mice that were six weeks of age received a left sciatic nerve transection and were treated with intraperitoneal injections of 200 µg/kg/day of G-CSF 7 days before and 7 days after the transection. The axotomy was performed after the cycles of muscular degeneration/regeneration, consistent with previous descriptions of this model of muscular dystrophy. C57BL/10 mice were used as control subjects. Seven days after the surgery, the animals were sacrificed and their lumbar spinal cords were processed for immunohistochemistry (anti-MHC I, anti-Synaptophysin, anti-GFAP and anti-IBA-1 and transmission electron microscopy. MHC I expression increased in both strains of mice after the axotomy. Nevertheless, the MDX mice displayed a significantly smaller MHC I upregulation than the control mice. Regarding GFAP expression, the MDX mice showed a stronger astrogliosis compared with the C57BL/10 mice across all groups. Both groups that were treated with G-CSF demonstrated preservation of synaptophysin expression compared with the untreated and placebo groups. The quantitative analysis of the ultrastructural level showed a preservation of the synaptic covering for the both groups that were treated with G-CSF and the axotomized groups showed a smaller loss of synaptic contact in relation to the treated groups after the lesion. CONCLUSIONS/SIGNIFICANCE: The reduction of active inputs to the alpha-motoneurons and increased astrogliosis in the axotomized and control groups may be associated with the cycles of muscle degeneration/regeneration that occur postnatally. The G-CSF treated group showed a preservation of the spinal cord microenvironment after the lesion. Moreover, the increase of MHC I expression in the MDX mice that were treated with G-CSF may

  3. Importância do camundongo mdx na fisiopatologia da distrofia muscular de Duchenne

    OpenAIRE

    Sandra Lopes Seixas; Jussara Lagrota-Cândido; Wilson Savino; Thereza Quirico-Santos

    1997-01-01

    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 nest...

  4. SY-1和MDX4-4210硅橡胶热老化性能试验%Heat ageing test of SY-1 and MDX4-4210 silicon rubber

    Institute of Scientific and Technical Information of China (English)

    邵龙泉; 赵铱民; 赵信义

    2003-01-01

    目的对比SY-1和MDX4-4210硅橡胶的热老化性能.方法在相同条件下对两种硅橡胶材料进行了热老化试验,对其老化性能加以评价.结果热老化后,SY-1硅橡胶的扯断强度性能变化百分比与MDX4-4210硅橡胶无显著差异(P>0.05);SY-1硅橡胶的邵氏硬度、扯断伸长率、永久变形率(3min后)、撕裂强度的性能变化百分比优于MDX4-4210硅橡胶(P<0.01).结论SY-1硅橡胶热老化性能略优于MDX4-4210硅橡胶,热老化性能可以满足作为面部软组织缺损赝复材料的要求.

  5. Constitutive properties, not molecular adaptations, mediate extraocular muscle sparing in dystrophic mdx mice.

    Science.gov (United States)

    Porter, John D; Merriam, Anita P; Khanna, Sangeeta; Andrade, Francisco H; Richmonds, Chelliah R; Leahy, Patrick; Cheng, Georgiana; Karathanasis, Paraskevi; Zhou, Xiaohua; Kusner, Linda L; Adams, Marvin E; Willem, Michael; Mayer, Ulrike; Kaminski, Henry J

    2003-05-01

    Extraocular muscle (EOM) is spared in Duchenne muscular dystrophy. Here, we tested putative EOM sparing mechanisms predicted from existing dystrophinopathy models. Data show that mdx mouse EOM contains dystrophin-glycoprotein complex (DGC)-competent and DGC-deficient myofibers distributed in a fiber type-specific pattern. Up-regulation of a dystrophin homologue, utrophin, mediates selective DGC retention. Counter to the DGC mechanical hypothesis, an intact DGC is not a precondition for EOM sarcolemmal integrity, and active adaptation at the level of calcium homeostasis is not mechanistic in protection. A partial, fiber type-specific retention of antiischemic nitric oxide to vascular smooth muscle signaling is not a factor in EOM sparing, because mice deficient in dystrophin and alpha-syntrophin, which localizes neuronal nitric oxide synthase to the sarcolemma, have normal EOMs. Moreover, an alternative transmembrane protein, alpha7beta1 integrin, does not appear to substitute for the DGC in EOM. Finally, genomewide expression profiling showed that EOM does not actively adapt to dystrophinopathy but identified candidate genes for the constitutive protection of mdx EOM. Taken together, data emphasize the conditional nature of dystrophinopathy and the potential importance of nonmechanical DGC roles and support the hypothesis that broad, constitutive structural cell signaling, and/or biochemical differences between EOM and other skeletal muscles are determinants of differential disease responsiveness.

  6. Therapeutic effects of exon skipping and losartan on skeletal muscle of mdx mice.

    Science.gov (United States)

    Lee, Eun-Joo; Kim, Ah-Young; Lee, Eun-Mi; Lee, Myeong-Mi; Min, Chang-Woo; Kang, Kyung-Ku; Park, Jin-Kyu; Hwang, Meeyul; Kwon, Soon-Hak; Tremblay, Jacques P; Jeong, Kyu-Shik

    2014-08-01

    Various attempts have been made to find treatments for Duchenne muscular dystrophy (DMD) patients. Exon skipping is one of the promising technologies for DMD treatment by restoring dystropin protein, which is one of the muscle components. It is well known that losartan, an angiotensin II type1 receptor blocker, promotes muscle regeneration and differentiation by lowering the level of transforming growth factor-beta1 signaling. In this study, we illustrated the combined effects of exon skipping and losartan on skeletal muscle of mdx mice. We supplied mdx mice with losartan for 2 weeks before exon skipping treatment. The losartan with the exon skipping group showed less expression of myf5 than the losartan treated group. Also the losartan with exon skipping group recovered normal muscle architecture, in contrast to the losartan group which still showed many central nuclei. However, the exon skipping efficiency and the restoration of dystrophin protein were lower in the losartan with exon skipping group compared to the exon skipping group. We reveal that losartan promotes muscle regeneration and shortens the time taken to restore normal muscle structure when combined with exon skipping. However, combined treatment of exon skipping and losartan decreases the restoration of dystrophin protein meaning decrease of exon skipping efficiency.

  7. Calcium-binding proteins in skeletal muscles of the mdx mice: potential role in the pathogenesis of Duchenne muscular dystrophy.

    Science.gov (United States)

    Pertille, Adriana; de Carvalho, Candida Luiza Tonizza; Matsumura, Cintia Yuri; Neto, Humberto Santo; Marques, Maria Julia

    2010-02-01

    Duchenne muscular dystrophy is one of the most common hereditary diseases. Abnormal ion handling renders dystrophic muscle fibers more susceptible to necrosis and a rise in intracellular calcium is an important initiating event in dystrophic muscle pathogenesis. In the mdx mice, muscles are affected with different intensities and some muscles are spared. We investigated the levels of the calcium-binding proteins calsequestrin and calmodulin in the non-spared axial (sternomastoid and diaphragm), limb (tibialis anterior and soleus), cardiac and in the spared extraocular muscles (EOM) of control and mdx mice. Immunoblotting analysis showed a significant increase of the proteins in the spared mdx EOM and a significant decrease in the most affected diaphragm. Both proteins were comparable to the cardiac muscle controls. In limb and sternomastoid muscles, calmodulin and calsequestrin were affected differently. These results suggest that differential levels of the calcium-handling proteins may be involved in the pathogenesis of myonecrosis in mdx muscles. Understanding the signaling mechanisms involving Ca(2+)-calmodulin activation and calsequestrin expression may be a valuable way to develop new therapeutic approaches to the dystrophinopaties.

  8. Novel adeno-associated viral vector delivering the utrophin gene regulator jazz counteracts dystrophic pathology in mdx mice.

    Science.gov (United States)

    Strimpakos, Georgios; Corbi, Nicoletta; Pisani, Cinzia; Di Certo, Maria Grazia; Onori, Annalisa; Luvisetto, Siro; Severini, Cinzia; Gabanella, Francesca; Monaco, Lucia; Mattei, Elisabetta; Passananti, Claudio

    2014-09-01

    Over-expression of the dystrophin-related gene utrophin represents a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). The strategy is based on the ability of utrophin to functionally replace defective dystrophin. We developed the artificial zinc finger transcription factor "Jazz" that up-regulates both the human and mouse utrophin promoter. We observed a significant recovery of muscle strength in dystrophic Jazz-transgenic mdx mice. Here we demonstrate the efficacy of an experimental gene therapy based on the systemic delivery of Jazz gene in mdx mice by adeno-associated virus (AAV). AAV serotype 8 was chosen on the basis of its high affinity for skeletal muscle. Muscle-specific expression of the therapeutic Jazz gene was enhanced by adding the muscle α-actin promoter to the AAV vector (mAAV). Injection of mAAV8-Jazz viral preparations into mdx mice resulted in muscle-specific Jazz expression coupled with up-regulation of the utrophin gene. We show a significant recovery from the dystrophic phenotype in mAAV8-Jazz-treated mdx mice. Histological and physiological analysis revealed a reduction of fiber necrosis and inflammatory cell infiltration associated with functional recovery in muscle contractile force. The combination of ZF-ATF technology with the AAV delivery can open a new avenue to obtain a therapeutic strategy for treatment of DMD. © 2014 Wiley Periodicals, Inc.

  9. Adeno-associated virus-mediated microdystrophin expression protects young mdx muscle from contraction-induced injury

    National Research Council Canada - National Science Library

    Liu, Mingju; Yue, Yongping; Harper, Scott Q; Grange, Robert W; Chamberlain, Jeffrey S; Duan, Dongsheng

    2005-01-01

    ... a CMV.DeltaR4/DeltaC cassette in AAV-5 and evaluated the transduction and muscle contractile profiles in the extensor digitorum longus muscles of young (7-week-old) and adult (9-month-old) mdx mice...

  10. Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice.

    Science.gov (United States)

    Leite, Paulo Emílio Correa; Gandía, Luís; de Pascual, Ricardo; Nanclares, Carmen; Colmena, Inés; Santos, Wilson C; Lagrota-Candido, Jussara; Quirico-Santos, Thereza

    2014-07-21

    Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChRα7(+/+) wild-type and nAChRα7(-/-) knockout mice with muscular injury induced with 60µL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRα7 agonist PNU282987 (0.3mg/kg and 1.0mg/kg) and the antagonist methyllycaconitine (MLA at 1.0mg/kg) injected intraperitoneally for 7 days. Selective nAChRα7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNFα and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WTα7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on α7KO, and MLA abolished the nAChRα7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChRα7 activation inhibits muscular inflammation and activates tissue remodeling by increasing muscular regeneration. These effects were not accompanied with fibrosis and/or deposition of non-functional collagen. The nAChRα7 activation may be considered as a potential target for pharmacological strategies to reduce inflammation and activate mechanisms of muscular regeneration.

  11. Dystrophic tendon functionality is recovered by muscle-specific expression of insulin-like growth factor in mdx mice.

    Science.gov (United States)

    Rizzuto, E; Catizone, A; Musarò, A; Del Prete, Z

    2013-02-01

    Duchenne muscular dystrophy (DMD) is a severe genetic disorder of skeletal muscle, characterized by a steady muscle weakness. By using the animal model for DMD, the mdx mice, we have previously demonstrated that biomechanical properties of tendinous tissue are also significantly affected in this muscle pathology. Muscle specific over-expression of insulin like growth factor-1 (mIgf-1) is known to induce a partial recovery in muscle functionality, in particular increasing the muscle absolute force, but not the specific force. To test whether Igf-1 muscle specific over-expression helps the recovery also in tendinous tissue, mechanical and cellular evaluation of mdx and mdx:MLC/mIgf-1 mice tendons has been performed. Mechanical properties were investigated by measuring the viscoelastic response of the tissue, while cell viability was evaluated by molecular assays. An absolute recovery in the mechanical properties of EDL and TA tendons was observed through the measurement of tissue viscoelasticity for several different frequencies of interest. Moreover, when compared with tendons from dystrophic mdx animals, mdx:MLC/mIgf-1 specimens showed an almost complete recovery in the number of viable cells for both extensor digitorum longus (EDL) and tibialis anterior (TA) tendons. Of note, the partial recovery in muscle functionality and the full recovery in tendons response, suggests that mIgf-1 muscle specific over-expression exerts its effect on tendons either indirectly, improving the tendon viability and its functional properties as a consequence of the reduction of the hostile muscle dystrophic environment, or acting directly on the tendon tissue, as a paracrine trophic factor. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Utrophin A is essential in mediating the functional adaptations of mdx mouse muscle following chronic AMPK activation.

    Science.gov (United States)

    Al-Rewashdy, Hasanen; Ljubicic, Vladimir; Lin, Wei; Renaud, Jean-Marc; Jasmin, Bernard J

    2015-03-01

    Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin along muscle fibers. An attractive therapeutic avenue for DMD consists in the upregulation of utrophin A, a protein with high sequence identity and functional redundancy with dystrophin. Recent work has shown that pharmacological interventions that induce a muscle fiber shift toward a slower, more oxidative phenotype with increased expression of utrophin A confer morphological and functional improvements in mdx mice. Whether such improvements result from the increased expression of utrophin A per se or are linked to other beneficial adaptations associated with the slow, oxidative phenotype remain to be established. To address this central issue, we capitalized on the use of double knockout (dKO) mice, which are mdx mice also deficient in utrophin. We first compared expression of signaling molecules and markers of the slow, oxidative phenotype in muscles of mdx versus dKO mice and found that both strains exhibit similar phenotypes. Chronic activation of 5' adenosine monophosphate-activated protein kinase with 5-amino-4-imidazolecarboxamide riboside (AICAR) resulted in expression of a slower, more oxidative phenotype in both mdx and dKO mice. In mdx mice, this fiber type shift was accompanied by clear functional improvements that included reductions in central nucleation, IgM sarcoplasmic penetration and sarcolemmal damage resulting from eccentric contractions, as well as in increased grip strength. These important morphological and functional adaptations were not seen in AICAR-treated dKO mice. Our findings show the central role of utrophin A in mediating the functional benefits associated with expression of a slower, more oxidative phenotype in dystrophic animals.

  13. Effects of Mechanical Overloading on the Properties of Soleus Muscle Fibers, with or without Damage in MDX and Wild Type Mice

    Science.gov (United States)

    Terada, Masahiro; Kawano, Fuminori; Ohira, Takashi; Oke, Yoshihiko; Nakai, Naoya; Ohira, Yoshinobu

    2008-06-01

    Effects of mechanical overloading on the characteristics of regenerating or not-regenerating soleus muscle fibers were studied. The muscle fibers of mdx mice were characterized by the localization of myonuclei. Muscle damage was also induced in wild type (WT) mice by injection of cardiotoxin (CTX) into soleus muscle. Overloading was applied for 14 days to the left soleus muscle in mdx and intact and CTX-injected WT mice by removing the distal tendons of plantaris and gastrocnemius muscles. The contralateral muscle served as the normal control. These animals were then allowed ambulation recovery in the cage. Central myonuclei were noted in many fibers of mdx and CTX-injected mice with or without overloading. In general, the fibers with central nuclei were considered as regenerating fibers. The fibers with more central nuclei were increased in mdx mice, but the fibers with more peripheral nuclei were increased in CTX-injected WT mice by overloading. The muscle satellite cells, neuromuscular junctions (NMJ), and myonuclei were stained. Most of the properties, such as number of myonuclei and satellite cells, size of NMJ, and fiber length, were not influenced by mechanical overloading in all mice. Approximately 0.6% branched fibers were seen in the intact soleus of mdx mice, although these fibers were not detected in WT mice. However, the percentage of these fibers was increased by overloading especially in mdx mice (~50% vs. ~2.5% in WT). In CTX-injected WT mice, these fibers were ~15% with or without overloading. The fiber cross sectional area in normal WT, but not in mdx and CTX-injected WT mice, was increased by overloading (pmuscle damage in mdx mice, but promoted the regeneration in CTX-injected WT mice.

  14. Gene expression in mdx mouse muscle in relation to age and exercise: aberrant mechanical-metabolic coupling and implications for pre-clinical studies in Duchenne muscular dystrophy.

    Science.gov (United States)

    Camerino, Giulia Maria; Cannone, Maria; Giustino, Arcangela; Massari, Ada Maria; Capogrosso, Roberta Francesca; Cozzoli, Anna; De Luca, Annamaria

    2014-11-01

    Weakness and fatigability are typical features of Duchenne muscular dystrophy patients and are aggravated in dystrophic mdx mice by chronic treadmill exercise. Mechanical activity modulates gene expression and muscle plasticity. Here, we investigated the outcome of 4 (T4, 8 weeks of age) and 12 (T12, 16 weeks of age) weeks of either exercise or cage-based activity on a large set of genes in the gastrocnemius muscle of mdx and wild-type (WT) mice using quantitative real-time PCR. Basal expression of the exercise-sensitive genes peroxisome-proliferator receptor γ coactivator 1α (Pgc-1α) and Sirtuin1 (Sirt1) was higher in mdx versus WT mice at both ages. Exercise increased Pgc-1α expression in WT mice; Pgc-1α was downregulated by T12 exercise in mdx muscles, along with Sirt1, Pparγ and the autophagy marker Bnip3. Sixteen weeks old mdx mice showed a basal overexpression of the slow Mhc1 isoform and Serca2; T12 exercise fully contrasted this basal adaptation as well as the high expression of follistatin and myogenin. Conversely, T12 exercise was ineffective in WT mice. Damage-related genes such as gp91-phox (NADPH-oxidase2), Tgfβ, Tnfα and c-Src tyrosine kinase were overexpressed in mdx muscles and not affected by exercise. Likewise, the anti-inflammatory adiponectin was lower in T12-exercised mdx muscles. Chronic exercise with minor adaptive effects in WT muscles leads to maladaptation in mdx muscles with a disequilibrium between protective and damaging signals. Increased understanding of the pathways involved in the altered mechanical-metabolic coupling may help guide appropriate physical therapies while better addressing pharmacological interventions in translational research.

  15. Whole body periodic acceleration is an effective therapy to ameliorate muscular dystrophy in mdx mice.

    Science.gov (United States)

    Altamirano, Francisco; Perez, Claudio F; Liu, Min; Widrick, Jeffrey; Barton, Elisabeth R; Allen, Paul D; Adams, Jose A; Lopez, Jose R

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a genetic disorder caused by the absence of dystrophin in both skeletal and cardiac muscles. This leads to severe muscle degeneration, and dilated cardiomyopathy that produces patient death, which in most cases occurs before the end of the second decade. Several lines of evidence have shown that modulators of nitric oxide (NO) pathway can improve skeletal muscle and cardiac function in the mdx mouse, a mouse model for DMD. Whole body periodic acceleration (pGz) is produced by applying sinusoidal motion to supine humans and in standing conscious rodents in a headward-footward direction using a motion platform. It adds small pulses as a function of movement frequency to the circulation thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of NO. In this study, we examined the potential therapeutic properties of pGz for the treatment of skeletal muscle pathology observed in the mdx mouse. We found that pGz (480 cpm, 8 days, 1 hr per day) decreased intracellular Ca(2+) and Na(+) overload, diminished serum levels of creatine kinase (CK) and reduced intracellular accumulation of Evans Blue. Furthermore, pGz increased muscle force generation and expression of both utrophin and the carboxy-terminal PDZ ligand of nNOS (CAPON). Likewise, pGz (120 cpm, 12 h) applied in vitro to skeletal muscle myotubes reduced Ca(2+) and Na(+) overload, diminished abnormal sarcolemmal Ca(2+) entry and increased phosphorylation of endothelial NOS. Overall, this study provides new insights into the potential therapeutic efficacy of pGz as a non-invasive and non-pharmacological approach for the treatment of DMD patients through activation of the NO pathway.

  16. Contribution of oxidative stress to pathology in diaphragm and limb muscles with Duchenne muscular dystrophy.

    Science.gov (United States)

    Kim, Jong-Hee; Kwak, Hyo-Bum; Thompson, LaDora V; Lawler, John M

    2013-02-01

    Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease that makes walking and breathing difficult. DMD is caused by an X-linked (Xp21) mutation in the dystrophin gene. Dystrophin is a scaffolding protein located in the sarcolemmal cytoskeleton, important in maintaining structural integrity and regulating muscle cell (muscle fiber) growth and repair. Dystrophin deficiency in mouse models (e.g., mdx mouse) destabilizes the interface between muscle fibers and the extracellular matrix, resulting in profound damage, inflammation, and weakness in diaphragm and limb muscles. While the link between dystrophin deficiency with inflammation and pathology is multi-factorial, elevated oxidative stress has been proposed as a central mediator. Unfortunately, the use of non-specific antioxidant scavengers in mouse and human studies has led to inconsistent results, obscuring our understanding of the importance of redox signaling in pathology of muscular dystrophy. However, recent studies with more mechanistic approaches in mdx mice suggest that NAD(P)H oxidase and nuclear factor-kappaB are important in amplifying dystrophin-deficient muscle pathology. Therefore, more targeted antioxidant therapeutics may ameliorate damage and weakness in human population, thus promoting better muscle function and quality of life. This review will focus upon the pathobiology of dystrophin deficiency in diaphragm and limb muscle primarily in mouse models, with a rationale for development of targeted therapeutic antioxidants in DMD patients.

  17. Heart Health - Brave Heart

    Science.gov (United States)

    ... Bar Home Current Issue Past Issues Cover Story Heart Health Brave Heart Past Issues / Winter 2009 Table of Contents For ... you can have a good life after a heart attack." Lifestyle Changes Surviving—and thriving—after such ...

  18. Ultrastructural changes in the interstitial cells of Cajal and gastric dysrhythmias in mice lacking full-length dystrophin (mdx mice).

    Science.gov (United States)

    Vannucchi, Maria-Giuliana; Zizzo, Maria-Grazia; Zardo, Claudio; Pieri, Laura; Serio, Rosa; Mulè, Flavia; Faussone-Pellegrini, Maria-Simonetta

    2004-05-01

    At least two populations of c-kit positive interstitial cells of Cajal (ICC) lie in the gastric wall, one located at the myenteric plexus level has a pace-making function and the other located intramuscularly is intermediary in the neurotransmission and regenerates the slow waves. Both of these ICC sub-types express full-length dystrophin. Mdx mice, an animal model lacking in full-length dystrophin and used to study Duchenne muscular dystrophy (DMD), show gastric dismotilities. The aim of the present study was to verify in mdx mice whether: (i) gastric ICC undergo morphological changes, through immunohistochemical and ultrastructural analyses; and (ii) there are alterations in the electrical activity, using intracellular recording technique. In control mice, ICC sub-types showed heterogeneous ultrastructural features, either intramuscularly or at the myenteric plexus level. In mdx mice, all of the ICC sub-types underwent important changes: coated vesicles were significantly more numerous and caveolae significantly fewer than in control; moreover, cytoskeleton and smooth endoplasmic reticulum were reduced and mitochondria enlarged. c-Kit-positivity and integrity of the ICC networks were maintained. In the circular muscle of normal mice slow waves, which consisted of initial and secondary components, occurred with a regular frequency. In mdx mice, slow waves occurred in a highly dysrhythmic fashion and they lacked a secondary component. We conclude that the lack of the full-length dystrophin is associated with ultrastructural modifications of gastric ICC, most of which can be interpreted as signs of new membrane formation and altered Ca(2+) handling, and with defective generation and regeneration of slow wave activity.

  19. Preclinical studies in the mdx mouse model of duchenne muscular dystrophy with the histone deacetylase inhibitor givinostat.

    Science.gov (United States)

    Consalvi, Silvia; Mozzetta, Chiara; Bettica, Paolo; Germani, Massimiliano; Fiorentini, Francesco; Del Bene, Francesca; Rocchetti, Maurizio; Leoni, Flavio; Monzani, Valmen; Mascagni, Paolo; Puri, Pier Lorenzo; Saccone, Valentina

    2013-05-20

    Previous work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice--the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients.

  20. Lack of the serum- and glucocorticoid-inducible kinase SGK1 improves muscle force characteristics and attenuates fibrosis in dystrophic mdx mouse muscle

    DEFF Research Database (Denmark)

    Steinberger, Martin; Föller, Michael; Vogelgesang, Silke

    2015-01-01

    size variations, central nuclei of muscle fibers, fibrosis in the diaphragm, and force reduction by 30–50 %. Muscles from sgk1 -/- mice were histologically overall intact and specific force was only slightly reduced compared to wild-type muscles. Surprisingly, soleus and diaphragm muscles of mdx/sgk1......Duchenne muscular dystrophy (DMD) is a human genetic disease characterized by fibrosis and severe muscle weakness. Currently, there is no effective treatment available to prevent progressive fibrosis in skeletal muscles. The serum- and glucocorticoid-inducible kinase SGK1 regulates a variety...... of physiological functions and participates in fibrosis stimulation. Here, we investigated whether SGK1 influences structure, function and/or fibrosis of the muscles from the mdx mouse, an animal model for DMD. As expected, mdx muscles showed the typical pathological features of muscular dystrophy including fiber...

  1. IFN-γ promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation.

    Science.gov (United States)

    Villalta, S Armando; Deng, Bo; Rinaldi, Chiara; Wehling-Henricks, Michelle; Tidball, James G

    2011-11-15

    Duchenne muscular dystrophy is a degenerative disorder that leads to death by the third decade of life. Previous investigations have shown that macrophages that invade dystrophic muscle are a heterogeneous population consisting of M1 and M2 macrophages that promote injury and repair, respectively. In the present investigation, we tested whether IFN-γ worsens the severity of mdx dystrophy by activating macrophages to a cytolytic M1 phenotype and by suppressing the activation of proregenerative macrophages to an M2 phenotype. IFN-γ is a strong inducer of the M1 phenotype and is elevated in mdx dystrophy. Contrary to our expectations, null mutation of IFN-γ caused no reduction of cytotoxicity of macrophages isolated from mdx muscle and did not reduce muscle fiber damage in vivo or improve gross motor function of mdx mice at the early, acute peak of pathology. In contrast, ablation of IFN-γ reduced muscle damage in vivo during the regenerative stage of the disease and increased activation of the M2 phenotype and improved motor function of mdx mice at that later stage of the disease. IFN-γ also inhibited muscle cell proliferation and differentiation in vitro, and IFN-γ mutation increased MyoD expression in mdx muscle in vivo, showing that IFN-γ can have direct effects on muscle cells that could impair repair. Taken together, the findings show that suppression of IFN-γ signaling in muscular dystrophy reduces muscle damage and improves motor performance by promoting the M2 macrophage phenotype and by direct actions on muscle cells.

  2. Clinical map document based on XML (cMDX: document architecture with mapping feature for reporting and analysing prostate cancer in radical prostatectomy specimens

    Directory of Open Access Journals (Sweden)

    Bettendorf Olaf

    2010-11-01

    Full Text Available Abstract Background The pathology report of radical prostatectomy specimens plays an important role in clinical decisions and the prognostic evaluation in Prostate Cancer (PCa. The anatomical schema is a helpful tool to document PCa extension for clinical and research purposes. To achieve electronic documentation and analysis, an appropriate documentation model for anatomical schemas is needed. For this purpose we developed cMDX. Methods The document architecture of cMDX was designed according to Open Packaging Conventions by separating the whole data into template data and patient data. Analogue custom XML elements were considered to harmonize the graphical representation (e.g. tumour extension with the textual data (e.g. histological patterns. The graphical documentation was based on the four-layer visualization model that forms the interaction between different custom XML elements. Sensible personal data were encrypted with a 256-bit cryptographic algorithm to avoid misuse. In order to assess the clinical value, we retrospectively analysed the tumour extension in 255 patients after radical prostatectomy. Results The pathology report with cMDX can represent pathological findings of the prostate in schematic styles. Such reports can be integrated into the hospital information system. "cMDX" documents can be converted into different data formats like text, graphics and PDF. Supplementary tools like cMDX Editor and an analyser tool were implemented. The graphical analysis of 255 prostatectomy specimens showed that PCa were mostly localized in the peripheral zone (Mean: 73% ± 25. 54% of PCa showed a multifocal growth pattern. Conclusions cMDX can be used for routine histopathological reporting of radical prostatectomy specimens and provide data for scientific analysis.

  3. Increased resting intracellular calcium modulates NF-κB-dependent inducible nitric-oxide synthase gene expression in dystrophic mdx skeletal myotubes.

    Science.gov (United States)

    Altamirano, Francisco; López, Jose R; Henríquez, Carlos; Molinski, Tadeusz; Allen, Paul D; Jaimovich, Enrique

    2012-06-15

    Duchenne muscular dystrophy (DMD) is a genetic disorder caused by dystrophin mutations, characterized by chronic inflammation and severe muscle wasting. Dystrophic muscles exhibit activated immune cell infiltrates, up-regulated inflammatory gene expression, and increased NF-κB activity, but the contribution of the skeletal muscle cell to this process has been unclear. The aim of this work was to study the pathways that contribute to the increased resting calcium ([Ca(2+)](rest)) observed in mdx myotubes and its possible link with up-regulation of NF-κB and pro-inflammatory gene expression in dystrophic muscle cells. [Ca(2+)](rest) was higher in mdx than in WT myotubes (308 ± 6 versus 113 ± 2 nm, p < 0.001). In mdx myotubes, both the inhibition of Ca(2+) entry (low Ca(2+) solution, Ca(2+)-free solution, and Gd(3+)) and blockade of either ryanodine receptors or inositol 1,4,5-trisphosphate receptors reduced [Ca(2+)](rest). Basal activity of NF-κB was significantly up-regulated in mdx versus WT myotubes. There was an increased transcriptional activity and p65 nuclear localization, which could be reversed when [Ca(2+)](rest) was reduced. Levels of mRNA for TNFα, IL-1β, and IL-6 were similar in WT and mdx myotubes, whereas inducible nitric-oxide synthase (iNOS) expression was increased 5-fold. Reducing [Ca(2+)](rest) using different strategies reduced iNOS gene expression presumably as a result of decreased activation of NF-κB. We propose that NF-κB, modulated by increased [Ca(2+)](rest), is constitutively active in mdx myotubes, and this mechanism can account for iNOS overexpression and the increase in reactive nitrogen species that promote damage in dystrophic skeletal muscle cells.

  4. EPA protects against muscle damage in the mdx mouse model of Duchenne muscular dystrophy by promoting a shift from the M1 to M2 macrophage phenotype.

    Science.gov (United States)

    Carvalho, Samara Camaçari de; Apolinário, Leticia Montanholi; Matheus, Selma Maria Michelin; Santo Neto, Humberto; Marques, Maria Julia

    2013-11-15

    In dystrophic mdx mice and in Duchenne muscular dystrophy, inflammation contributes to myonecrosis. Previously, we demonstrated that eicosapentaenoic acid (EPA) decreased inflammation and necrosis in dystrophic muscle. In the present study, we examined the effects of EPA and the corticoid deflazacort (DFZ) as modulators of M1 (iNOS-expressing cells) and M2 (CD206-expressing cells) macrophages. Mdx mice (14 days old) received EPA or DFZ for 16 days. The diaphragm, biceps brachii and quadriceps muscles were studied. Immunofluorescence, immunoblotting and ELISA assays showed that EPA increased interleucin-10, reduced interferon-γ and was more effective than DFZ in promoting a shift from M1 to M2.

  5. Dystrophic changes in extraocular muscles after gamma irradiation in mdx:utrophin(+/-) mice.

    Science.gov (United States)

    McDonald, Abby A; Kunz, Matthew D; McLoon, Linda K

    2014-01-01

    Extraocular muscles (EOM) have a strikingly different disease profile than limb skeletal muscles. It has long been known that they are spared in Duchenne (DMD) and other forms of muscular dystrophy. Despite many studies, the cause for this sparing is not understood. We have proposed that differences in myogenic precursor cell properties in EOM maintain normal morphology over the lifetime of individuals with DMD due to either greater proliferative potential or greater resistance to injury. This hypothesis was tested by exposing wild type and mdx:utrophin(+/-) (het) mouse EOM and limb skeletal muscles to 18 Gy gamma irradiation, a dose known to inhibit satellite cell proliferation in limb muscles. As expected, over time het limb skeletal muscles displayed reduced central nucleation mirrored by a reduction in Pax7-positive cells, demonstrating a significant loss in regenerative potential. In contrast, in the first month post-irradiation in the het EOM, myofiber cross-sectional areas first decreased, then increased, but ultimately returned to normal compared to non-irradiated het EOM. Central nucleation significantly increased in the first post-irradiation month, resembling the dystrophic limb phenotype. This correlated with decreased EECD34 stem cells and a concomitant increase and subsequent return to normalcy of both Pax7 and Pitx2-positive cell density. By two months, normal het EOM morphology returned. It appears that irradiation disrupts the normal method of EOM remodeling, which react paradoxically to produce increased numbers of myogenic precursor cells. This suggests that the EOM contain myogenic precursor cell types resistant to 18 Gy gamma irradiation, allowing return to normal morphology 2 months post-irradiation. This supports our hypothesis that ongoing proliferation of specialized regenerative populations in the het EOM actively maintains normal EOM morphology in DMD. Ongoing studies are working to define the differences in the myogenic precursor cells

  6. Heart Disease

    Science.gov (United States)

    ... type of heart disease you have. Symptoms of heart disease in your blood vessels (atherosclerotic disease) Cardiovascular disease ... can sometimes be found early with regular evaluations. Heart disease symptoms caused by abnormal heartbeats (heart arrhythmias) A ...

  7. Therapeutic effects of mouse adipose-derived stem cells and losartan in the skeletal muscle of injured mdx mice.

    Science.gov (United States)

    Lee, Eun-Mi; Kim, Ah-Young; Lee, Eun-Joo; Park, Jin-Kyu; Lee, Myeong-Mi; Hwang, Meeyul; Kim, Choong-Yong; Kim, Shin-Yoon; Jeong, Kyu-Shik

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder caused by mutations in the dystrophin gene. Adipose-derived stem cells (ASCs) are an attractive source of cells for stem cell therapy. Losartan has been reported to improve ASC transplantation in injured mouse muscles. In the present study, we investigated whether the combined treatment of losartan and ASCs in the injured muscles of mdx mice improves regeneration. The combined treatment of ASCs and losartan remarkably improved muscle regeneration and induced muscle hypertrophy. In addition, ASCs and losartan treatment downregulated transforming growth factor-β and inhibited muscle fibrosis. We observed cells coexpressing green fluorescent protein (GFP) and dystrophin in the muscle samples of mice transplanted with GFP-positive ASCs. In the coculture in vitro experiment, we also observed that the GFP ASCs differentiated into dystrophin-expressing myotubes. The present study shows that the combination of transplanted ASCs and treatment with losartan ameliorated muscle fibrosis and improved muscle regeneration in injured mdx mice. Thus, we suggest that combined treatment with losartan and ASCs could help to improve muscle regeneration in the muscles of injured patients, including DMD patients.

  8. Revertant fibers in the mdx murine model of Duchenne muscular dystrophy: an age- and muscle-related reappraisal.

    Directory of Open Access Journals (Sweden)

    Sarah R Pigozzo

    Full Text Available Muscles in Duchenne dystrophy patients are characterized by the absence of dystrophin, yet transverse sections show a small percentage of fibers (termed "revertant fibers" positive for dystrophin expression. This phenomenon, whose biological bases have not been fully elucidated, is present also in the murine and canine models of DMD and can confound the evaluation of therapeutic approaches. We analyzed 11 different muscles in a cohort of 40 mdx mice, the most commonly model used in pre-clinical studies, belonging to four age groups; such number of animals allowed us to perform solid ANOVA statistical analysis. We assessed the average number of dystrophin-positive fibers, both absolute and normalized for muscle size, and the correlation between their formation and the ageing process. Our results indicate that various muscles develop different numbers of revertant fibers, with different time trends; besides, they suggest that the biological mechanism(s behind dystrophin re-expression might not be limited to the early development phases but could actually continue during adulthood. Importantly, such finding was seen also in cardiac muscle, a fact that does not fit into the current hypothesis of the clonal origin of "revertant" myonuclei from satellite cells. This work represents the largest, statistically significant analysis of revertant fibers in mdx mice so far, which can now be used as a reference point for improving the evaluation of therapeutic approaches for DMD. At the same time, it provides new clues about the formation of revertant fibers/cardiomyocytes in dystrophic skeletal and cardiac muscle.

  9. Insulin-like growth factor-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage.

    Science.gov (United States)

    Gehrig, Stefan M; Ryall, James G; Schertzer, Jonathan D; Lynch, Gordon S

    2008-11-01

    Contraction-mediated injury is a major contributing factor to the pathophysiology of muscular dystrophy and therefore therapies that can attenuate this type of injury have clinical relevance. Systemic administration of insulin-like growth factor-I (IGF-I) has been shown to improve muscle function in dystrophic mdx mice, an effect associated with a shift towards a more oxidative muscle phenotype and a reduced susceptibility to contraction-mediated damage. The actions of IGF-I in vivo are modulated by IGF binding proteins (IGFBPs), which generally act to inhibit IGF-I signalling. We tested the hypothesis that an analogue of IGF-I (LR IGF-I), which has significantly reduced binding affinity for IGFBPs, would improve the dystrophic pathology by reducing the susceptibility to muscle injury. Dystrophic mdx and wild-type (C57BL/10) mice were administered LR IGF-I continuously ( approximately 1.5 mg kg(-1) day(-1)) via osmotic mini-pump for 4 weeks. Administration of LR IGF-I reduced the susceptibility of extensor digitorum longus, soleus and diaphragm muscles to contraction damage, as evident from lower force deficits after a protocol of lengthening contractions. In contrast to the mechanism of protection conferred by administration of IGF-I, the protection conferred by LR IGF-I was independent of changes in muscle fatigue and oxidative metabolism. This study further indicates that modulation of IGF-I signalling has therapeutic potential for muscular diseases.

  10. Unloaded speed of shortening in voltage-clamped intact skeletal muscle fibers from wt, mdx, and transgenic minidystrophin mice using a novel high-speed acquisition system.

    Science.gov (United States)

    Friedrich, O; Weber, C; von Wegner, F; Chamberlain, J S; Fink, R H A

    2008-06-01

    Skeletal muscle unloaded shortening has been indirectly determined in the past. Here, we present a novel high-speed optical tracking technique that allows recording of unloaded shortening in single intact, voltage-clamped mammalian skeletal muscle fibers with 2-ms time resolution. L-type Ca(2+) currents were simultaneously recorded. The time course of shortening was biexponential: a fast initial phase, tau(1), and a slower successive phase, tau(2,) with activation energies of 59 kJ/mol and 47 kJ/mol. Maximum unloaded shortening speed, v(u,max), was faster than that derived using other techniques, e.g., approximately 14.0 L(0) s(-1) at 30 degrees C. Our technique also allowed direct determination of shortening acceleration. We applied our technique to single fibers from C57 wild-type, dystrophic mdx, and minidystrophin-expressing mice to test whether unloaded shortening was affected in the pathophysiological mechanism of Duchenne muscular dystrophy. v(u,max) and a(u,max) values were not significantly different in the three strains, whereas tau(1) and tau(2) were increased in mdx fibers. The results were complemented by myosin heavy and light chain (MLC) determinations that showed the same myosin heavy chain IIA profiles in the interossei muscles from the different strains. In mdx muscle, MLC-1f was significantly increased and MLC-2f and MLC-3f somewhat reduced. Fast initial active shortening seems almost unaffected in mdx muscle.

  11. Myofiber-specific TEAD1 overexpression drives satellite cell hyperplasia and counters pathological effects of dystrophin deficiency

    Science.gov (United States)

    Southard, Sheryl; Kim, Ju-Ryoung; Low, SiewHui; Tsika, Richard W; Lepper, Christoph

    2016-01-01

    When unperturbed, somatic stem cells are poised to affect immediate tissue restoration upon trauma. Yet, little is known regarding the mechanistic basis controlling initial and homeostatic ‘scaling’ of stem cell pool sizes relative to their target tissues for effective regeneration. Here, we show that TEAD1-expressing skeletal muscle of transgenic mice features a dramatic hyperplasia of muscle stem cells (i.e. satellite cells, SCs) but surprisingly without affecting muscle tissue size. Super-numeral SCs attain a ‘normal’ quiescent state, accelerate regeneration, and maintain regenerative capacity over several injury-induced regeneration bouts. In dystrophic muscle, the TEAD1 transgene also ameliorated the pathology. We further demonstrate that hyperplastic SCs accumulate non-cell-autonomously via signal(s) from the TEAD1-expressing myofiber, suggesting that myofiber-specific TEAD1 overexpression activates a physiological signaling pathway(s) that determines initial and homeostatic SC pool size. We propose that TEAD1 and its downstream effectors are medically relevant targets for enhancing muscle regeneration and ameliorating muscle pathology. DOI: http://dx.doi.org/10.7554/eLife.15461.001 PMID:27725085

  12. In vivo anisotropic mechanical properties of dystrophic skeletal muscles measured by anisotropic MR elastographic imaging: the mdx mouse model of muscular dystrophy.

    Science.gov (United States)

    Qin, Eric C; Jugé, Lauriane; Lambert, Simon A; Paradis, Valérie; Sinkus, Ralph; Bilston, Lynne E

    2014-12-01

    To evaluate the utility of mechanical anisotropy (shear storage modulus parallel to fiber/shear storage modulus perpendicular to fiber) measured by combined magnetic resonance (MR) elastography and diffusion-tensor imaging ( DTI diffusion-tensor imaging ) technique (anisotropic MR elastography) to distinguish between healthy and necrotic muscle with different degrees of muscle necrosis in the mdx mouse model of muscular dystrophy. The experimental protocol was approved by the regional animal ethics committee. Twenty-one mdx and 21 wild-type ( WT wild type ) mice were used in our study. Animals were divided into exercised and sedentary groups. Anisotropic MR elastography was used to obtain mechanical anisotropic shear moduli for the lateral gastrocnemius and plantaris muscles in a 7-T MR imager, from which the mechanical anisotropic ratio was calculated. The animals were imaged before and after 10 weeks of a horizontal treadmill running protocol. Spearman rank correlations were used to compare MR elastographic data with muscle necrotic area percentage from histologic analysis. Mechanical anisotropy in WT wild type and mdx mice muscle were compared by using t test and one-way analysis of variance, and receiver operating characteristic curves were constructed by using statistical software. Anisotropic MR elastography was able to be used to distinguish between the muscles of mdx and WT wild type mice, with an area under the receiver operating characteristic curve of 0.8. Strong negative correlation (rs = -0.701; P mechanical anisotropic ratio and the percentage of muscle necrotic area was found. By comparing mice with no or mild (0%-5% mean necrotic area) and severe (>5% mean necrotic area) muscle necrosis, an area under the receiver operating characteristic curve of 0.964 was achieved. Diffusion parameters alone were unable to distinguish between the WT wild type and mdx mice at any time point. The mechanical anisotropic ratio of the shear storage moduli measured by

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

    Science.gov (United States)

    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

    2009-03-01

    The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:beta1,4-N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcbeta1,4[NeuAc(orGc)alpha2, 3]Galbeta1,4GlcNAcbeta-}. 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 to how Galgt2 may inhibit the development of muscle pathology in mdx animals. Both Galgt2 transgenic wild-type and mdx skeletal muscles showed a marked improvement in normalized isometric force during repetitive eccentric contractions relative to nontransgenic littermates, even using a paradigm where nontransgenic muscles had force reductions of 95% or more. Muscles from Galgt2 transgenic mice, however, showed a significant decrement in normalized specific force and in hindlimb and forelimb grip strength at some ages. Overexpression of Galgt2 in muscles of young adult mdx mice, where Galgt2 has no effect on muscle size, also caused a significant decrease in force drop during eccentric contractions and increased normalized specific force. A comparison of Galgt2 and microdystrophin overexpression using a therapeutically relevant intravascular gene delivery protocol showed Galgt2 was as effective as microdystrophin at preventing loss of force during eccentric contractions. These experiments provide a mechanism to explain why Galgt2 overexpression inhibits muscular dystrophy in mdx muscles. That overexpression also prevents loss of force in nondystrophic muscles suggests that Galgt2 is a therapeutic target with broad potential applications.

  14. Role of dystrophin in airway smooth muscle phenotype, contraction and lung function.

    Directory of Open Access Journals (Sweden)

    Pawan Sharma

    Full Text Available Dystrophin links the transmembrane dystrophin-glycoprotein complex to the actin cytoskeleton. We have shown that dystrophin-glycoprotein complex subunits are markers for airway smooth muscle phenotype maturation and together with caveolin-1, play an important role in calcium homeostasis. We tested if dystrophin affects phenotype maturation, tracheal contraction and lung physiology. We used dystrophin deficient Golden Retriever dogs (GRMD and mdx mice vs healthy control animals in our approach. We found significant reduction of contractile protein markers: smooth muscle myosin heavy chain (smMHC and calponin and reduced Ca2+ response to contractile agonist in dystrophin deficient cells. Immunocytochemistry revealed reduced stress fibers and number of smMHC positive cells in dystrophin-deficient cells, when compared to control. Immunoblot analysis of Akt1, GSK3β and mTOR phosphorylation further revealed that downstream PI3K signaling, which is essential for phenotype maturation, was suppressed in dystrophin deficient cell cultures. Tracheal rings from mdx mice showed significant reduction in the isometric contraction to methacholine (MCh when compared to genetic control BL10ScSnJ mice (wild-type. In vivo lung function studies using a small animal ventilator revealed a significant reduction in peak airway resistance induced by maximum concentrations of inhaled MCh in mdx mice, while there was no change in other lung function parameters. These data show that the lack of dystrophin is associated with a concomitant suppression of ASM cell phenotype maturation in vitro, ASM contraction ex vivo and lung function in vivo, indicating that a linkage between the DGC and the actin cytoskeleton via dystrophin is a determinant of the phenotype and functional properties of ASM.

  15. Heart Disease

    Science.gov (United States)

    ... daily aspirin to prevent heart attack? Does taking birth control pills increase my risk for heart disease? Does using ... tells you to. Return to top Does taking birth control pills increase my risk for heart disease? Taking birth ...

  16. Identification of muscle necrosis in the mdx mouse model of Duchenne muscular dystrophy using three-dimensional optical coherence tomography

    Science.gov (United States)

    Klyen, Blake R.; Shavlakadze, Thea; Radley-Crabb, Hannah G.; Grounds, Miranda D.; Sampson, David D.

    2011-07-01

    Three-dimensional optical coherence tomography (3D-OCT) was used to image the structure and pathology of skeletal muscle tissue from the treadmill-exercised mdx mouse model of human Duchenne muscular dystrophy. Optical coherence tomography (OCT) images of excised muscle samples were compared with co-registered hematoxylin and eosin-stained and Evans blue dye fluorescence histology. We show, for the first time, structural 3D-OCT images of skeletal muscle dystropathology well correlated with co-located histology. OCT could identify morphological features of interest and necrotic lesions within the muscle tissue samples based on intrinsic optical contrast. These findings demonstrate the utility of 3D-OCT for the evaluation of small-animal skeletal muscle morphology and pathology, particularly for studies of mouse models of muscular dystrophy.

  17. Adipose-derived stem cells enhance myogenic differentiation in the mdx mouse model of muscular dystrophy via paracrine signaling

    Directory of Open Access Journals (Sweden)

    Ji-qing Cao

    2016-01-01

    Full Text Available Adipose-derived stem cells have been shown to promote peripheral nerve regeneration through the paracrine secretion of neurotrophic factors. However, it is unclear whether these cells can promote myogenic differentiation in muscular dystrophy. Adipose-derived stem cells (6 × 10 6 were injected into the gastrocnemius muscle of mdx mice at various sites. Dystrophin expression was found in the muscle fibers. Phosphorylation levels of Akt, mammalian target of rapamycin (mTOR, eIF-4E binding protein 1 and S6 kinase 1 were increased, and the Akt/mTOR pathway was activated. Simultaneously, myogenin levels were increased, whereas cleaved caspase 3 and vimentin levels were decreased. Necrosis and fibrosis were reduced in the muscle fibers. These findings suggest that adipose-derived stem cells promote the regeneration and survival of muscle cells by inhibiting apoptosis and fibrosis, thereby alleviating muscle damage in muscular dystrophy.

  18. Adipose-derived stem cells enhance myogenic differentiation in the mdx mouse model of muscular dystrophyvia paracrine signaling

    Institute of Scientific and Technical Information of China (English)

    Ji-qing Cao; Jie Kong; Cheng Zhang; Ying-yin Liang; Ya-qin Li; Hui-li Zhang; Yu-ling Zhu; Jia Geng; Li-qing Yang; Shan-wei Feng; Juan Yang

    2016-01-01

    Adipose-derived stem cells have been shown to promote peripheral nerve regeneration through the paracrine secretion of neurotrophic factors. However, it is unclear whether these cells can promote myogenic differentiation in muscular dystrophy. Adipose-derived stem cells (6 × 106) were injected into the gastrocnemius muscle of mdx mice at various sites. Dystrophin expression was found in the muscle ifbers. Phosphorylation levels of Akt, mammalian target of rapamycin (mTOR), eIF-4E binding protein 1 and S6 kinase 1 were increased, and the Akt/mTOR pathway was activated. Simultaneously, myogenin levels were increased, whereas cleaved caspase 3 and vimentin levels were decreased. Necrosis and ifbrosis were reduced in the muscle ifbers. hTese ifndings suggest that adipose-derived stem cells promote the re-generation and survival of muscle cells by inhibiting apoptosis and ifbrosis, thereby alleviating muscle damage in muscular dystrophy.

  19. DESREGULACION DE LA ACTIVIDAD DEL FACTOR DE TRANSCRIPCION NF-KB MEDIADA POR CALCIO EN CELULAS MUSCULARES DISTROFICAS MDX

    OpenAIRE

    ALTAMIRANO FULLA, FRANCISCO JAVIER; ALTAMIRANO FULLA; FRANCISCO JAVIER

    2012-01-01

    La Distrofia Muscular de Duchenne (DMD) es una enfermedad genética recesiva,ligada al cromosoma X, que afecta a 1 de cada 3500 hombres nacidos. La causa de esta enfermedad es la mutación del gen de la distrofina en humanos y en ratones mdx (modelo animal de DMD). La DMD es una enfermedad progresiva que se caracteriza por daños en la membrana de las fibras musculares, infiltración de células inmunes en el músculo,inflamación crónica, daño de sarcómeros, muerte celular y degeneración severa del...

  20. In vitro mouse model in Duchenne muscular dystrophy diagnosis using 50-MHz ultrasound waves.

    Science.gov (United States)

    Laux, D; Blasco, H; Ferrandis, J Y; Hugon, G; Despaux, G; Leydier, A; Mornet, D

    2010-08-01

    Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, the protein that plays a key mechanical role in maintaining muscle membrane integrity. One of the major consequences of dystrophin deficiency is the degeneration of muscle fibres, with a progressive loss in muscle strength. The objective of this research was to find an ultrasonic parameter sensitive to DMD, which could give relevant information related to microstructure if compared to traditional investigations such as morphometrical analysis. This "in vitro" study focused on the Mdx mouse model and investigated the potential differences between wild-type and dystrophin-deficient mice diaphragms. Using a 50MHz ultrasonic sensor built in our group, we recorded an increase in ultrasonic wave attenuation in the dystrophin-deficient samples in comparison with normal muscles. A correlation between attenuation, mouse age and the percentage of non-muscular proportion in muscle was observed. As Mdx mouse is the best animal model for DMD and reproduces the degenerative pattern observed in human DMD muscles, this approach could be a powerful tool for in vitro DMD investigation and, more generally, for the characterisation of muscle properties. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  1. Altered ROS production, NF-κB activation and Interleukin-6 gene expression induced by electrical stimulation of in dystrophic mdx skeletal muscle cells

    Science.gov (United States)

    Henríquez-Olguín, Carlos; Altamirano, Francisco; Valladares, Denisse; López, José R.; Allen, Paul D.; Jaimovich, Enrique

    2015-01-01

    Duchenne Muscular Dystrophy (DMD) is a fatal X-linked genetic disease, caused by mutations in the dystrophin gene, which cause functional loss of this protein. DMD pathology is associated with an increased production of reactive oxygen and nitrogen species (ROS and RNS). The aim of this work was to study the alterations in NF-κB activation and Interleukin-6 (IL-6) expression induced by membrane depolarization in dystrophic mdx myotubes. Membrane depolarization elicited by electrical stimulation (ES) increased p65 phosphorylation, NF-κB transcriptional activity and NF-κB-dependent IL-6 expression in wt myotubes, whereas in mdx myotubes it had the opposite effect. We have previously shown that depolarization-induced intracellular Ca2+ increases and ROS production are necessary for NF-κB activation and stimulation of gene expression in wt myotubes. Dystrophic myotubes showed a reduced amplitude and area under the curve of the Ca2+ transient elicited by ES. On the other hand, ES induced higher ROS production in mdx than wt myotubes, which were blocked by NOX2 inhibitors. Moreover, mRNA expression and protein levels of the NADPH oxidase subunits; p47phox and gp91phox were increased in mdx myotubes. Looking at ROS-dependence of NF-κB activation we found that in wt myotubes external administration of 50µM H2O2 increased NF-κB activity; after administration of 100 and 200 µM H2O2 there was no effect. In mdx myotubes there was a dose-dependent reduction in NF-κB activity in response to external administration of H2O2, with a significant effect of 100 µM and 200 µM, suggesting that ROS levels are critical for NF-κB activity. Prior blockage with NOX2 inhibitors blunted the effects of ES in both NF-κB activation and IL-6 expression. Finally, to ascertain whether stimulation of NF-κB and IL-6 gene expression by the inflammatory pathway is also impaired in mdx myotubes, we studied the effect of lipopolysaccharide (LPS) on both NF-κB activation and IL-6 expression

  2. Characterization of 65 epitope-specific dystrophin monoclonal antibodies in canine and murine models of duchenne muscular dystrophy by immunostaining and western blot.

    Science.gov (United States)

    Kodippili, Kasun; Vince, Lauren; Shin, Jin-Hong; Yue, Yongping; Morris, Glenn E; McIntosh, Mark A; Duan, Dongsheng

    2014-01-01

    Epitope-specific monoclonal antibodies can provide unique insights for studying cellular proteins. Dystrophin is one of the largest cytoskeleton proteins encoded by 79 exons. The absence of dystrophin results in Duchenne muscular dystrophy (DMD). Over the last two decades, dozens of exon-specific human dystrophin monoclonal antibodies have been developed and successfully used for DMD diagnosis. Unfortunately, the majority of these antibodies have not been thoroughly characterized in dystrophin-deficient dogs, an outstanding large animal model for translational research. To fill the gap, we performed a comprehensive study on 65 dystrophin monoclonal antibodies in normal and dystrophic dogs (heart and skeletal muscle) by immunofluorescence staining and western blot. For comparison, we also included striated muscles from normal BL10 and dystrophin-null mdx mice. Our analysis revealed distinctive species, tissue and assay-dependent recognition patterns of different antibodies. Importantly, we identified 15 antibodies that can consistently detect full-length canine dystrophin in both immunostaining and western blot. Our results will serve as an important reference for studying DMD in the canine model.

  3. Heart Transplantation

    Science.gov (United States)

    A heart transplant removes a damaged or diseased heart and replaces it with a healthy one. The healthy heart comes from a donor who has died. It is the last resort for people with heart failure when all other treatments have failed. The ...

  4. Heart Diseases

    Science.gov (United States)

    ... you're like most people, you think that heart disease is a problem for others. But heart disease is the number one killer in the U.S. ... of disability. There are many different forms of heart disease. The most common cause of heart disease is ...

  5. The physiological effects of IGF-1 (class 1:Ea transgene) over-expression on exercise-induced damage and adaptation in dystrophic muscles of mdx mice.

    Science.gov (United States)

    Ridgley, James A; Pinniger, Gavin J; Hamer, Peter W; Grounds, Miranda D

    2009-03-01

    Duchenne muscular dystrophy (DMD) is a genetic disorder in which muscle weakness and fragility contribute to ongoing muscle degeneration. Although exercise-induced muscle damage is associated with adaptation that protects normal muscle from further damage, exploiting this process to protect dystrophic muscle has been avoided for fear of inducing excessive muscle degeneration. However, muscle-specific over-expression of the class 1:Ea isoform of insulin-like growth factor-1 (IGF-1) reduces myofibre necrosis in dystrophic mdx mice (a model for DMD) and, therefore, may enhance the adaptation process in response to eccentric exercise. To test this hypothesis, we evaluated the effect of transgenic class 1:Ea IGF-1 over-expression on the susceptibility to muscle damage and subsequent adaptation in 12-week-old dystrophic mdx and non-dystrophic control mice. Experiments were conducted in vivo using a custom-built isokinetic mouse dynamometer to measure the deficit in joint torque (indicating muscle damage) after 20 maximal lengthening (eccentric) contractions. Adaptation to this damaging exercise was evaluated by repeating the protocol 7 days after the initial exercise. The over-expression of IGF-1 significantly increased the normalised joint torque in non-dystrophic mice and appeared to ameliorate the muscle weakness in dystrophic mice. All mice displayed a marked reduction in the susceptibility to muscle damage on day 7; however, this adaptation was unaffected by IGF-1, showing that IGF-1 does not protect the dystrophic muscles of adult mdx mice against damage resulting from maximal lengthening contractions.

  6. 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

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

    Science.gov (United States)

    Mijares, Alfredo; Altamirano, Francisco; Kolster, Juan; Adams, José A.; López, José R.

    2014-01-01

    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. PMID:25242522

  8. Heart Failure

    Science.gov (United States)

    ... heart failure due to systolic dysfunction. http://www.uptodate.com/home. Accessed Sept. 26, 2014. Colucci WS. ... patient with heart failure or cardiomyopathy. http://www.uptodate.com/home. Accessed Sept. 26, 2014. Colucci WS. ...

  9. Heart palpitations

    Science.gov (United States)

    ... Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 10th ... Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of ...

  10. Heart pacemaker

    Science.gov (United States)

    ... Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 10th ... Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of ...

  11. Heart Attack

    Science.gov (United States)

    ... a million people in the U.S. have a heart attack. About half of them die. Many people have permanent heart damage or die because they don't get ... It's important to know the symptoms of a heart attack and call 9-1-1 if someone ...

  12. Polyquaternium-mediated delivery of morpholino oligonucleotides for exon-skipping in vitro and in mdx mice.

    Science.gov (United States)

    Wang, Mingxing; Wu, Bo; Shah, Sapana N; Lu, Peijuan; Lu, Qilong

    2017-11-01

    Antisense oligonucleotide therapy for Duchenne muscular dystrophy has shown great potential in preclinical and clinical trials, but its therapeutic applications are still limited due to inefficient delivery. In this study, we investigated a few polyquaterniums (PQs) with different size and composition for their potential to improve delivery performance of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that Luviquat(TM) series, especially PQ-1 and PQ-3, promoted the exon-skipping efficiency comparable to Endoporter-mediated PMO delivery in vitro. Significant enhancement in skipping dystrophin exon 23 has also been achieved with PQ-3 up to seven-fold when compared to PMO alone in mdx mice. Cytotoxicity of the PQs was lower than Endoporter and PEI 25 K in vitro and muscle damage not clearly detected in vivo under the tested concentrations. These results together demonstrate that the optimization of PQ in molecular size, composition and distribution of positive charges is the key factor to achieve enhanced PMO exon-skipping efficiency. The higher efficiency and lower toxicity endow polyquaternium series as AO delivery enhancing agents for treating muscular dystrophy and other diseases.

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

    Science.gov (United States)

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

    2015-01-01

    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.

  14. 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.

  15. Correlated NOS-Imu and myf5 expression by satellite cells in mdx mouse muscle regeneration during NOS manipulation and deflazacort treatment.

    Science.gov (United States)

    Anderson, Judy E; Vargas, Cinthya

    2003-06-01

    Satellite cells, muscle precursor cells in skeletal muscle, are normally quiescent and become activated by disease or injury. A lack of dystrophin and changes in the expression or activity of neuronal nitric oxide synthase (NOS-I) affect the timing of activation in vivo. Nitric oxide synthase inhibition delays muscle repair in normal mice, and worsens muscular dystrophy in the mdx mouse, a genetic homologue of Duchenne muscular dystrophy. However, the potential role of activation and repair events mediated by nitric oxide in determining the outcome of steroid or other treatments for muscular dystrophy is not clear. We tested the hypothesis that the extent of repair in dystrophic muscles of mdx mice is partly dependent on NOS-Imu expression and activity. Myotube formation in regenerating muscle was promoted by deflazacort treatment of mdx dystrophic mice (PImu mRNA expression and activity were present in satellite cells and very new myotubes of regenerating and dystrophic muscle. Deflazacort treatment resulted in increased NOS-Imu expression in regenerating muscles in a strong and specific correlation with myf5 expression (r=0.95, PImu and myf5 expression in the diaphragm without affecting the diameter of non-regenerating fibres. These in vivo studies suggest that gains in NOS-Imu expression and nitric oxide synthase activity in satellite cells can increase the extent and speed of repair, even in the absence of dystrophin in muscle fibres. NOS-Imu may be a useful therapeutic target to augment the effects of steroidal or other treatments of muscular dystrophy.

  16. Comparative study of inorganic elements determined in whole blood from Dmd(mdx)/J mice strain by EDXRF and NAA analytical techniques.

    Science.gov (United States)

    Redígolo, M M; Sato, I M; Metairon, S; Zamboni, C B

    2016-04-01

    Several diseases can be diagnosed observing the variation of specific elements concentration in body fluids. In this study the concentration of inorganic elements in blood samples of dystrophic (Dmd(mdx)/J) and C57BL/6J (control group) mice strain were determined. The results obtained from Energy Dispersive X-ray Fluorescence (EDXRF) were compared with Neutron Activation Analysis (NAA) technique. Both analytical techniques showed to be appropriate and complementary offering a new contribution for veterinary medicine as well as detailed knowledge of this pathology.

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

    OpenAIRE

    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 f...

  18. Hypoplastic left heart syndrome

    Science.gov (United States)

    HLHS; Congenital heart - hypoplastic left heart; Cyanotic heart disease - hypoplastic left heart ... Hypoplastic left heart is a rare type of congenital heart disease. It is more common in males than in ...

  19. Heart transplantation

    OpenAIRE

    Cheng, Allen; Slaughter, Mark S.

    2014-01-01

    Heart failure remains a major global problem with approximately 6 million individuals suffering from heart failure in the United States alone. The surgical technique of heart transplantation, popularized by Dr. Norman Shumway, has led to its success and currently remains the best treatment options for patients with end-stage. However, with the continued limitation of donor organs and the rapid development of ventricular assist device technology, the number of patients bridged to transplant wi...

  20. Heart attack

    Science.gov (United States)

    ... Saunders; 2014:chap 51. Read More Arrhythmias Cardiogenic shock Diabetes Hardening of the arteries Heart failure - overview High blood pressure Implantable cardioverter-defibrillator Lipoprotein- ...

  1. Human adipose tissue derived pericytes increase life span in Utrn (tm1Ked) Dmd (mdx) /J mice.

    Science.gov (United States)

    Valadares, M C; Gomes, J P; Castello, G; Assoni, A; Pellati, M; Bueno, C; Corselli, M; Silva, H; Bartolini, P; Vainzof, M; Margarido, P F; Baracat, E; Péault, B; Zatz, M

    2014-12-01

    Duchenne muscular dystrophy (DMD) is still an untreatable lethal X-linked disorder, which affects 1 in 3500 male births. It is caused by the absence of muscle dystrophin due to mutations in the dystrophin gene. The potential regenerative capacity as well as immune privileged properties of mesenchymal Stem Cells (MSC) has been under investigation for many years in an attempt to treat DMD. One of the questions to be addressed is whether stem cells from distinct sources have comparable clinical effects when injected in murine or canine muscular dystrophy animal models. Many studies comparing different stem cells from various sources were reported but these cells were obtained from different donors and thus with different genetic backgrounds. Here we investigated whether human pericytes obtained from 4 different tissues (muscle, adipose tissue, fallopian tube and endometrium) from the same donor have a similar clinical impact when injected in double mutant Utrn (tm1Ked) Dmd (mdx) /J mice, a clinically relevant model for DMD. After a weekly regimen of intraperitoneal injections of 10(6) cells per 8 weeks we evaluated the motor ability as well as the life span of the treated mice as compared to controls. Our experiment showed that only adipose tissue derived pericytes are able to increase significantly (39 days on average) the life span of affected mice. Microarray analysis showed an inhibition of the interferon pathway by adipose derived pericytes. Our results suggest that the clinical benefit associated with intraperitoneal injections of these adult stem cells is related to immune modulation rather than tissue regeneration.

  2. Heart transplant

    Science.gov (United States)

    ... factors include the type and severity of your heart disease, and how sick you are at the time you are listed. The amount of time you spend on a waiting list is usually NOT a factor for how soon you get a heart, except in the case of children. Most, but ...

  3. Heart failure

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    970284 Effects of enalapril on heart rate variabilityin patients with congestive heart failure. ZHANGYouhua(章友华), et a1. Dept Cardiol, Cardiovasc Instit& Fuwai Hosp, CAMS & PUMC, Beijing, 100037. ChinCir J 1996; 11(2): 729-732.

  4. Heart Anatomy

    Science.gov (United States)

    ... from the left ventricle into the aorta, your body's largest artery. See also on this site: The Heartbeat The Conduction System (illustration) Electrical impulses from your heart muscle (the myocardium) cause your heart to contract. This electrical signal begins in the sinoatrial (SA) node, located at ...

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

    Directory of Open Access Journals (Sweden)

    Mingxing Wang

    2016-01-01

    Full Text Available A series of poly(esteramines (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.

  6. Gentamicin treatment in exercised mdx mice: Identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle.

    Science.gov (United States)

    De Luca, Annamaria; Nico, Beatrice; Rolland, Jean-François; Cozzoli, Anna; Burdi, Rosa; Mangieri, Domenica; Giannuzzi, Viviana; Liantonio, Antonella; Cippone, Valentina; De Bellis, Michela; Nicchia, Grazia Paola; Camerino, Giulia Maria; Frigeri, Antonio; Svelto, Maria; Camerino, Diana Conte

    2008-11-01

    Aminoglycosides force read through of premature stop codon mutations and introduce new mutation-specific gene-corrective strategies in Duchenne muscular dystrophy. A chronic treatment with gentamicin (32 mg/kg/daily i.p., 8-12 weeks) was performed in exercised mdx mice with the dual aim to clarify the dependence on dystrophin of the functional, biochemical and histological alterations present in dystrophic muscle and to verify the long term efficiency of small molecule gene-corrective strategies in work-loaded dystrophic muscle. The treatment counteracted the exercise-induced impairment of in vivo forelimb strength after 6-8 weeks. We observed an increase in dystrophin expression level in all the fibers, although lower than that observed in normal fibers, and found a concomitant recovery of aquaporin-4 at sarcolemma. A significant reduction in centronucleated fibers, in the area of necrosis and in the percentage of nuclear factor-kB-positive nuclei was observed in gastrocnemious muscle of treated animals. Plasma creatine kinase was reduced by 70%. Ex vivo, gentamicin restored membrane ionic conductance in mdx diaphragm and limb muscle fibers. No effects were observed on the altered calcium homeostasis and sarcolemmal calcium permeability, detected by electrophysiological and microspectrofluorimetric approaches. Thus, the maintenance of a partial level of dystrophin is sufficient to reinforce sarcolemmal stability, reducing leakiness, inflammation and fiber damage, while correction of altered calcium homeostasis needs greater expression of dystrophin or direct interventions on the channels involved.

  7. Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor.

    Science.gov (United States)

    Vidal, Berta; Ardite, Esther; Suelves, Mònica; Ruiz-Bonilla, Vanessa; Janué, Anna; Flick, Matthew J; Degen, Jay L; Serrano, Antonio L; Muñoz-Cánoves, Pura

    2012-05-01

    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 dystrophy progression in mdx mice. These benefits appear to be tied to: (i) a decrease in leukocyte integrin α(M)β(2)-mediated proinflammatory programs, thereby attenuating counterproductive inflammation and muscle degeneration; and (ii) a release of satellite cells from persistent inhibitory signals, thereby promoting regeneration. Remarkably, Fib-gamma(390-396A) (Fibγ(390-396A)) mice expressing a mutant form of fibrinogen with normal clotting function, but lacking the α(M)β(2) binding motif, ameliorated dystrophic pathology. Delivery of a fibrinogen/α(M)β(2) blocking peptide was similarly beneficial. Conversely, intramuscular fibrinogen delivery sufficed to induce inflammation and degeneration in fibrinogen-null mice. Thus, local fibrin(ogen) deposition drives dystrophic muscle inflammation and dysfunction, and disruption of fibrin(ogen)-α(M)β(2) interactions may provide a novel strategy for DMD treatment.

  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. Simple, heart-smart substitutions

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    Coronary artery disease - heart smart substitutions; Atherosclerosis - heart smart substitutions; Cholesterol - heart smart substitutions; Coronary heart disease - heart smart substitutions; Healthy diet - heart ...

  10. Wine and heart health

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    Health and wine; Wine and heart disease; Preventing heart disease - wine; Preventing heart disease - alcohol ... more often just to lower your risk of heart disease. Heavier drinking can harm the heart and ...

  11. How the Heart Works

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  13. Men and Heart Disease

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    ... Pressure Salt Cholesterol Million Hearts® WISEWOMAN Men and Heart Disease Fact Sheet Recommend on Facebook Tweet Share Compartir Source: Interactive Atlas of Heart Disease and Stroke Heart Disease Facts in Men Heart disease is the leading ...

  14. About Heart Failure

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    ... talk about your health and the medicines About Heart Failure Heart failure is a disease where the heart cannot do ... very important for your health. common causes of heart failure are diseases or conditions that damage the heart. ...

  15. What Is Heart Failure?

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    ... page from the NHLBI on Twitter. What Is Heart Failure? Heart failure is a condition in which the heart can' ... force. Some people have both problems. The term "heart failure" doesn't mean that your heart has stopped ...

  16. Heart Disease

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    ... Atherosclerosis is also the most common cause of cardiovascular disease. It can be caused by correctable problems, such as an unhealthy diet, lack of exercise, being overweight and smoking. Causes of heart arrhythmia ...

  17. Heart Attack

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    ... tear in the heart artery (spontaneous coronary artery dissection). Certain factors contribute to the unwanted buildup of ... logo are trademarks of Mayo Foundation for Medical Education and Research. © 1998-2017 Mayo Foundation for Medical ...

  18. Heart failure

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008275 Relationship of calcineure in mRNA level in peripheral blood and cardiac muscle of patients with heart failure.WANG Mengmeng(王萌萌),et al.Dept Cardiol,Shandong Prov Hosp,Shandong Univ,Jinan 250021.Chin Cir J 2008;23(2):113-116.Objective To study the relationship of calcineurin mRNA level between peripheral lymphocytes and cardiac muscles of patients with chronic heart failure.Methods

  19. Heart failure

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008037 Factors associated with efficacy of cardiac resynchronization therapy for patients with congestive heart failure. SHI Haoying(史浩颖), et al. Dept Cardiol, Zhongshan Hosp Fudan Univ, Shanghai 200032. Chin J Cardiol 2007;35(12):1099-1163. Objective The efficacy of cardiac resynchronization therapy (CRT) in patients with congestive heart failure and the potential factors associated with responder or nonresponder were investigated. Methods Fifty

  20. Specific expression of myogenic,adipogenic and osteogenic gene in skeletal muscle of mdx mice%mdx小鼠骨骼肌组织成肌、成脂、成骨基因的特异性表达

    Institute of Scientific and Technical Information of China (English)

    冷雁; 张为西; 周琛; 郑振扬; 张成; 李秋玲

    2011-01-01

    BACKGROUND: Duchenne's muscular dystrophy (DMD) is a fatal recessive X-Iinked form of muscular dystrophy characterized by prog ressive muscular degeneration, and there is no cure for DMD currently. Stem cell transplantation may provide us with a creative perspective. But the myogenic differentiation rate of transplanted cells is quite low in skeletal muscle. OBJECTIVE: The differences of myogenic, adipogenic and osteogenic gene expression levels in skeletal muscle between mdx mice and C57BL/6J mice were compared, with the purpose of investigating the underlying mechanism of pathological changes in skeletal muscle from mdx mice.METHODS : Frozen sections of skeletal muscle from mdx and C57BL/6J mice were prepared, stained with hematoxylin-eosin staining and Vonkossa staining. The morphological changes of the muscles were observed under microscope. Additionally, total RNA of skeletal muscle from mdx and C57BL/6J mice was extracted, reversed, and the expression levels of myogenic,adipogenic and osteogenic characteristic genes were examined by real-time PCR.RESULTS AND CONCLUSION: Necrosis and regeneration were found in skeletal muscles of mdx mice, and mild adipose hyperplasia and fibrous connective tissue hyperplasia were also observed. Moreover, calcium deposition nodules were easily detected by Vonkossa staining. The form of skeletal muscle cells from C57 mice was clear, and the nuclei were located in the cell periphery. Osteogenic and adipogenic gene expressions of skeletal muscle from mdx mice were elevated to a certain degree by real-time PCR (P < 0.05), compared with C57 mice, whereas myogenic gene expression was decreased (P< 0.05). The reason why adipocyte and osteoblast in skeletal muscle of mdx mice overgrew may be due to degeneration and necrosis of skeletal muscle which caused by dystrophin gene deletion, and it differentiates into osteoblasts and adipocytes instead of myoblasts.%背景:干细胞移植是治疗肌营养不良症的有效方法之一,

  1. 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.

  2. Heart failure - tests

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    CHF - tests; Congestive heart failure - tests; Cardiomyopathy - tests; HF - tests ... the best test to: Identify which type of heart failure (systolic versus diastolic, valvular) Monitor your heart failure ...

  3. Problem: Heart Valve Stenosis

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    ... Cholesterol Tools & Resources Congenital Defects Children & Adults About Congenital Heart Defects The Impact of Congenital Heart Defects Understand Your Risk for Congenital Heart Defects Symptoms & ...

  4. Healthy Heart Quizzes

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    ... Cholesterol Tools & Resources Congenital Defects Children & Adults About Congenital Heart Defects The Impact of Congenital Heart Defects Understand Your Risk for Congenital Heart Defects Symptoms & ...

  5. Problem: Heart Valve Regurgitation

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    ... Cholesterol Tools & Resources Congenital Defects Children & Adults About Congenital Heart Defects The Impact of Congenital Heart Defects Understand Your Risk for Congenital Heart Defects Symptoms & ...

  6. Travel and Heart Disease

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    ... Cholesterol Tools & Resources Congenital Defects Children & Adults About Congenital Heart Defects The Impact of Congenital Heart Defects Understand Your Risk for Congenital Heart Defects Symptoms & ...

  7. GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy.

    Science.gov (United States)

    Cozzoli, Anna; Capogrosso, Roberta Francesca; Sblendorio, Valeriana Teresa; Dinardo, Maria Maddalena; Jagerschmidt, Catherine; Namour, Florence; Camerino, Giulia Maria; De Luca, Annamaria

    2013-06-01

    Anabolic drugs may counteract muscle wasting and dysfunction in Duchenne muscular dystrophy (DMD); however, steroids have unwanted side effects. We focused on GLPG0492, a new non-steroidal selective androgen receptor modulator that is currently under development for musculo-skeletal diseases such as sarcopenia and cachexia. GLPG0492 was tested in the exercised mdx mouse model of DMD in a 4-week trial at a single high dose (30 mg/kg, 6 day/week s.c.), and the results were compared with those from the administration of α-methylprednisolone (PDN; 1 mg/kg, i.p.) and nandrolone (NAND, 5 mg/kg, s.c.). This assessment was followed by a 12-week dose-dependence study (0.3-30 mg/kg s.c.). The outcomes were evaluated in vivo and ex vivo on functional, histological and biochemical parameters. Similar to PDN and NAND, GLPG0492 significantly increased mouse strength. In acute exhaustion tests, a surrogate of the 6-min walking test used in DMD patients, GLPG0492 preserved running performance, whereas vehicle- or comparator-treated animals showed a significant increase in fatigue (30-50%). Ex vivo, all drugs resulted in a modest but significant increase of diaphragm force. In parallel, a decrease in the non-muscle area and markers of fibrosis was observed in GLPG0492- and NAND-treated mice. The drugs exerted minor effects on limb muscles; however, electrophysiological biomarkers were ameliorated in extensor digitorum longus muscle. The longer dose-dependence study confirmed the effect on mdx mouse strength and resistance to fatigue and demonstrated the efficacy of lower drug doses on in vivo and ex vivo functional parameters. These results support the interest of further studies of GLPG0492 as a potential treatment for DMD. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Heart Health: The Heart Truth Campaign 2009

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    ... Past Issues Cover Story Heart Health The Heart Truth Campaign 2009 Past Issues / Winter 2009 Table of ... of the celebrities supporting this year's The Heart Truth campaign. Both R&B singer Ashanti (center) and ...

  9. Women's Heart Disease: Heart Attack Symptoms

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    ... this page please turn JavaScript on. Feature: Women's Heart Disease Heart Attack Symptoms Past Issues / Winter 2014 Table ... NHLBI has uncovered some of the causes of heart diseases and conditions, as well as ways to prevent ...

  10. Women's Heart Disease: Heart Disease Risk Factors

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    ... this page please turn JavaScript on. Feature: Women's Heart Disease Heart Disease Risk Factors Past Issues / Winter 2014 Table of ... or habits may raise your risk for coronary heart disease (CHD). These conditions are known as risk factors. ...

  11. Heart failure

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    2009170 Curcumin attenuates left ventricular dysfunction and remodeling in rabbits with chronic heart failure. TANG Yanhong(唐艳红),et al.Dept Cardiol,Renmin Hosp,Wuhan Univ,Wuhan 430060.Chin J Cardiol,2009;37(3):262-267.

  12. Heart failure

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008411 Expression of S100B during heart failure in rats. JIANG Zhenni(蒋珍妮), et al. Dept Cardiol, 2nd Affili Hosp, Zhejiang Univ, Coll Med Hangzhou 310009. Chin J Emerg Med 2008;17(5):475-478. Objective To evaluate the value of S100B gene on cardiovascular remodeling in rats with abdominal aorta coarctation.

  13. Heart attack first aid

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    First aid - heart attack; First aid - cardiopulmonary arrest; First aid - cardiac arrest ... A heart attack occurs when the blood flow that carries oxygen to the heart is blocked. The heart muscle ...

  14. Pediatric heart surgery

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    Heart surgery - pediatric; Heart surgery for children; Acquired heart disease; Heart valve surgery - children ... the type of defect, and the type of surgery that was done. Many children recover completely and lead normal, active lives.

  15. Diabetic Heart Disease

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    ... be coronary heart disease (CHD), heart failure, and diabetic cardiomyopathy. Diabetes by itself puts you at risk for heart disease. Other risk factors include Family history of heart disease Carrying extra ...

  16. Coronary heart disease

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    Heart disease, Coronary heart disease, Coronary artery disease; Arteriosclerotic heart disease; CHD; CAD ... slow down or stop. A risk factor for heart disease is something that increases your chance of getting ...

  17. Heart Diseases and Disorders

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    ... Resources Heart Diseases & Disorders Back to Patient Resources Heart Diseases & Disorders Millions of people experience irregular heartbeats, called ... harmless and happen in healthy people free of heart disease. However, some abnormal heart rhythms can be serious ...

  18. Overview of Heart Tumors

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    ... develop in the sac that surrounds the heart (pericardium). Tumors in the pericardium may squeeze (constrict) the heart, preventing it from ... Heart wall Fibroma Hemangioma Rhabdomyoma Outside surface Lipoma Pericardium (outer sac covering heart) Pericardial cyst Base of ...

  19. Classes of Heart Failure

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    ... Disease Venous Thromboembolism Aortic Aneurysm More Classes of Heart Failure Updated:Sep 28,2016 Doctors usually classify patients' ... Blood Pressure Tracker Find additional helpful resources here Heart Failure • Home • About Heart Failure Introduction Types of Heart ...

  20. Heart valve surgery

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    ... Tricuspid valve stenosis Risks The risks of having cardiac surgery include: Death Heart attack Heart failure Bleeding requiring ... and the A.D.A.M. Editorial team. Heart Surgery Read more Heart Valve Diseases Read more Latest ...

  1. MDX-station

    CERN Document Server

    Chechin, A I

    2000-01-01

    The installation for carrying out the investigations of synchrotron radiation (SR) and of electron beam diagnostics, Mossbauer and XAFS experiments was made. The installation is multipurpose due to its block construction. It consists of two precision double-crystal monochromators (range of rotation -- 360 deg. , precision -- 5'', step -- 0.545''), X-ray goniometer (range of rotation -- 360 deg. , precision -- 18'', step -- 3''), control and registration systems (time resolution 5 ns). It is possible to have fixed-in-space monochromatic SR beam.

  2. Tissue Doppler imaging for detection of radial and longitudinal myocardial dysfunction in a family of cats affected by dystrophin-deficient hypertrophic muscular dystrophy.

    Science.gov (United States)

    Chetboul, Valérie; Blot, Stephane; Sampedrano, Carolina Carlos; Thibaud, Jean-Laurent; Granger, Nicolas; Tissier, Renaud; Bruneval, Patrick; Gaschen, Frederic; Gouni, Vassiliki; Nicolle, Audrey P; Pouchelon, Jean-Louis

    2006-01-01

    Diagnosis of feline hypertrophic cardiomyopathy currently is based on the presence of myocardial hypertrophy detected using conventional echocardiography. The accuracy of tissue Doppler imaging (TDI) for earlier detection of the disease has never been described. The objective of this sudy was to quantify left ventricular free wall (LVFW) velocities in cats with hypertrophic muscular dystrophy (HFMD) during preclinical cardiomyopathy using TDI. The study animals included 22 healthy controls and 7 cats belonging to a family of cats with HFMD (2 affected adult males, 2 heterozygous adult females, one 2.5-month-old affected male kitten, and 2 phenotypically normal female kittens from the same litter). All cats were examined via conventional echocardiography and 2-dimensional color TDI. No LVFW hypertrophy was detected in the 2 carriers or in the affected kitten when using conventional echocardiography and histologic examination, respectively. The LVFW also was normal for 1 affected male and at the upper limit of normal for the 2nd male. Conversely, LVFW dysfunction was detected in all affected and carrier cats with HFMD when using TDI. TDI consistently detects LVFW dysfunction in cats with HFMD despite the absence of myocardial hypertrophy. Therefore, TDI appears more sensitive than conventional echocardiography in detecting regional myocardial abnormalities.

  3. A new technique for the quantitative assessment of 8-oxoguanine in nuclear DNA as a marker of oxidative stress. Application to dystrophin-deficient DMD skeletal muscles.

    Science.gov (United States)

    Nakae, Yoshiko; Stoward, Peter J; Bespalov, Ivan A; Melamede, Robert J; Wallace, Susan S

    2005-09-01

    This is the first report on the development of an immunohistochemical technique, combined with quantitative image analysis, for the assessment of oxidative stress quantitatively in nuclear DNA in situ, and its application to measure DNA damage in Duchenne muscular dystrophic (DMD) muscles. Three sequential staining procedures for cell nuclei, a cell marker, and a product of oxidative DNA damage, 8-oxoguanine (8-oxoG), were performed. First, the nuclei in muscle sections were stained with Neutral Red followed by the capture of their images with an image analysis system used for absorbance measurements. Second, the same sections were then immunostained for laminin in basement membranes as the cell marker. Next, the sections were treated with 2 N HCl to remove the bound Neutral Red and to denature tissue DNA. Third, the sections were immunostained for 8-oxoG in DNA, using diaminobenzidine (DAB) to reveal the antibody complex. This was followed by capture of the images of the immunostained sections as previously. The absorbances at 451.2 nm of bound Neutral Red and DAB polymer oxides, the final product of 8-oxoG immunostaining, were measured in the same myonuclei in the sections. Analysis of these absorbances permitted indices of the 8-oxoG content, independent of the nuclear densities, to be determined in nuclear DNA in single myofibres and myosatellite cells surrounded by basement membranes. We found that the mean index for the myonuclei in biceps brachii muscles of 2- to 7-year-old patients was 14% higher than that in age-matched normal controls. This finding of the increased oxidative stress in the myonuclei in young DMD muscles agrees with the previous reports of increased oxidative stress in the cytoplasm in the DMD myofibres and myosatellite cells. The present technique for the quantitative assessment of oxidative stress in nuclear DNA in situ is applicable not only in biomedical research but also in the development of effective drugs for degenerative diseases related to oxidative stress.

  4. Heart failure

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    2005186 The diagnostic application of bedside measurement of plasma brain natriuretic in patients with heart failure. SHAO Le-wen (邵乐文) , Advanced Ward Dept, 1st Hosp, Med Sch, Zhejiang Univ, Hangzhou 310003. Chin J Intern Med, 2005;44(2): 99-101. Objective: To investigate differential diagnosis value of ultra-rapid bedside measurement of brain na-triuretic peptide (BNP) in patients with dyspnea.

  5. Heart failure

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    2010316 Tissue doppler imaging observation on effect of long-term use of gingko biloba tabtet on left ventricular function in patients with chronic heart failure. ZHANG Hui(张辉),et al. Dept Cardiovasc Med, 2nd Hosp, Hebei Med Univ,Shijiazhuang 050000. Chin J Integr Tradit & West Med 2010;30(5):478-481. Objective To quantitatively observe the effect of long-term

  6. CT-GalNAc transferase overexpression in adult mice is associated with extrasynaptic utrophin in skeletal muscle fibres.

    Science.gov (United States)

    Durko, Margaret; Allen, Carol; Nalbantoglu, Josephine; Karpati, George

    2010-09-01

    Duchenne muscular dystrophy is a genetic muscle disease characterized by the absence of sub-sarcolemmal dystrophin that results in muscle fibre necrosis, progressive muscle wasting and is fatal. Numerous experimental studies with dystrophin-deficient mdx mice, an animal model for the disease, have demonstrated that extrasynaptic upregulation of utrophin, an analogue of dystrophin, can prevent muscle fibre deterioration and reduce or negate the dystrophic phenotype. A different approach for ectopic expression of utrophin relies on augmentation of CT-GalNAc transferase in muscle fibre. We investigated whether CT-GalNAc transferase overexpression in adult mice influence appearance of utrophin in the extrasynaptic sarcolemma. After electrotransfer of plasmid DNA carrying an expression cassette of CT-GalNAc transferase into tibialis anterior muscle of wild type and dystrophic mice, muscle sections were examined by immunofluorescence. CT-GalNAc transgene expression augmented sarcolemmal carbohydrate glycosylation and was accompanied by extrasynaptic utrophin. A 6-week time course study showed that the highest efficiency of utrophin overexpression in a plasmid harboured muscle fibres was 32.2% in CD-1 and 52% in mdx mice, 2 and 4 weeks after CT-GalNAc gene transfer, respectively. The study provides evidence that postnatal CT-GalNAc transferase overexpression stimulates utrophin upregulation that is inherently beneficial for muscle structure and strength restoration. Thus CT-GalNAc may provide an important therapeutic molecule for treatment of dystrophin deficiency in Duchenne muscular dystrophy.

  7. 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

  8. 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.

  9. Types of Heart Failure

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    ... Disease Venous Thromboembolism Aortic Aneurysm More Types of Heart Failure Updated:Feb 9,2017 Left-sided heart failure ... making. This content was last reviewed April 2015. Heart Failure • Home • About Heart Failure Introduction Types of Heart ...

  10. Left heart catheterization

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    Catheterization - left heart ... to help guide the catheters up into your heart and arteries. Dye will be injected into your ... in the blood vessels that lead to your heart. The catheter is then moved through the aortic ...

  11. Heart-Healthy Exercise

    Science.gov (United States)

    ... American Heart Association Cardiology Patient Page Heart-Healthy Exercise Lauren Healey Mellett , Gisele Bousquet Download PDF https:// ... if you already have heart disease. How Can Exercise Help? There are many modifiable risk factors for ...

  12. Heart pacemaker - discharge

    Science.gov (United States)

    ... pacemaker can be used for patients with heart failure. It has three leads to help the heart beat in a more coordinated manner. Some pacemakers also can deliver electric shocks to the heart that can stop life-threatening ...

  13. Honolulu Heart Program

    Science.gov (United States)

    2016-04-13

    Cardiovascular Diseases; Coronary Disease; Cerebrovascular Accident; Heart Diseases; Heart Failure, Congestive; Myocardial Infarction; Asthma; Emphysema; Lung Diseases, Obstructive; Aortic Aneurysm, Abdominal; Bronchitis; Dementia; Hypertension; Chronic Obstructive Pulmonary Disease; Heart Failure

  14. Heart Health Tests

    Science.gov (United States)

    ... is easier to treat. Blood tests and heart health tests can help find heart diseases or identify ... diseases. There are several different types of heart health tests. Your doctor will decide which test or ...

  15. Pediatric heart surgery - discharge

    Science.gov (United States)

    ... discharge; Heart valve surgery - children - discharge; Heart surgery - pediatric - discharge; Heart transplant - pediatric - discharge ... Geme JW, Schor NF, eds. Nelson Textbook of Pediatrics . 20th ed. Philadelphia, PA: Elsevier; 2016:chap 434. ...

  16. Heart and Down Syndrome

    Science.gov (United States)

    ... Associated Conditions » The Heart & Down Syndrome The Heart & Down Syndrome Abnormalities of the cardiovascular system are common in ... the Most Common Heart Defects in Children With Down Syndrome? The most common defects are Atrioventricular Septal Defect ( ...

  17. Congenital heart disease

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/001114.htm Congenital heart disease To use the sharing features on this page, please enable JavaScript. Congenital heart disease (CHD) is a problem with the heart's structure ...

  18. Cyanotic heart disease

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/001104.htm Cyanotic heart disease To use the sharing features on this page, please enable JavaScript. Cyanotic heart disease refers to a group of many different heart ...

  19. Heart Disease Risk Factors

    Science.gov (United States)

    ... Hearts® WISEWOMAN Program Other Chronic Disease Topics Diabetes Nutrition Obesity Physical Activity Stroke Heart Disease Risk Factors Recommend ... Hearts® WISEWOMAN Program Other Chronic Disease Topics Diabetes Nutrition Obesity Physical Activity Stroke File Formats Help: How do ...

  20. Heart disease and depression

    Science.gov (United States)

    ... gov/ency/patientinstructions/000790.htm Heart disease and depression To use the sharing features on this page, ... a heart attack or heart surgery Signs of Depression It is pretty common to feel down or ...

  1. Living with Heart Failure

    Science.gov (United States)

    ... page from the NHLBI on Twitter. Living With Heart Failure Currently, heart failure has no cure. You'll ... avoid harmful side effects. Take Steps To Prevent Heart Failure From Getting Worse Certain actions can worsen your ...

  2. Who Needs Heart Surgery?

    Science.gov (United States)

    ... this page from the NHLBI on Twitter. Who Needs Heart Surgery? Heart surgery is used to treat ... will work with you to decide whether you need heart surgery. A cardiologist specializes in diagnosing and ...

  3. Revealing Hearts

    DEFF Research Database (Denmark)

    Saghaug, Kristin Falck; Pattison, George; Lindgren, Peter

    2014-01-01

    Some small business owners want to balance personal values as well as economic values. “I have to follow my heart” or “it must be meaningful” some of them say. But how might they be able to know what gives meaning to the heart? The philosophical theologian Paul Tillich finds that the problem...... with reference to Tillich’s account of the meaning of revelation through culture and art, summed up in the statement that “(...) revelation is the manifestation of the ground of being for human knowledge” (Tillich, 1951, p.94), which, we argue, can be extended to everyday experiences, for example, in business...... life. In Tillich’s own terms, even preliminary concerns may point at an ultimate concern (Tillich, 1964), which can also be understood as ‘knowledge of the heart’. Our account is also connected to wider discussions concerning the nature of intuition....

  4. Quantitative assessment of muscle damage in the mdx mouse model of Duchenne muscular dystrophy using polarization-sensitive optical coherence tomography.

    Science.gov (United States)

    Yang, Xiaojie; Chin, Lixin; Klyen, Blake R; Shavlakadze, Tea; McLaughlin, Robert A; Grounds, Miranda D; Sampson, David D

    2013-11-01

    Minimally invasive, high-resolution imaging of muscle necrosis has the potential to aid in the assessment of diseases such as Duchenne muscular dystrophy. Undamaged muscle tissue possesses high levels of optical birefringence due to its anisotropic ultrastructure, and this birefringence decreases when the tissue undergoes necrosis. In this study, we present a novel technique to image muscle necrosis using polarization-sensitive optical coherence tomography (PS-OCT). From PS-OCT scans, our technique is able to quantify the birefringence in muscle tissue, generating an image indicative of the tissue ultrastructure, with areas of abnormally low birefringence indicating necrosis. The technique is demonstrated on excised skeletal muscles from exercised dystrophic mdx mice and control C57BL/10ScSn mice with the resulting images validated against colocated histological sections. The technique additionally gives a measure of the proportion (volume fraction) of necrotic tissue within the three-dimensional imaging field of view. The percentage necrosis assessed by this technique is compared against the percentage necrosis obtained from manual assessment of histological sections, and the difference between the two methods is found to be comparable to the interobserver variability of the histological assessment. This is the first published demonstration of PS-OCT to provide automated assessment of muscle necrosis.

  5. Simultaneous Pathoproteomic Evaluation of the Dystrophin-Glycoprotein Complex and Secondary Changes in the mdx-4cv Mouse Model of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Sandra Murphy

    2015-06-01

    Full Text Available In skeletal muscle, the dystrophin-glycoprotein complex forms a membrane-associated assembly of relatively low abundance, making its detailed proteomic characterization in normal versus dystrophic tissues technically challenging. To overcome this analytical problem, we have enriched the muscle membrane fraction by a minimal differential centrifugation step followed by the comprehensive label-free mass spectrometric analysis of microsomal membrane preparations. This organelle proteomic approach successfully identified dystrophin and its binding partners in normal versus dystrophic hind limb muscles. The introduction of a simple pre-fractionation step enabled the simultaneous proteomic comparison of the reduction in the dystrophin-glycoprotein complex and secondary changes in the mdx-4cv mouse model of dystrophinopathy in a single analytical run. The proteomic screening of the microsomal fraction from dystrophic hind limb muscle identified the full-length dystrophin isoform Dp427 as the most drastically reduced protein in dystrophinopathy, demonstrating the remarkable analytical power of comparative muscle proteomics. Secondary pathoproteomic expression patterns were established for 281 proteins, including dystrophin-associated proteins and components involved in metabolism, signalling, contraction, ion-regulation, protein folding, the extracellular matrix and the cytoskeleton. Key findings were verified by immunoblotting. Increased levels of the sarcolemmal Na+/K+-ATPase in dystrophic leg muscles were also confirmed by immunofluorescence microscopy. Thus, the reduction of sample complexity in organelle-focused proteomics can be advantageous for the profiling of supramolecular protein complexes in highly intricate systems, such as skeletal muscle tissue.

  6. Understanding chronic heart failure

    OpenAIRE

    Fenton, Matthew; Burch, Michael

    2007-01-01

    The key principles of chronic heart failure and the development of clinical management strategies are described. The physiological changes in chronic heart failure and the clinical management of children with heart failure are considered, but the treatment of heart failure related to congenital heart disease or the intensive care management of heart failure are not mentioned as both topics require consideration in their own right. A greater understanding of the maladaptive responses to chroni...

  7. Heart failure - home monitoring

    Science.gov (United States)

    ... failure - discharge Heart failure - fluids and diuretics Heart failure - what to ask ... Medical Center, University of Washington Medical School, Seattle, WA. Also reviewed by David Zieve, MD, ...

  8. Take heart!

    CERN Multimedia

    Alizée Dauvergne

    2010-01-01

    Recently, ten new semi-automatic defibrillators were installed at various locations around CERN. This is a preventive measure intended to provide cardiac arrest victims with the best possible response. The first responder could be you!   The Director-General has welcomed the initiative of the Medical Service and Fire Brigade for the installation of ten new semi-automatic defibrillators. You have probably seen them on your way to the restaurant, for example:  brand new semi-automatic defibrillators, ready for an emergency. Housed in a white wall-mounted case, the bright red defibrillators are marked with a white heart symbol crossed by a lightning bolt (see photo). The defibrillator is designed so that anyone can use it. “Anyone can use it, you don’t need to be a health professional,” says Dr Reymond from CERN's Medical Service. Together with the CERN Fire Brigade, he is behind the initiative to have these units put in place. And with good reason, as the unit...

  9. Hypoplastic left heart syndrome (image)

    Science.gov (United States)

    Hypoplastic left heart syndrome is a congenital heart condition that occurs during the development of the heart in the ... womb. During the heart's development, parts of the left side of the heart (mitral valve, left ventricle ...

  10. What Causes Heart Disease?

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Causes Heart Disease? Research suggests that coronary heart disease (CHD) begins with damage to the lining and ... causing coronary microvascular disease (MVD). Coronary MVD is heart disease that affects the heart's tiny arteries. The cause ...

  11. Heart Disease in Women

    Science.gov (United States)

    ... United States, 1 in 4 women dies from heart disease. The most common cause of heart disease in both men and women is narrowing or ... It's the major reason people have heart attacks. Heart diseases that affect women more than men include Coronary ...

  12. Heart rate variability in isolated rabbit hearts.

    Science.gov (United States)

    Frey, B; Heger, G; Mayer, C; Kiegler, B; Stöhr, H; Steurer, G

    1996-11-01

    The presence of heart rate variability (HRV) in patients with cardiac denervation after heart transplantation raised our interest in HRV of isolated, denervated hearts. Hearts from seven adult white ELCO rabbits were transferred to a perfusion apparatus. All hearts were perfused in the working mode and in the Langendorff mode for 20 minutes each. HRV was analyzed in the frequency domain. A computer simulated test ECG at a constant rate of 2 Hz was used for error estimation of the system. In the isolated, denervated heart, HRV was of random, broadband fluctuations, different from the well-characterized oscillations at specific frequencies in intact animals. Mean NN was 423 +/- 51 ms in the Langendorff mode, 406 +/- 33 ms in the working heart mode, and 500 ms in the test ECG. Total power was 663 +/- 207 ms2, 817 +/- 318 ms2, and 3.7 ms2, respectively. There was no significant difference in any measure of HRV between Langendorff and working heart modes. The data provide evidence for the presence of HRV in isolated, denervated rabbit hearts. Left atrial and ventricular filling, i.e., the working heart mode, did not alter HRV, indicating that left atrial or ventricular stretch did not influence the sinus nodal discharge rate.

  13. Cellular trafficking determines the exon skipping activity of Pip6a-PMO in mdx skeletal and cardiac muscle cells.

    Science.gov (United States)

    Lehto, Taavi; Castillo Alvarez, Alejandra; Gauck, Sarah; Gait, Michael J; Coursindel, Thibault; Wood, Matthew J A; Lebleu, Bernard; Boisguerin, Prisca

    2014-03-01

    Cell-penetrating peptide-mediated delivery of phosphorodiamidate morpholino oligomers (PMOs) has shown great promise for exon-skipping therapy of Duchenne Muscular Dystrophy (DMD). Pip6a-PMO, a recently developed conjugate, is particularly efficient in a murine DMD model, although mechanisms responsible for its increased biological activity have not been studied. Here, we evaluate the cellular trafficking and the biological activity of Pip6a-PMO in skeletal muscle cells and primary cardiomyocytes. Our results indicate that Pip6a-PMO is taken up in the skeletal muscle cells by an energy- and caveolae-mediated endocytosis. Interestingly, its cellular distribution is different in undifferentiated and differentiated skeletal muscle cells (vesicular versus nuclear). Likewise, Pip6a-PMO mainly accumulates in cytoplasmic vesicles in primary cardiomyocytes, in which clathrin-mediated endocytosis seems to be the pre-dominant uptake pathway. These differences in cellular trafficking correspond well with the exon-skipping data, with higher activity in myotubes than in myoblasts or cardiomyocytes. These differences in cellular trafficking thus provide a possible mechanistic explanation for the variations in exon-skipping activity and restoration of dystrophin protein in heart muscle compared with skeletal muscle tissues in DMD models. Overall, Pip6a-PMO appears as the most efficient conjugate to date (low nanomolar EC50), even if limitations remain from endosomal escape.

  14. All about Heart Rate (Pulse)

    Science.gov (United States)

    ... Cholesterol Tools & Resources Congenital Defects Children & Adults About Congenital Heart Defects The Impact of Congenital Heart Defects Understand Your Risk for Congenital Heart Defects Symptoms & ...

  15. Smoking Thickens Heart Wall, Leading to Heart Failure: Study

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_160932.html Smoking Thickens Heart Wall, Leading to Heart Failure: Study ... 13, 2016 TUESDAY, Sept. 13, 2016 (HealthDay News) -- Smoking leads to heart failure by causing thickened heart ...

  16. Heart Disease Affects Far More Than the Heart

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_163584.html Heart Disease Affects Far More Than the Heart Blocked arteries ... 14, 2017 TUESDAY, Feb. 14, 2017 (HealthDay News) -- Heart disease affects more than just the heart. It also ...

  17. Texas Heart Institute

    Science.gov (United States)

    ... Cardiovascular Regenerative Medicine today with a keynote from Texas State Senator Paul Bettencourt Dr. Taylor received the ... in cardiovascular discovery is happening here at the Texas Heart Institute. Visit www.thenextfirst.org . Your Heart ...

  18. Heart Diseases--Prevention

    Science.gov (United States)

    ... you have a close family member who had heart disease at an early age. Fortunately, there are many things you can do reduce your chances of getting heart disease. You should Know your blood pressure and keep ...

  19. Heart failure - discharge

    Science.gov (United States)

    ... Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 10th ... Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of ...

  20. Heart and Stroke Encyclopedia

    Science.gov (United States)

    ... Venous Thromboembolism Aortic Aneurysm More The Heart and Stroke Encyclopedia Click a letter below to get a ... dozens of cardiovascular terms from our Heart and Stroke Encyclopedia and get links to in-depth information. ...

  1. Open heart surgery

    Science.gov (United States)

    Heart surgery - open ... lung machine is used in most cases during open heart surgery. While the surgeon works on the ... with these procedures, the surgeon may have to open the chest to do the surgery.

  2. Valvular heart disease

    OpenAIRE

    Gelson, E; Gatzoulis, M; Johnson, M.

    2007-01-01

    Valvular disease may be unmasked in pregnancy when physiological changes increase demands on the heart. Women with valvular heart disease require close follow-up during pregnancy, delivery, and postpartum

  3. Hypothyroidism and Heart Disease

    Science.gov (United States)

    ... in Balance › Hypothyroidism and Heart Disease Fact Sheet Hypothyroidism and Heart Disease January 2014 Download PDFs English ... nervous system, body temperature, and weight. What is hypothyroidism and what are its symptoms? Hypothyroidism, also called ...

  4. Heart disease - risk factors

    Science.gov (United States)

    Heart disease - prevention; CVD - risk factors; Cardiovascular disease - risk factors; Coronary artery disease - risk factors; CAD - risk ... a certain health condition. Some risk factors for heart disease you cannot change, but some you can. ...

  5. Anatomy of the Heart

    Science.gov (United States)

    ... Share this page from the NHLBI on Twitter. Anatomy of the Heart Your heart is located under your ribcage in the center of your chest between your right and left lungs. Its muscular walls beat, or contract, pumping blood ...

  6. Heart Health for Women

    Science.gov (United States)

    ... it Email Print En Español In Chinese - In Korean - In Vietnamese - In French Creole You may think ... Download and Share: Social Media Toolkit (PDF 481KB) Learn More About Heart Disease: The Heart Truth Campaign ...

  7. Heart Attack Payment - Hospital

    Data.gov (United States)

    U.S. Department of Health & Human Services — Payment for heart attack patients measure – provider data. This data set includes provider data for payments associated with a 30-day episode of care for heart...

  8. Inflammation and Heart Disease

    Science.gov (United States)

    ... Disease Venous Thromboembolism Aortic Aneurysm More Inflammation and Heart Disease Updated:Oct 12,2016 Understand the risks of ... inflammation causes cardiovascular disease, inflammation is common for heart disease and stroke patients and is thought to be ...

  9. Meditation and Heart Health

    Science.gov (United States)

    ... Check Meal Certification Program Nutrition Requirements Heart-Check Professional Resources Contact the Heart-Check Certification Program Simple Cooking and Recipes Dining Out Choosing a Restaurant Deciphering the Menu Ordering Your Meal Eating Fast ...

  10. Alcohol and Heart Health

    Science.gov (United States)

    ... Check Meal Certification Program Nutrition Requirements Heart-Check Professional Resources Contact the Heart-Check Certification Program Simple Cooking and Recipes Dining Out Choosing a Restaurant Deciphering the Menu Ordering Your Meal Eating Fast ...

  11. Heart disease and women

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/007188.htm Heart disease and women To use the sharing features on ... please enable JavaScript. People often DO NOT consider heart disease a woman's disease. Yet cardiovascular disease is the ...

  12. Aspirin and heart disease

    Science.gov (United States)

    ... medlineplus.gov/ency/patientinstructions/000092.htm Aspirin and heart disease To use the sharing features on this page, ... healthy people who are at low risk for heart disease. You provider will consider your overall medical condition ...

  13. [Understanding heart failure].

    Science.gov (United States)

    Boo, José Fernando Guadalajara

    2006-01-01

    Heart failure is a disease with several definitions. The term "heart failure" is used by has brougth about confusion in the terminology. For this reason, the value of the ejection fraction (< 0.40 or < 0.35) is used in most meganalyses on the treatment of heart failure, avoiding the term "heart failure" that is a confounding concept. In this paper we carefully analyze the meaning of contractility, ventricular function or performance, preload, afterload, heart failure, compensation mechanisms in heart failure, myocardial oxygen consumption, inadequate, adequate and inappropriate hypertrophy, systole, diastole, compliance, problems of relaxation, and diastolic dysfunction. Their definitions are supported by the original scientific descriptions in an attempt to clarify the concepts about ventricular function and heart failure and, in this way, use the same scientific language about the meaning of ventricular function, heart failure, and diastolic dysfunction.

  14. Pericarditis - after heart attack

    Science.gov (United States)

    ... and swelling of the covering of the heart (pericardium). It can occur in the days or weeks ... Symptoms include: Anxiety Chest pain from the swollen pericardium rubbing on the heart. The pain may be ...

  15. Heart failure - medicines

    Science.gov (United States)

    ... are working and to measure your potassium levels. Beta Blockers Beta blockers slow your heart rate and decrease the strength ... muscle contracts in the short term. Long term beta blockers help keep your heart failure from becoming worse. ...

  16. Know Your Heart's Numbers

    Science.gov (United States)

    ... of body fat based on height and weight), waist circumference, blood sugar and weight. The telephone survey of ... for heart health. Just 36 percent knew that waist circumference is important measure of heart disease risk. The ...

  17. Heart Attack Payment - State

    Data.gov (United States)

    U.S. Department of Health & Human Services — Payment for heart attack patients measure – state data. This data set includes state-level data for payments associated with a 30-day episode of care for heart...

  18. Heart Attack Payment - National

    Data.gov (United States)

    U.S. Department of Health & Human Services — Payment for heart attack patients measure – national data. This data set includes national-level data for payments associated with a 30-day episode of care for heart...

  19. DenHeart

    DEFF Research Database (Denmark)

    Berg, Selina Kikkenborg; Rasmussen, Trine Bernholdt; Thrysøe, Lars

    2017-01-01

    differences were found in all patient reported outcomes across diagnostic groups. Listed from worst to best outcomes were heart failure, heart valve disease, ischemic heart disease, infectious heart disease, arrhythmia, congenital heart disease and heart transplant. Also “observation for cardiac disease...... reported outcomes. Methods A national cross-sectional survey combined with national register data. From April 2013 to April 2014 all patients (n = 34,564) discharged or transferred from one of five Danish Heart Centres were invited to participate. 16,712 patients (51%) responded; 67% male and mean age 64...... years. All diagnostic groups were represented similar to real life proportions. Patient reported outcome measures included: SF-12, Hospital Anxiety and Depression Scale, EQ-5D, Brief Illness Perception Questionnaire, HeartQoL and Edmonton Symptom Assessment Scale. Results Statistically significant...

  20. Right heart ventriculography

    Science.gov (United States)

    Angiography - right heart ... The catheter will be moved forward into the right side of the heart. As the catheter is advanced, the doctor can record pressures from the right atrium and right ventricle. Contrast material ("dye") is ...

  1. Menopause and Heart Disease

    Science.gov (United States)

    ... Peripheral Artery Disease Venous Thromboembolism Aortic Aneurysm More Menopause and Heart Disease Updated:Jun 23,2017 Heart ... can become more evident after the onset of menopause. Menopause does not cause cardiovascular diseases . However, certain ...

  2. Heart-lung transplantation

    OpenAIRE

    Griffith, Bartley P.; Magliato, Kathy E.

    2014-01-01

    Heart-lung transplantation itself is not a particularly difficult operation technically. It is the setting in which this procedure is performed which is difficult. The three issues of importance in a successful outcome are appropriate harvest of the heart-lung bloc from the donor, careful explant of the heart and lungs of the recipient, and finally the implant of the heart-lung bloc into the recipient. None of this requires extraordinary technical skill, but does require careful coordination ...

  3. Heart Valve Diseases

    Science.gov (United States)

    Your heart has four valves. Normally, these valves open to let blood flow through or out of your heart, and then shut to keep it from flowing ... close tightly. It's one of the most common heart valve conditions. Sometimes it causes regurgitation. Stenosis - when ...

  4. Heart failure overview

    Science.gov (United States)

    ... symptoms) You feel a severe crushing chest pain Prevention Most cases of heart failure can be prevented by living a healthy lifestyle and taking steps aimed at reducing your risk for heart disease . . Alternative Names CHF; Congestive heart failure; Left-sided ...

  5. The Danish Heart Registry

    DEFF Research Database (Denmark)

    Özcan, Cengiz; Juel, Knud; Lassen, Jens Flensted

    2016-01-01

    AIM: The Danish Heart Registry (DHR) seeks to monitor nationwide activity and quality of invasive diagnostic and treatment strategies in patients with ischemic heart disease as well as valvular heart disease and to provide data for research. STUDY POPULATION: All adult (≥15 years) patients...

  6. Heart valve surgery - discharge

    Science.gov (United States)

    ... ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College ... Editorial team. Related MedlinePlus Health Topics Heart Surgery Heart Valve Diseases Browse the Encyclopedia A.D.A.M., Inc. ...

  7. The Heart of Coaching

    Science.gov (United States)

    Docheff, Dennis M.; Gerdes, Dan

    2015-01-01

    This article challenges coaches to address the more personal, human elements of coaching--the HEART of coaching. While there is much research on numerous aspects of coaching, this article provides ideas that make a lasting impact on the hearts of athletes. Using HEART as an acronym, five elements of effective coaching are presented: Humility,…

  8. Heart Truth for Latinas

    Science.gov (United States)

    ... That’s a man’s disease.” But here’s The Heart Truth : Heart disease is the #1 killer of Latinas ... TAKING ACTION Now that you know The Heart Truth , what should you do? First, find out your ...

  9. The Heart of Coaching

    Science.gov (United States)

    Docheff, Dennis M.; Gerdes, Dan

    2015-01-01

    This article challenges coaches to address the more personal, human elements of coaching--the HEART of coaching. While there is much research on numerous aspects of coaching, this article provides ideas that make a lasting impact on the hearts of athletes. Using HEART as an acronym, five elements of effective coaching are presented: Humility,…

  10. Living with Heart Disease

    Science.gov (United States)

    ... page from the NHLBI on Twitter. Living With Heart Disease If you have coronary heart disease (CHD), you can take steps to control its ... the section of this article titled "How Is Heart Disease Treated?" You also can visit the Health Topics ...

  11. Women and Heart Disease

    Institute of Scientific and Technical Information of China (English)

    邹国如

    2005-01-01

    Heart disease is the leading killer of Americans. But it kills more women than men. The American Heart Association says heart disease and other cardiovascular (心血管的) disorders kill about five hundred thousand women a year. That is more than the next seven causes of death combined.

  12. Implantable Heart Aid

    Science.gov (United States)

    1984-01-01

    CPI's human-implantable automatic implantable defibrillator (AID) is a heart assist system, derived from NASA's space circuitry technology, that can prevent erratic heart action known as arrhythmias. Implanted AID, consisting of microcomputer power source and two electrodes for sensing heart activity, recognizes onset of ventricular fibrillation (VF) and delivers corrective electrical countershock to restore rhythmic heartbeat.

  13. Tachycardia | Fast Heart Rate

    Science.gov (United States)

    ... SA) node --- the heart's natural pacemaker - sends out electrical signals faster than usual. The heart rate is fast, but the heart beats properly. Causes of sinus tachycardia A rapid heartbeat may be your body's response to common conditions such as: Fever Anxiety ...

  14. Congenital Heart Disease in Adults

    Science.gov (United States)

    ... and genetics may play a role. Why congenital heart disease resurfaces in adulthood Some adults may find that ... in following adults with congenital heart disease. Congenital heart disease and pregnancy Women with congenital heart disease who ...

  15. Managing Feelings about Heart Failure

    Science.gov (United States)

    ... About Heart Failure Module 6: Managing Feelings About Heart Failure Download Module Order Hardcopy Heart failure can cause ... professional help for emotional problems. Common Feelings About Heart Failure It is common for people to feel depressed ...

  16. Illegal Drugs and Heart Disease

    Science.gov (United States)

    ... Venous Thromboembolism Aortic Aneurysm More Illegal Drugs and Heart Disease Updated:May 17,2017 Most illegal drugs can ... www.dea.gov/druginfo/factsheets.shtml Alcohol and Heart Disease Caffeine and Heart Disease Tobacco and Heart Disease ...

  17. What Are Congenital Heart Defects?

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Are Congenital Heart Defects? Congenital (kon-JEN-ih-tal) heart defects are problems ... carry blood to the heart or the body Congenital heart defects change the normal flow of blood through the ...

  18. Dystrophin/α1-syntrophin scaffold regulated PLC/PKC-dependent store-operated calcium entry in myotubes.

    Science.gov (United States)

    Sabourin, Jessica; Harisseh, Rania; Harnois, Thomas; Magaud, Christophe; Bourmeyster, Nicolas; Déliot, Nadine; Constantin, Bruno

    2012-12-01

    In skeletal muscles from patient suffering of Duchenne Muscular Dystrophy and from mdx mice, the absence of the cytoskeleton protein dystrophin has been shown to be essential for maintaining a normal calcium influx. We showed that a TRPC store-dependent cation influx is increased by loss of dystrophin or a scaffolding protein α1-syntrophin, however the mechanisms of this calcium mishandling are incompletely understood. First of all, we confirmed that TRPC1 but also STIM1 and Orai1 are supporting the store-operated cation entry which is enhanced in dystrophin-deficient myotubes. Next, we demonstrated that inhibition of PLC or PKC in dystrophin-deficient myotubes restores elevated cation entry to normal levels similarly to enforced minidystrophin expression. In addition, silencing α1-syntrophin also increased cation influx in a PLC/PKC dependent pathway. We also showed that α1-syntrophin and PLCβ are part of a same protein complex reinforcing the idea of their inter-relation in calcium influx regulation. This elevated cation entry was decreased to normal levels by chelating intracellular free calcium with BAPTA-AM. Double treatments with BAPTA-AM and PLC or PKC inhibitors suggested that the elevation of cation influx by PLC/PKC pathway is dependent on cytosolic calcium. All these results demonstrate an involvement in dystrophin-deficient myotubes of a specific calcium/PKC/PLC pathway in elevation of store-operated cation influx supported by the STIM1/Orai1/TRPC1 proteins, which is normally regulated by the α1-syntrophin/dystrophin scaffold.

  19. Direct observation of failing fibers in muscles of dystrophic mice provides mechanistic insight into muscular dystrophy.

    Science.gov (United States)

    Claflin, Dennis R; Brooks, Susan V

    2008-02-01

    Duchenne muscular dystrophy is caused by the absence of the protein dystrophin. Dystrophin's function is not known, but its cellular location and associations with both the force-generating contractile core and membrane-spanning entities suggest a role in mechanically coupling force from its intracellular origins to the fiber membrane and beyond. We report here the presence of destructive contractile activity in lumbrical muscles from dystrophin-deficient (mdx) mice during nominally quiescent periods following exposure to mechanical stress. The ectopic activity, which was observable microscopically, resulted in longitudinal separation and clotting of fiber myoplasm and was absent when calcium (Ca(2+)) was removed from the bathing medium. Separation and clotting of myoplasm were also produced in dystrophin-deficient muscles by local application of a Ca(2+) ionophore to create membrane breaches in the absence of mechanical stress, whereas muscles from control mice tolerated ionophore-induced entry of Ca(2+) without damage. These observations suggest a failure cascade in dystrophin-deficient fibers that 1) is initiated by a stress-induced influx of extracellular Ca(2+), causing localized activation to continue after cessation of stimulation, and 2) proceeds as the persistent local activation, combined with reduced lateral mechanical coupling between the contractile core and the extracellular matrix, results in longitudinal separation of myoplasm in nonactivated regions of the fiber. This mechanism invokes both the membrane stabilization and the mechanical coupling functions frequently proposed for dystrophin and suggests that, whereas the absence of either function alone is not sufficient to cause fiber failure, their combined absence is catastrophic.

  20. The Danish Heart Registry

    DEFF Research Database (Denmark)

    Özcan, Cengiz; Juel, Knud; Flensted Lassen, Jens;

    2016-01-01

    AIM: The Danish Heart Registry (DHR) seeks to monitor nationwide activity and quality of invasive diagnostic and treatment strategies in patients with ischemic heart disease as well as valvular heart disease and to provide data for research. STUDY POPULATION: All adult (≥15 years) patients...... undergoing coronary angiography (CAG), percutaneous coronary intervention (PCI), coronary artery bypass grafting, and heart valve surgery performed across all Danish hospitals were included. MAIN VARIABLES: The DHR contains a subset of the data stored in the Eastern and Western Denmark Heart Registries (EDHR...

  1. Heart Age PSA (:60)

    Centers for Disease Control (CDC) Podcasts

    2015-09-01

    This 60 second public service announcement is based on the September 2015 CDC Vital Signs report. Your heart age is the age of your heart and blood vessels as a result of your risk factors for heart attack and stroke. If you smoke or have high blood pressure, your heart age will be much higher than your actual age. Learn what you can do to lower your heart age and keep it low.  Created: 9/1/2015 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 9/1/2015.

  2. Phenotypic improvement of dystrophic muscles by rAAV/microdystrophin vectors is augmented by Igf1 codelivery.

    Science.gov (United States)

    Abmayr, Simone; Gregorevic, Paul; Allen, James M; Chamberlain, Jeffrey S

    2005-09-01

    The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to sarcolemmal instability and enhances the susceptibility of muscle fibers to contraction-induced injury. Various viral vectors have been used to deliver mini- and microdystrophin expression cassettes to muscles of dystrophin-deficient mdx mice, significantly increasing both the morphological and the functional properties of the muscles. However, dystrophin delivery to adult mdx mice has not yielded a complete rescue of the dystrophic phenotype. Here we investigated a novel strategy involving dual gene transfer of recombinant adeno-associated viral vectors expressing either microdystrophin (rAAV-muDys) or a muscle-specific isoform of Igf-1 (rAAV-mIgf-1). Injection of mdx muscles with rAAV-muDys reduced myofiber degeneration and turnover and increased their resistance to mechanical injury, but did not increase muscle mass or force generation. Injection of mdx muscles with rAAV-mIgf-1 led to increased muscle mass, but did not provide protection against mechanical injury or halt myofiber degeneration, leading to loss of the vector over time. In contrast, co-injection of the rAAV-muDys and rAAV-mIgf-1 vectors resulted in increased muscle mass and strength, reduced myofiber degeneration, and increased protection against contraction-induced injury. These results suggest that a dual-gene, combinatorial strategy could enhance the efficacy of gene therapy of DMD.

  3. Heart transplantation in adult congenital heart disease.

    Science.gov (United States)

    Burchill, Luke J

    2016-12-01

    Heart failure (HF) in adult congenital heart disease (ACHD) is vastly different to that observed in acquired heart disease. Unlike acquired HF in which pharmacological strategies are the cornerstone for protecting and improving ventricular function, ACHD-related HF relies heavily upon structural and other interventions to achieve these aims. patients with ACHD constitute a small percentage of the total adult heart transplant population (∼3%), although the number of ACHD heart transplant recipients is growing rapidly with a 40% increase over the last two decades. The worldwide experience to date has confirmed heart transplantation as an effective life-extending treatment option in carefully selected patients with ACHD with end-stage cardiac disease. Opportunities for improving outcomes in patients with ACHD-related HF include (i) earlier recognition and referral to centres with combined expertise in ACHD and HF, (ii) increased awareness of arrhythmia and sudden cardiac death risk in this population, (iii) greater collaboration between HF and ACHD specialists at the time of heart transplant assessment, (iv) expert surgical planning to reduce ischaemic time and bleeding risk at the time of transplant, (v) tailored immunosuppression in the post-transplant period and (vi) development and validation of ACHD-specific risk scores to predict mortality and guide patient selection. The purpose of this article is to review current approaches to diagnosing and treating advanced HF in patients with ACHD including indications, contraindications and clinical outcomes after heart transplantation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  4. Dystrophin and utrophin influence fiber type composition and post-synaptic membrane structure.

    Science.gov (United States)

    Rafael, J A; Townsend, E R; Squire, S E; Potter, A C; Chamberlain, J S; Davies, K E

    2000-05-22

    The X-linked muscle wasting disease Duchenne muscular dystrophy is caused by the lack of dystrophin in muscle. Protein structure predictions, patient mutations, in vitro binding studies and transgenic and knockout mice suggest that dystrophin plays a mechanical role in skeletal muscle, linking the subsarcolemmal cytoskeleton with the extracellular matrix through its direct interaction with the dystrophin-associated protein complex (DAPC). Although a signaling role for dystrophin has been postulated, definitive data have been lacking. To identify potential non-mechanical roles of dystrophin, we tested the ability of various truncated dystrophin transgenes to prevent any of the skeletal muscle abnormalities associated with the double knockout mouse deficient for both dystrophin and the dystrophin-related protein utrophin. We show that restoration of the DAPC with Dp71 does not prevent the structural abnormalities of the post-synaptic membrane or the abnormal oxidative properties of utrophin/dystrophin-deficient muscle. In marked contrast, a dystrophin protein lacking the cysteine-rich domain, which is unable to prevent dystrophy in the mdx mouse, is able to ameliorate these abnormalities in utrophin/dystrophin-deficient mice. These experiments provide the first direct evidence that in addition to a mechanical role and relocalization of the DAPC, dystrophin and utrophin are able to alter both structural and biochemical properties of skeletal muscle. In addition, these mice provide unique insights into skeletal muscle fiber type composition.

  5. Heart rate index

    DEFF Research Database (Denmark)

    Haedersdal, C; Pedersen, F H; Svendsen, J H

    1992-01-01

    The present study compares the variables assessed by standard exercise test with the left ventricular ejection fraction (LVEF) measured by multigated radionuclide angiocardiography (MUGA) in 77 patients early after myocardial infarction. The exercise test and MUGA were performed within two weeks...... after the myocardial infarction. A significant correlation (Spearman's correlation coefficient rs, p less than 0.05) was found between LVEF at rest and the following variables assessed at exercise test: 1) the heart rate at rest, 2) rise in heart rate, 3) ratio between maximal heart rate and heart rate...... at rest, 4) rise in systolic blood pressure, 5) rate pressure product at rest, 6) rise in rate pressure product, 7) ratio (rHR) between maximal rate pressure product and rate pressure product at rest, 8) total exercise time. The heart rate was corrected for effects caused by age (heart index (HR...

  6. Patterns of Heart Attacks

    Science.gov (United States)

    2010-06-01

    Hypertension (high blood pressure), smoking, family history of heart disease, and diabetes mellitus (both types 1 and 2) are also factors that increase the risk...breath 16% 19% Hyperlipidemia 2% Asthma 23% Coronary Artery Disease 15% Chest Pain 4% Pneumonia 24% 38% Diabetes 7% Congestive Heart Failure 9% 6...Pain Diabetes Congestive Heart Failure Hypertension Asthma Table 5.7: Diagnoses that distinguish cluster 8 from the cost bucket 2 population average. The

  7. Music and the heart

    OpenAIRE

    Koelsch, Stefan; Jäncke, Lutz

    2017-01-01

    Music can powerfully evoke and modulate emotions and moods, along with changes in heart activity, blood pressure (BP), and breathing. Although there is great heterogeneity in methods and quality among previous studies on effects of music on the heart, the following findings emerge from the literature: Heart rate (HR) and respiratory rate (RR) are higher in response to exciting music compared with tranquilizing music. During musical frissons (involving shivers and piloerection), both HR and RR...

  8. Changes in calsequestrin, TNF-α, TGF-β and MyoD levels during the progression of skeletal muscle dystrophy in mdx mice: a comparative analysis of the quadriceps, diaphragm and intrinsic laryngeal muscles.

    Science.gov (United States)

    Barros Maranhão, Juliana; de Oliveira Moreira, Drielen; Maurício, Adriana Fogagnolo; de Carvalho, Samara Camaçari; Ferretti, Renato; Pereira, Juliano Alves; Santo Neto, Humberto; Marques, Maria Julia

    2015-10-01

    In Duchenne muscular dystrophy (DMD), the search for new biomarkers to follow the evolution of the disease is of fundamental importance in the light of the evolving gene and pharmacological therapies. In addition to the lack of dystrophin, secondary events including changes in calcium levels, inflammation and fibrosis greatly contribute to DMD progression and the molecules involved in these events may represent potential biomarkers. In this study, we performed a comparative evaluation of the progression of dystrophy within muscles that are differently affected by dystrophy (diaphragm; DIA and quadriceps; QDR) or spared (intrinsic laryngeal muscles) using the mdx mice model of DMD. We assessed muscle levels of calsequestrin (calcium-related protein), tumour necrosis factor (TNF-α; pro-inflammatory cytokine), tumour growth factor (TGF-β; pro-fibrotic factor) and MyoD (muscle proliferation) vs. histopathology at early (1 and 4 months of age) and late (9 months of age) stages of dystrophy. Fibrosis was the primary feature in the DIA of mdx mice (9 months: 32% fibrosis), which was greater than in the QDR (9 months: 0.6% fibrosis). Muscle regeneration was the primary feature in the QDR (9 months: 90% of centrally nucleated fibres areas vs. 33% in the DIA). The QDR expressed higher levels of calsequestrin than the DIA. Laryngeal muscles showed normal levels of TNF-α, TGF-β and MyoD. A positive correlation between histopathology and cytokine levels was observed only in the diaphragm, suggesting that TNF-α and TGF-β serve as markers of dystrophy primarily for the diaphragm.

  9. Heart Rate Monitors

    Science.gov (United States)

    1990-01-01

    Under a NASA grant, Dr. Robert M. Davis and Dr. William M. Portnoy came up with a new type of electrocardiographic electrode that would enable long term use on astronauts. Their invention was an insulated capacitive electrode constructed of a thin dielectric film. NASA subsequently licensed the electrode technology to Richard Charnitski, inventor of the VersaClimber, who founded Heart Rate, Inc., to further develop and manufacture personal heart monitors and to produce exercise machines using the technology for the physical fitness, medical and home markets. Same technology is on both the Home and Institutional Model VersaClimbers. On the Home Model an infrared heart beat transmitter is worn under exercise clothing. Transmitted heart rate is used to control the work intensity on the VersaClimber using the heart rate as the speedometer of the exercise. This offers advantages to a full range of users from the cardiac rehab patient to the high level physical conditioning of elite athletes. The company manufactures and markets five models of the 1*2*3 HEART RATE monitors that are used wherever people exercise to accurately monitor their heart rate. Company is developing a talking heart rate monitor that works with portable headset radios. A version of the heart beat transmitter will be available to the manufacturers of other aerobic exercise machines.

  10. Anesthesia for Heart Transplantation.

    Science.gov (United States)

    Ramsingh, Davinder; Harvey, Reed; Runyon, Alec; Benggon, Michael

    2017-09-01

    This article seeks to evaluate current practices in heart transplantation. The goals of this article were to review current practices for heart transplantation and its anesthesia management. The article reviews current demographics and discusses the current criteria for candidacy for heart transplantation. The process for donor and receipt selection is reviewed. This is followed by a review of mechanical circulatory support devices as they pertain to heart transplantation. The preanesthesia and intraoperative considerations are also discussed. Finally, management after transplantation is also reviewed. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. [Heart transplantation and infection].

    Science.gov (United States)

    Ozábalová, Eva; Krejčí, Jan; Hude, Petr; Godava, Julius; Honek, Tomáš; Špinarová, Lenka; Pavlík, Petr; Bedáňová, Helena; Němec, Petr

    2017-01-01

    Heart transplantation (HTx) is a method of treatment for patients with end-stage heart failure with severe symptoms despite complex therapy. Post-transplant difficulties include acute rejection and infectious complications, which are the most common reason of morbidity and mortality in the first year after heart transplant. It requires the patient to remain on immunosuppressive medication to avoid the possibility of graft rejection. Therefore the range of infection is much larger. The diagnosis and treatment of viral, bacterial and fungal infections is often difficult.Key words: heart transplantation - immunosuppression - infection.

  12. All about Heart Rate (Pulse)

    Science.gov (United States)

    ... get a picture of your health. Learn more: Blood Pressure Vs. Heart Rate Target Heart Rate Arrhythmias (abnormal heart rhythms) This ... Healthy 6 What are the Symptoms of High Blood Pressure? 7 All About Heart Rate (Pulse) 8 Warning Signs of a Heart Attack ...

  13. Dimensional analysis of heart rate variability in heart transplant recipients

    Energy Technology Data Exchange (ETDEWEB)

    Zbilut, J.P.; Mayer-Kress, G.; Geist, K.

    1987-01-01

    We discuss periodicities in the heart rate in normal and transplanted hearts. We then consider the possibility of dimensional analysis of these periodicities in transplanted hearts and problems associated with the record.

  14. Women's Heart Disease: Join the Heart Truth Community

    Science.gov (United States)

    ... this page please turn JavaScript on. Feature: Women's Heart Disease Join The Heart Truth Community Past Issues / Winter ... introduced as the national symbol for women and heart disease awareness in 2002 by the NHLBI. The Red ...

  15. Women and Heart Disease: Sharing Advice from the Heart

    Science.gov (United States)

    ... page please turn JavaScript on. Feature: Women and Heart Disease Sharing Advice From The Heart Past Issues / Spring ... gowns in an effort to raise awareness that heart disease is the leading cause of death among women. ...

  16. Mapping the Heart

    Science.gov (United States)

    Hulse, Grace

    2012-01-01

    In this article, the author describes how her fourth graders made ceramic heart maps. The impetus for this project came from reading "My Map Book" by Sara Fanelli. This book is a collection of quirky, hand-drawn and collaged maps that diagram a child's world. There are maps of her stomach, her day, her family, and her heart, among others. The…

  17. Chronic heart failure

    African Journals Online (AJOL)

    population, and up to 10% in people aged 75 years and older. It is also estimated that ... The first step in the development of heart failure is an injury to the myocardium ... treatment of heart failure by blocking the compensatory mechanisms with ... pulmonary disease, cognitive dysfunction, depression, chronic kidney disease ...

  18. Heart Surgery Terms

    Science.gov (United States)

    ... CABG) The surgical procedure to treat narrowing or " stenosis " of the coronary arteries is called coronary artery bypass, or CABG ( ... blood flow to the heart. Coronary artery disease Coronary artery disease is characterized by a narrowing or " stenosis " of the blood vessels to the heart resulting ...

  19. The total artificial heart.

    Science.gov (United States)

    Cook, Jason A; Shah, Keyur B; Quader, Mohammed A; Cooke, Richard H; Kasirajan, Vigneshwar; Rao, Kris K; Smallfield, Melissa C; Tchoukina, Inna; Tang, Daniel G

    2015-12-01

    The total artificial heart (TAH) is a form of mechanical circulatory support in which the patient's native ventricles and valves are explanted and replaced by a pneumatically powered artificial heart. Currently, the TAH is approved for use in end-stage biventricular heart failure as a bridge to heart transplantation. However, with an increasing global burden of cardiovascular disease and congestive heart failure, the number of patients with end-stage heart failure awaiting heart transplantation now far exceeds the number of available hearts. As a result, the use of mechanical circulatory support, including the TAH and left ventricular assist device (LVAD), is growing exponentially. The LVAD is already widely used as destination therapy, and destination therapy for the TAH is under investigation. While most patients requiring mechanical circulatory support are effectively treated with LVADs, there is a subset of patients with concurrent right ventricular failure or major structural barriers to LVAD placement in whom TAH may be more appropriate. The history, indications, surgical implantation, post device management, outcomes, complications, and future direction of the TAH are discussed in this review.

  20. Heart failure in COPD

    NARCIS (Netherlands)

    Rutten, Frans Hendrik

    2005-01-01

    The main aim of the thesis was to assess the prevalence of heart failure in patients with a diagnosis of chronic obstructive pulmonary disease (COPD). Furthermore, to explore diagnostic strategies (including natriuretic peptides and cardiovascular magnetic resonance imaging (CMR)) to identify heart

  1. Mapping the Heart

    Science.gov (United States)

    Hulse, Grace

    2012-01-01

    In this article, the author describes how her fourth graders made ceramic heart maps. The impetus for this project came from reading "My Map Book" by Sara Fanelli. This book is a collection of quirky, hand-drawn and collaged maps that diagram a child's world. There are maps of her stomach, her day, her family, and her heart, among others. The…

  2. Music and the heart.

    Science.gov (United States)

    Koelsch, Stefan; Jäncke, Lutz

    2015-11-21

    Music can powerfully evoke and modulate emotions and moods, along with changes in heart activity, blood pressure (BP), and breathing. Although there is great heterogeneity in methods and quality among previous studies on effects of music on the heart, the following findings emerge from the literature: Heart rate (HR) and respiratory rate (RR) are higher in response to exciting music compared with tranquilizing music. During musical frissons (involving shivers and piloerection), both HR and RR increase. Moreover, HR and RR tend to increase in response to music compared with silence, and HR appears to decrease in response to unpleasant music compared with pleasant music. We found no studies that would provide evidence for entrainment of HR to musical beats. Corresponding to the increase in HR, listening to exciting music (compared with tranquilizing music) is associated with a reduction of heart rate variability (HRV), including reductions of both low-frequency and high-frequency power of the HRV. Recent findings also suggest effects of music-evoked emotions on regional activity of the heart, as reflected in electrocardiogram amplitude patterns. In patients with heart disease (similar to other patient groups), music can reduce pain and anxiety, associated with lower HR and lower BP. In general, effects of music on the heart are small, and there is great inhomogeneity among studies with regard to methods, findings, and quality. Therefore, there is urgent need for systematic high-quality research on the effects of music on the heart, and on the beneficial effects of music in clinical settings.

  3. Heart imaging method

    Science.gov (United States)

    Collins, H. Dale; Gribble, R. Parks; Busse, Lawrence J.

    1991-01-01

    A method for providing an image of the human heart's electrical system derives time-of-flight data from an array of EKG electrodes and this data is transformed into phase information. The phase information, treated as a hologram, is reconstructed to provide an image in one or two dimensions of the electrical system of the functioning heart.

  4. Guidelines for heart transplantation

    OpenAIRE

    de Jonge, N; Kirkels, J.H.; Klöpping, C.; Lahpor, J.R.; Caliskan, K.; Maat, A.P.W.M.; Brügemann, J; Erasmus, M.E.; Klautz, R. J. M.; Verwey, H.F; Oomen, A.; Peels, C.H.; Golüke, A.E.J.; Nicastia, D.; Koole, M.A.C.

    2008-01-01

    Based on the changes in the field of heart transplantation and the treatment and prognosis of patients with heart failure, these updated guidelines were composed by a committee under the supervision of both the Netherlands Society of Cardiology and the Netherlands Association for Cardiothoracic surgery (NVVC and NVT).

  5. Guidelines for heart transplantation

    NARCIS (Netherlands)

    Kirkels, J. H.; Klopping, C.; Lahpor, J. R.; Caliskan, K.; Maat, A. P. W. M.; Brugemann, J.; Erasmus, M. E.; Klautz, R. J. M.; Verwey, H. F.; Oomen, A.; Peels, C. H.; Goluke, A. E. J.; Nicastia, D. M.; Koole, M. A. C.; Balk, A. H. M. M.; de Jonge, N.

    Based on the changes in the field of heart transplantation and the treatment and prognosis of patients with heart failure, these updated guidelines were composed by a committee under the supervision of both the Netherlands Society of Cardiology and the Netherlands Association for Cardiothoracic

  6. World Heart Day

    Centers for Disease Control (CDC) Podcasts

    2009-09-01

    For World Heart Day, learn more about what heart-healthy steps you can take in the workplace.  Created: 9/1/2009 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 9/9/2009.

  7. "The Heart Game"

    DEFF Research Database (Denmark)

    Dithmer, Marcus; Rasmussen, Jack Ord; Grönvall, Erik

    2016-01-01

    Objective: The aim of this article is to describe the development and testing of a prototype application (“The Heart Game”) using gamification principles to assist heart patients in their telerehabilitation process in the Teledialog project. Materials and Methods: A prototype game was developed via...... tool as a part of their telerehabilitation process in everyday life. Gamification and gameful design principles such as leaderboards, relationships, and achievements engaged the patients and relatives. The inclusion of a close relative in the game motivated the patients to perform rehabilitation...... activities. Conclusions: “The Heart Game” concept presents a new way to motivate heart patients by using technology as a social and active approach to telerehabilitation. The findings show the potential of using gamification for heart patients as part of a telerehabilitation program. The evaluation indicated...

  8. Theory of heart

    Energy Technology Data Exchange (ETDEWEB)

    Glass, L. (ed.) (McGill Univ., Montreal (Canada). Dept. of Physiology); Hunter, P. (ed.) (Auckland Univ., Auckland (New Zealand). Dept. of Engineering Science); McCulloch, A. (ed.) (California Univ., San Diego (United States))

    1991-01-01

    In recent years there has been a growth in interest in studying the heart from the perspective of the physical sciences: mechanics, fluid flow, electromechanics. This volume is the result of a workshop held in July 1989 at the Institute for Nonlinear Sciences at the University of California at San Diego that brought together scientists and clinicians with graduate students and postdoctoral fellows who share an interest in the heart. The chapters were prepared by the invited speakers as didactic reviews of their subjects but also include up-to-date results in their fields. Topics covered include the structure, mechanical properties, and function of the heart and the myocardium, electrical activity of the heart and myocardium, and mathematical models of heart function. Individual chapters are abstracted separately.

  9. Types of Congenital Heart Defects

    Science.gov (United States)

    ... heart develops. Examples of Simple Congenital Heart Defects Holes in the Heart (Septal Defects) The septum is ... Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG CONTACT US National Institutes of Health ...

  10. Can Pregnancy Harm Your Heart?

    Science.gov (United States)

    ... and women's heart health, said Dr. Mary Ann Bauman, a spokeswoman for the American Heart Association. "We ... of the mechanisms of women and heart disease," Bauman said. "Women aren't just men with ovaries. ...

  11. Heart Disease and African Americans

    Science.gov (United States)

    ... Minority Population Profiles > Black/African American > Heart Disease Heart Disease and African Americans Although African American adults are ... were 30 percent more likely to die from heart disease than non-Hispanic whites. African American women are ...

  12. Heart Disease and Stroke Prevention

    Science.gov (United States)

    ... Heart Health and Stroke Heart disease and stroke prevention Related information Learn more about healthy eating and ... top More information on Heart disease and stroke prevention Read more from womenshealth.gov A Lifetime of ...

  13. Living with Coronary Heart Disease

    Science.gov (United States)

    ... from the NHLBI on Twitter. Living With Coronary Heart Disease Coronary heart disease (CHD) can cause serious complications. However, if you ... changes and medicines, go to "How Is Coronary Heart Disease Treated?" Work closely with your doctor to control ...

  14. Living with Diabetic Heart Disease

    Science.gov (United States)

    ... from the NHLBI on Twitter. Living With Diabetic Heart Disease Diabetic heart disease (DHD) increases the likelihood of earlier and more ... also tend to have less success from certain heart disease treatments, such as coronary artery bypass grafting and ...

  15. About the Operation: Heart Transplant

    Science.gov (United States)

    ... There are two very different surgical approaches to heart transplantation: the orthotopic and the heterotopic approach. Because the ... begins. Heterotopic Approach. Heterotopic transplantation, also called ... by leaving the recipient's heart in place and connecting the donor heart to ...

  16. Heart Disease and Stroke Statistics

    Science.gov (United States)

    ... Media for Heart.org Heart and Stroke Association Statistics Banner 1 - Stats white banner Each year, the ... health and disease in the population. Heart & Stroke Statistics FAQs What is Prevalence? Prevalence is an estimate ...

  17. What Causes Heart Valve Disease?

    Science.gov (United States)

    ... a heart attack or injury to the heart. Rheumatic Fever Untreated strep throat or other infections with strep bacteria that progress to rheumatic fever can cause heart valve disease. When the body ...

  18. Angioplasty and stent placement - heart

    Science.gov (United States)

    ... angioplasty; Coronary artery angioplasty; Percutaneous transluminal coronary angioplasty; Heart artery dilatation ... to carefully guide the catheter up into your heart and arteries. Dye will be injected into your ...

  19. Lungs in Heart Failure

    Directory of Open Access Journals (Sweden)

    Anna Apostolo

    2012-01-01

    Full Text Available Lung function abnormalities both at rest and during exercise are frequently observed in patients with chronic heart failure, also in the absence of respiratory disease. Alterations of respiratory mechanics and of gas exchange capacity are strictly related to heart failure. Severe heart failure patients often show a restrictive respiratory pattern, secondary to heart enlargement and increased lung fluids, and impairment of alveolar-capillary gas diffusion, mainly due to an increased resistance to molecular diffusion across the alveolar capillary membrane. Reduced gas diffusion contributes to exercise intolerance and to a worse prognosis. Cardiopulmonary exercise test is considered the “gold standard” when studying the cardiovascular, pulmonary, and metabolic adaptations to exercise in cardiac patients. During exercise, hyperventilation and consequent reduction of ventilation efficiency are often observed in heart failure patients, resulting in an increased slope of ventilation/carbon dioxide (VE/VCO2 relationship. Ventilatory efficiency is as strong prognostic and an important stratification marker. This paper describes the pulmonary abnormalities at rest and during exercise in the patients with heart failure, highlighting the principal diagnostic tools for evaluation of lungs function, the possible pharmacological interventions, and the parameters that could be useful in prognostic assessment of heart failure patients.

  20. Heart rate turbulence.

    Science.gov (United States)

    Cygankiewicz, Iwona

    2013-01-01

    Heart rate turbulence (HRT) is a baroreflex-mediated biphasic reaction of heart rate in response to premature ventricular beats. Heart rate turbulence is quantified by: turbulence onset (TO) reflecting the initial acceleration of heart rate following premature beat and turbulence slope (TS) describing subsequent deceleration of heart rate. Abnormal HRT identifies patients with autonomic dysfunction or impaired baroreflex sensitivity due to variety of disorders, but also may reflect changes in autonomic nervous system induced by different therapeutic modalities such as drugs, revascularization, or cardiac resynchronization therapy. More importantly, impaired HRT has been shown to identify patients at high risk of all-cause mortality and sudden death, particularly in postinfarction and congestive heart failure patients. It should be emphasized that abnormal HRT has a well-established role in stratification of postinfarction and heart failure patients with relatively preserved left ventricular ejection fraction. The ongoing clinical trials will document whether HRT can be used to guide implantation of cardioverter-defibrillators in this subset of patients, not covered yet by ICD guidelines. This review focuses on the current state-of-the-art knowledge regarding clinical significance of HRT in detection of autonomic dysfunction and regarding the prognostic significance of this parameter in predicting all-cause mortality and sudden death. © 2013.

  1. The coronary heart team.

    Science.gov (United States)

    Yanagawa, Bobby; Puskas, John D; Bhatt, Deepak L; Verma, Subodh

    2017-09-01

    The concept of a Coronary Heart Team has generated increased interest, including support from major practice guidelines. Here, we review the rationale and the published experience of Coronary Heart Teams. A Coronary Heart Team should be led by both cardiology and cardiac surgery with a shared decision-making approach. The team should incorporate data from anatomic and clinical risk prediction models to offer individualized care. Most teams focus on management of complex patients and those with indications for both coronary artery bypass graft and percutaneous coronary intervention. The potential benefits of a Coronary Heart Team include balanced decision-making, greater adherence to evidence-based practice guidelines, as well as promoting greater collegiality and exchange of knowledge between specialties. Single-center series have demonstrated consistency in decision-making by Coronary Heart Teams but prospective data demonstrating improved patient outcomes and/or cost effectiveness are necessary. The concept of a Coronary Heart Team is gaining traction for patients with complex coronary artery disease. There is a growing literature in support of Coronary Heart Teams but comparative and prospective data demonstrating improved patient outcomes are needed.

  2. [Ischemic heart disease].

    Science.gov (United States)

    Yamamuro, Megumi; Ogawa, Hisao

    2009-04-01

    It has been reported that antihypertensive therapy reduces the risk of ischemic heart disease. Except for the antihypertensive effects, the angiotensin converting enzyme (ACE) inhibitors are proved to be very effective in primary and secondary event onset prophylaxis by many clinical trials. The angiotensin II receptor antagonists (ARBs) used briskly in recent years inhibits angiotensin II type 1 receptor alternatively. Although ARBs protect organs, especially blood vessel, heart, brain and kidney in sites of pharmacology, ARBs are still not much as effective results as ACE inhibitors for the patients with ischemic heart disease, by many clinical trials.

  3. Thyroid and the Heart

    Directory of Open Access Journals (Sweden)

    A Karas

    2009-09-01

    Full Text Available The cardiovascular signs and symptoms of thyroid disease are some of the most clinically relevant findings that accompany both hyperthyroidism and hypothyroidism. On the basis of the understanding of the mechanisms of thyroid hormone action on the heart and cardiovascular system, it is possible to explain the changes in cardiac output, cardiac contractility, blood pressure and rhythm disturbances that result from thyroid dysfunction. In the present review will integrate what is known about the mechanisms of thyroid hormone action on the heart and the alterations in thyroid hormone metabolism that accompany chronic congestive heart failure.

  4. Heart to Heart Art: Empowering Homeless Children and Youth

    Science.gov (United States)

    Shepard, Jerri; Booth, Deborah

    2009-01-01

    This article describes Heart to Heart Art, an after-school program developed for homeless children and youth at the YWCA in Spokane, Washington. Pre-service teacher candidates from a local university create meaningful activities that engage homeless students in visual art, music, drama, cooking, and community service. Heart to Heart Art was…

  5. Data and Statistics: Women and Heart Disease

    Science.gov (United States)

    ... Pressure Salt Cholesterol Million Hearts® WISEWOMAN Women and Heart Disease Fact Sheet Recommend on Facebook Tweet Share Compartir ... Atlas of Heart Disease Facts on Women and Heart Disease Heart disease is the leading cause of death ...

  6. Caffeine and Heart Disease

    Science.gov (United States)

    ... dehydration. Caffeine is in coffee, tea, soft drinks, chocolate and some nuts. Whether high caffeine intake increases ... and Heart Disease Healthy Eating • Healthy Eating Home • Nutrition AHA Diet and Lifestyle Recommendations Making Healthy Choices ...

  7. Heart disease. Third edition

    Energy Technology Data Exchange (ETDEWEB)

    Braunwald, E.

    1988-01-01

    This book contains 62 chapters. Some of the chapter titles are: Radiological and Angiographic Examination of the Heart; Newer Cardiac Imaging Techniques: Digital Subtraction Angiography, Computerized Tomography, Magnetic Resonance Imaging; Nuclear Cardiology; and Genetics and Cardiovascular Disease.

  8. Heart attack - discharge

    Science.gov (United States)

    ... nih.gov/pubmed/23166211 . Giugliano RP, Cannon CP, Braunwald E. Non-ST elevation acute coronary syndromes. In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of ...

  9. Advanced Heart Failure

    Science.gov (United States)

    ... patients and their doctors, making good decisions requires teamwork. Through shared decision making, doctors and patients consider ... Heart Failure and Knowing Your Options Planning Ahead Communicating With Your Healthcare Provider Overcoming Barriers to Shared ...

  10. Heart and vascular services

    Science.gov (United States)

    ... CT angiography (CTA) and magnetic resonance angiography (MRA) Echocardiogram PET scan of the heart Stress tests (many ... most cases, such procedures do not need general anesthesia . Patients often do not need to stay in ...

  11. Heart disease and diet

    Science.gov (United States)

    ... liver, and prepared meats such as sausage, hot dogs, and high-fat lunch meats. Adults should eat ... risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. ...

  12. Hyperkalemia in Heart Failure.

    Science.gov (United States)

    Sarwar, Chaudhry M S; Papadimitriou, Lampros; Pitt, Bertram; Piña, Ileana; Zannad, Faiez; Anker, Stefan D; Gheorghiade, Mihai; Butler, Javed

    2016-10-01

    Disorders of potassium homeostasis can potentiate the already elevated risk of arrhythmia in heart failure. Heart failure patients have a high prevalence of chronic kidney disease, which further heightens the risk of hyperkalemia, especially when renin-angiotensin-aldosterone system inhibitors are used. Acute treatment for hyperkalemia may not be tolerated in the long term. Recent data for patiromer and sodium zirconium cyclosilicate, used to treat and prevent high serum potassium levels on a more chronic basis, have sparked interest in the treatment of hyperkalemia, as well as the potential use of renin-angiotensin-aldosterone system inhibitors in patients who were previously unable to take these drugs or tolerated only low doses. This review discusses the epidemiology, pathophysiology, and outcomes of hyperkalemia in heart failure; provides an overview of traditional and novel ways to approach management of hyperkalemia; and discusses the need for further research to optimally treat heart failure.

  13. Picturing the Heart

    Science.gov (United States)

    ... Links for Students Glossary Picturing the Heart SCIENCE EDUCATION Science Topics Resource Links for General Public Resource Links for Parents/Teachers Resource Links for Students Glossary Government Resources Kids.gov – Science Information and services on the web ...

  14. A heart for interaction

    DEFF Research Database (Denmark)

    Fusaroli, Riccardo; Roepstorff, Andreas; Tylén, Kristian

    2016-01-01

    Interpersonally shared physiological dynamics are increasingly argued to underlie rapport, empathy, and even team performance. Inspired by the model of interpersonal synergy, we critically investigate the presence, temporal development, possible mechanisms and impact of shared interpersonal heart...

  15. Heart CT scan

    Science.gov (United States)

    ... stored, viewed on a monitor, or printed on film. 3D or three-dimensional models of the heart ... Cardiology, Harborview Medical Center, University of Washington Medical School, Seattle, WA. Also reviewed by David Zieve, MD, ...

  16. Protein and Heart Health

    Science.gov (United States)

    ... It Works Healthy Workplace Food and Beverage Toolkit Protein and Heart Health Updated:May 5,2015 Protein ... said. What’s the harm in getting too much protein? The main problem is that often the extra ...

  17. Stress and your heart

    Science.gov (United States)

    ... Newly Reported Coronary Heart Disease Among US Active Duty and Reserve Forces. Circulation . 2014;129(18):1813- ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  18. Types of Heart Surgery

    Science.gov (United States)

    ... from the NHLBI on Twitter. Types of Heart Surgery Coronary Artery Bypass Grafting Coronary artery bypass grafting ( ... TAHs) might be used to treat these patients. Surgery To Place Ventricular Assist Devices or Total Artificial ...

  19. Acute heart failure syndrome

    African Journals Online (AJOL)

    tandfonline.com/ ... When heart failure develops gradually, there is time for the compensatory ... of this can be seen in acute brain injury, some forms of takotsubo syndrome or .... reduce blood pressure in cases presenting with elevated blood pressure.

  20. Heart Healthy Eating

    Science.gov (United States)

    ... of heart disease and stroke? You should limit: Saturated fats. Saturated fat is usually in pizza, ice cream, fried chicken, ... and hamburgers. Check the Nutrition Facts label for saturated fat. Less than 10% of your daily calories should ...

  1. Heart PET scan

    Science.gov (United States)

    ... nuclear medicine scan; Heart positron emission tomography; Myocardial PET scan ... A PET scan requires a small amount of radioactive material (tracer). This tracer is given through a vein (IV), ...

  2. Target Heart Rates

    Science.gov (United States)

    ... morning after you’ve had a good night’s sleep and before you get out of bed. According to the National Institute of Health, the average resting heart rate: for children 10 years and older, and adults ( ...

  3. Pathophysiology of heart failure.

    Science.gov (United States)

    Chiariello, M; Perrone-Filardi, P

    1999-01-01

    Heart failure is a leading cause of mortality and morbidity in Western countries. Common etiology is mostly represented by ischemic and hypertensive heart disease. Clinically, heart failure can be defined as an impaired cardiac performance, unable to meet the energy requirements of the periphery. Pathophysiologically, the clinical onset of heart failure symptoms already represents an advanced stage of disease when compensatory mechanisms triggered by the underlying decrease in contractility are no longer capable of maintaining adequate cardiac performance during exercise and, subsequently, under resting conditions. Independent of its underlying etiology, cardiac failure is always characterized by an impairment in the intrinsic contractility of myocytes. As a consequence of reduced contractility, a number of central and peripheral compensatory mechanisms take place that are capable of effectively counteracting reduced intravascular intrinsic performance for a long period of time. Among them, recruitment of preload reserve, enhanced neurohormonal stimulation and cardiac hypertrophy are the most important. All of them, however, also carry unfavorable effects that contribute to further deterioration of cardiac function. In fact, increased end-diastolic volume determines increased wall stress that further reduces systolic performance; sympathetic and angiotensin stimulation increases peripheral resistance and contributes to increase volume expansion; hypertrophic myocytes demonstrate impaired intrinsic contractility and relaxation, and hypertrophy causes a clinically relevant deterioration of ventricular relaxation and compliance that substantially participates in increased end-diastolic pressure, and, therefore, to limited exercise performance. Diastolic dysfunction usually accompanies systolic dysfunction, although in some cases it may represent the prevalent mechanism of congestive heart failure in patients in whom systolic performance is preserved. Biological causes

  4. Life After a Heart Attack

    Science.gov (United States)

    ... symptoms of a heart attack. It presents one woman's real-life experience with heart attack symptoms, which started during her pregnancy. The video also explains how a heart attack occurs and encourages women to seek care right away for heart attack symptoms. For more information, ...

  5. What Is a Heart Attack?

    Science.gov (United States)

    ... symptoms of a heart attack. It presents one woman's real-life experience with heart attack symptoms, which started during her pregnancy. The video also explains how a heart attack occurs and encourages women to seek care right away for heart attack symptoms. For more information, ...

  6. What Causes a Heart Attack?

    Science.gov (United States)

    ... symptoms of a heart attack. It presents one woman's real-life experience with heart attack symptoms, which started during her pregnancy. The video also explains how a heart attack occurs and encourages women to seek care right away for heart attack symptoms. For more information, ...

  7. Risks for Heart Disease & Stroke

    Science.gov (United States)

    ... for Heart Disease & Stroke Risks for Heart Disease & Stroke About 1.5 million heart attacks and strokes happen every year in the United States. You ... some of your risks for heart disease and stroke, but you can manage many of your risks ...

  8. How Is Heart Disease Diagnosed?

    Science.gov (United States)

    ... heart tests are done. If you can't exercise, you may be given medicines to increase your heart rate. When your heart is working hard and beating fast, it needs more blood and oxygen. Plaque-narrowed coronary (heart) arteries can' ...

  9. Novel therapies in heart failure

    NARCIS (Netherlands)

    Liu, Licette Cécile Yang

    2016-01-01

    Heart failure is a clinical condition that is characterized by the inability of the heart to meet the oxygen requirements of peripheral tissues and organs, despite normal filling pressures. Despite recent developments in the treatment of heart failure, the prognosis of heart failure patients remains

  10. Predicting Outcome of Heart Transplantation

    NARCIS (Netherlands)

    Tjang, Y.S.

    2008-01-01

    Heart transplantation has become the treatment of choice for patients with end-stage heart diseases. Originally, strict recipient and donor selection criteria were developed to minimize morbidity and mortality after heart transplantation. However, the increasing demand for heart transplantation has

  11. Congenital Heart Defects (For Parents)

    Science.gov (United States)

    ... Old Feeding Your 1- to 2-Year-Old Congenital Heart Defects KidsHealth > For Parents > Congenital Heart Defects A A A What's in this article? How ... a Problem en español Anomalías cardíacas congénitas A congenital heart defect is a problem in the heart's structure that ...

  12. Novel therapies in heart failure

    NARCIS (Netherlands)

    Liu, Licette Cécile Yang

    2016-01-01

    Heart failure is a clinical condition that is characterized by the inability of the heart to meet the oxygen requirements of peripheral tissues and organs, despite normal filling pressures. Despite recent developments in the treatment of heart failure, the prognosis of heart failure patients remains

  13. What is Broken Heart Syndrome

    Science.gov (United States)

    ... having a heart attack , a more common medical emergency caused by a blocked coronary (heart) artery. The two conditions have similar symptoms, ... after exposure to the unexpected stress. Many seek emergency care, concerned they are having a heart attack. Often, patients who have broken heart syndrome ...

  14. Carcinoid heart disease.

    Science.gov (United States)

    Hassan, Saamir A; Banchs, Jose; Iliescu, Cezar; Dasari, Arvind; Lopez-Mattei, Juan; Yusuf, Syed Wamique

    2017-10-01

    Rare neuroendocrine tumours (NETs) that most commonly arise in the gastrointestinal tract can lead to carcinoid syndrome and carcinoid heart disease. Patients with carcinoid syndrome present with vasomotor changes, hypermotility of the gastrointestinal system, hypotension and bronchospasm. Medical therapy for carcinoid syndrome, typically with somatostatin analogues, can help control symptoms, inhibit tumour progression and prolong survival. Carcinoid heart disease occurs in more than 50% of these patients and is the initial presentation of carcinoid syndrome in up to 20% of patients. Carcinoid heart disease has characteristic findings of plaque-like deposits composed of smooth muscle cells, myofibroblasts, extracellular matrix and an overlying endothelial layer which can lead to valve dysfunction. Valvular dysfunction can lead to oedema, ascites and right-sided heart failure. Medical therapy of carcinoid heart disease is limited to symptom control and palliation. Valve surgery for carcinoid heart disease should be considered for symptomatic patients with controlled metastatic carcinoid syndrome. A multidisciplinary approach is needed to guide optimal management. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  15. [Heart failure and comorbidities].

    Science.gov (United States)

    Boully, Clémence; Hanon, Olivier

    2015-03-01

    Heart failure is a frequent disease in the elderly. Its clinical presentation is less typical and the prognosis more severe than in younger subjects because heart failure occurs in patients with multiple comorbidities. A comprehensive geriatric assessment should therefore be performed to detect the vulnerabilities and manage the comorbidities. The main diseases associated with heart failure are dementia, depression, malnutrition, atrial fibrillation, coronary artery disease, orthostatic hypotension, renal failure, anemia and iron deficiency. Comorbidities worsen heart failure and makes its treatment more difficult. The identification and treatment of comorbidities improve the prognosis in terms of mortality but especially in terms of quality of life. Caution with drugs is necessary because of pharmacokinetic or pharmacodynamic changes related to aging and the comorbidities. In this context, clinical and laboratory monitoring should be increased, mostly during an acute event (acute heart failure, infection, dehydration, fall, new therapy…). Therefore, the follow-up of elderly patients with heart failure requires a multidisciplinary approach that involves close cooperation between cardiologists, geriatricians, general practitioners, nurses, and pharmacists.

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

    Institute of Scientific and Technical Information of China (English)

    孔杰; 操基清; 陈菲; 杨娟; 张成

    2015-01-01

    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 transplantation should be a promising cure therapy for DMD.%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,

  17. Lengthening-contractions in isolated myocardium impact force development and worsen cardiac contractile function in the mdx mouse model of muscular dystrophy

    OpenAIRE

    Xu, Ying; Delfín, Dawn A.; Rafael-Fortney, Jill A; Janssen, Paul M.L.

    2010-01-01

    Lengthening-contractions exert eccentric stress on myofibers in normal myocardium. In congestive heart failure caused by a variety of diseases, the impact of lengthening-contractions of myocardium likely becomes more prevalent and severe. The present study introduces a method to investigate the role of stretching imposed by repetitive lengthening-contractions in myocardium under near-physiological conditions. By exerting various stretch-release ramps while the muscle is contracting, consecuti...

  18. COMBINED HEART-KIDNEY TRANSPLANTATION

    OpenAIRE

    V. N. Poptsov

    2016-01-01

    Combined heart-kidney transplantation may be performed in carefully selected patients with end-stage heart disease and renal failure. There are two types of combined transplantation of heart and kidney: 1) simultaneous heart-kidney transplantation (SHKT) from the same donor; 2) staged transplantation of heart and kidneys from two genetically different donors. The ISHLT registry in 2014 reported an increase in the number of SHKT over the years: from 22 in 1994 to 97 in 2012. World experience d...

  19. [Mechanobiology and the Heart].

    Science.gov (United States)

    Ishiguro, Yoshiki

    2016-05-01

    Mechanobiology has been focusing on biological research regarding mechanisms of muscle force generation, or recently sensing and response to the force applied to the tissue or each cell. Therefore, the heart has been one of the target organs and studied extensively for a long time since late 19th century. Its force-length relationship was demonstrated as the Starling's law of the heart, which is one of the most important findings in mechanobiology. In late 20th century, excitation-contraction coupling in the muscle was demonstrated and then, molecular mechanisms are gradually elucidated including calcium homeostasis and signal transductions in various situations: under the effects of catecholamines, other vasoactive agents, or ischemia. Among them, recent findings suggest possible involvement of titin, the giant elastic protein connected with both actin and myosin, with basic mechanism of the Starling's law of the heart Pathological proliferation of the heart as hypertrophic remodeling has also been extensively studied in recent years, and its signal transduction from pressure overload and volume overload to respective morphological changes of the heart chamber are partially clarified.

  20. [Heart failure and anemia].

    Science.gov (United States)

    Reda, S; Motloch, L J; Hoppe, U C

    2013-09-01

    Chronic heart failure has an age-dependent prevalence of 2% and is therefore one of the most frequent diseases in western societies. A reduced hemoglobin concentration according to the definition of the World Health Organization is a common comorbidity affecting more than half of all heart failure patients. Elderly patients, patients suffering from renal impairment and women are more likely to develop anemia but a definitive etiology of anemia is only identified in the minority of cases. Anemia is associated with a poor clinical status and a greater risk of hospitalization and is a predictive factor for increased mortality. The incidence of anemia appears to increase with a poorer functional class. Intravenous iron therapy improves the exercise capacity in patients with systolic heart failure and iron deficiency and is currently being recommended for patients with persistent symptoms despite optimal medical and device therapy. However, erythropoietin-stimulating agents as a treatment for anemia in chronic heart failure have failed to improve clinical outcome in a large randomized trial. In patients with heart failure but with maintained ejection fraction, anemia is also associated with a poor prognosis. Specific therapeutic recommendations for these patients are still not available.

  1. Heart transplantation in adults with congenital heart disease.

    Science.gov (United States)

    Houyel, Lucile; To-Dumortier, Ngoc-Tram; Lepers, Yannick; Petit, Jérôme; Roussin, Régine; Ly, Mohamed; Lebret, Emmanuel; Fadel, Elie; Hörer, Jürgen; Hascoët, Sébastien

    2017-02-22

    With the advances in congenital cardiac surgery and postoperative care, an increasing number of children with complex congenital heart disease now reach adulthood. There are already more adults than children living with a congenital heart defect, including patients with complex congenital heart defects. Among these adults with congenital heart disease, a significant number will develop ventricular dysfunction over time. Heart failure accounts for 26-42% of deaths in adults with congenital heart defects. Heart transplantation, or heart-lung transplantation in Eisenmenger syndrome, then becomes the ultimate therapeutic possibility for these patients. This population is deemed to be at high risk of mortality after heart transplantation, although their long-term survival is similar to that of patients transplanted for other reasons. Indeed, heart transplantation in adults with congenital heart disease is often challenging, because of several potential problems: complex cardiac and vascular anatomy, multiple previous palliative and corrective surgeries, and effects on other organs (kidney, liver, lungs) of long-standing cardiac dysfunction or cyanosis, with frequent elevation of pulmonary vascular resistance. In this review, we focus on the specific problems relating to heart and heart-lung transplantation in this population, revisit the indications/contraindications, and update the long-term outcomes.

  2. Race By Hearts

    DEFF Research Database (Denmark)

    Sonne, Tobias; Jensen, Mads Møller

    2014-01-01

    In this paper, we explore the qualities of sharing biometric data in re- al-time between athletes, in order to increase two motivational factors for gym- goers: Enjoyment and social interaction. We present a novel smartphone appli- cation, called Race By Hearts, which enables competition based...... on heart rate data sharing between users in real-time. Through an empirical study conducted in the gym, we show that sharing biometric data in real-time can strengthen so- cial relations between participants, increase motivation, and improve the en- joyment of the fitness activity. Nevertheless, we found...

  3. Protect Your Heart in the Heat

    Science.gov (United States)

    ... Cholesterol Tools & Resources Congenital Defects Children & Adults About Congenital Heart Defects The Impact of Congenital Heart Defects Understand Your Risk for Congenital Heart Defects Symptoms & ...

  4. When a Heart Murmur Signals Valve Disease

    Science.gov (United States)

    ... Cholesterol Tools & Resources Congenital Defects Children & Adults About Congenital Heart Defects The Impact of Congenital Heart Defects Understand Your Risk for Congenital Heart Defects Symptoms & ...

  5. Combined heart-kidney transplantation after total artificial heart insertion.

    Science.gov (United States)

    Ruzza, A; Czer, L S C; Ihnken, K A; Sasevich, M; Trento, A; Ramzy, D; Esmailian, F; Moriguchi, J; Kobashigawa, J; Arabia, F

    2015-01-01

    We present the first single-center report of 2 consecutive cases of combined heart and kidney transplantation after insertion of a total artificial heart (TAH). Both patients had advanced heart failure and developed dialysis-dependent renal failure after implantation of the TAH. The 2 patients underwent successful heart and kidney transplantation, with restoration of normal heart and kidney function. On the basis of this limited experience, we consider TAH a safe and feasible option for bridging carefully selected patients with heart and kidney failure to combined heart and kidney transplantation. Recent FDA approval of the Freedom driver may allow outpatient management at substantial cost savings. The TAH, by virtue of its capability of providing pulsatile flow at 6 to 10 L/min, may be the mechanical circulatory support device most likely to recover patients with marginal renal function and advanced heart failure.

  6. Heart Truth for Women: If You Have Heart Disease

    Science.gov (United States)

    ... of physical activity • Unhealthy diet • Diabetes and prediabetes • Metabolic syndrome Other conditions and factors also may contribute to ... The Heart Truth is a way of informing women about what they can do to prevent heart ...

  7. Towards defining heart failure in adults with congenital heart disease.

    Science.gov (United States)

    Bolger, Aidan P; Gatzoulis, Michael A

    2004-12-01

    Injury to the myocardium disrupts geometric integrity and results in changes to intracardiac pressure, wall stress and tension, and the pattern of blood flow through the heart. Significant disruption to pump function results in heart failure which is defined in terms of symptoms: breathlessness and fatigue, signs of salt and water retention, and neurohormonal activation. This syndrome most commonly occurs in the context of injury due to ischaemic heart disease and dilated cardiomyopathy but because patients with congenital heart disease (CHD) are born with sometimes gross distortions of cardiac anatomy they too are subject to the forces that drive heart failure. This paper explores the available data relating to the clinical and neurohormonal manifestations of heart failure in patients with congenital heart disease and describes how, by additionally exploring events at a cellular level, we may be able to arrive at a definition of heart failure relevant to this population.

  8. Eccentric contractions lead to myofibrillar dysfunction in muscular dystrophy.

    Science.gov (United States)

    Blaauw, Bert; Agatea, Lisa; Toniolo, Luana; Canato, Marta; Quarta, Marco; Dyar, Kenneth A; Danieli-Betto, Daniela; Betto, Romeo; Schiaffino, Stefano; Reggiani, Carlo

    2010-01-01

    It is commonly accepted that skeletal muscles from dystrophin-deficient mdx mice are more susceptible than those from wild-type mice to damage from eccentric contractions. However, the downstream mechanisms involved in this enhanced force drop remain controversial. We studied the reduction of contractile force induced by eccentric contractions elicited in vivo in the gastrocnemius muscle of wild-type mice and three distinct models of muscle dystrophy: mdx, alpha-sarcoglycan (Sgca)-null, and collagen 6A1 (Col6a1)-null mice. In mdx and Sgca-null mice, force decreased 35% compared with 14% in wild-type mice. Drop of force in Col6a1-null mice was comparable to that in wild-type mice. To identify the determinants of the force drop, we measured force generation in permeabilized fibers dissected from gastrocnemius muscle that had been exposed in vivo to eccentric contractions and from the contralateral unstimulated muscle. A force loss in skinned fibers after in vivo eccentric contractions was detectable in fibers from mdx and Sgca-null, but not wild-type and Col6a1-null, mice. The enhanced force reduction in mdx and Sgca-null mice was observed only when eccentric contractions were elicited in vivo, since eccentric contractions elicited in vitro had identical effects in wild-type and dystrophic skinned fibers. These results suggest that 1) the enhanced force loss is due to a myofibrillar impairment that is present in all fibers, and not to individual fiber degeneration, and 2) the mechanism causing the enhanced force reduction is active in vivo and is lost after fiber permeabilization.

  9. Treatment with a nitric oxide-donating NSAID alleviates functional muscle ischemia in the mouse model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Thomas, Gail D; Ye, Jianfeng; De Nardi, Claudio; Monopoli, Angela; Ongini, Ennio; Victor, Ronald G

    2012-01-01

    In patients with Duchenne muscular dystrophy (DMD) and the standard mdx mouse model of DMD, dystrophin deficiency causes loss of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma, producing functional ischemia when the muscles are exercised. We asked if functional muscle ischemia would be eliminated and normal blood flow regulation restored by treatment with an exogenous nitric oxide (NO)-donating drug. Beginning at 8 weeks of age, mdx mice were fed a standard diet supplemented with 1% soybean oil alone or in combination with a low (15 mg/kg) or high (45 mg/kg) dose of HCT 1026, a NO-donating nonsteroidal anti-inflammatory agent which has previously been shown to slow disease progression in the mdx model. After 1 month of treatment, vasoconstrictor responses to intra-arterial norepinephrine (NE) were compared in resting and contracting hindlimbs. In untreated mdx mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired, resulting in functional ischemia: NE evoked similar decreases in femoral blood flow velocity and femoral vascular conductance (FVC) in the contracting compared to resting hindlimbs (ΔFVC contraction/ΔFVC rest=0.88 ± 0.03). NE-induced functional ischemia was unaffected by low dose HCT 1026 (ΔFVC ratio=0.92 ± 0.04; P>0.05 vs untreated), but was alleviated by the high dose of the drug (ΔFVC ratio=0.22 ± 0.03; P<0.05 vs untreated or low dose). The beneficial effect of high dose HCT 1026 was maintained with treatment up to 3 months. The effect of the NO-donating drug HCT 1026 to normalize blood flow regulation in contracting mdx mouse hindlimb muscles suggests a putative novel treatment for DMD. Further translational research is warranted.

  10. Heart Health: Learn the Truth About Your Heart

    Science.gov (United States)

    ... Bar Home Current Issue Past Issues Cover Story Heart Health Learn the Truth About Your Heart Past Issues / Winter 2009 Table of Contents For ... turn Javascript on. Photo: iStock February is American Heart Month. Now is the time to make sure ...

  11. Sweet & Simple Clay Hearts

    Science.gov (United States)

    White, Heather

    2010-01-01

    Nothing pleases parents more than receiving handmade gifts from their children, especially if the gift is in the shape of a heart. Nothing pleases an art teacher more than having a lesson that is easy to follow, teaches basic skills, and enables students to be successful with the activity. In this article, the author describes how to create a…

  12. Copeptin in Heart Failure

    DEFF Research Database (Denmark)

    Balling, Louise; Gustafsson, Finn

    2016-01-01

    Heart failure (HF) is one of the most common causes of hospitalization and mortality in the modern Western world and an increasing proportion of the population will be affected by HF in the future. Although HF management has improved quality of life and prognosis, mortality remains very high...

  13. Diabetic Heart Disease

    Science.gov (United States)

    ... develop DHD. The higher a person's blood sugar level is, the higher his or her risk of DHD. Diabetes affects heart disease risk in three major ways. ... is that many lifestyle changes help control multiple risk factors. For example, ... treatment plan for diabetes and see your doctor for ongoing care. If ...

  14. Hypertensive Heart Disease

    DEFF Research Database (Denmark)

    Wachtell, Kristian

    2011-01-01

    Abstract Hypertensive heart disease is prevalent and during the last decade it has been determined that patients with left ventricular (LV) hypertrophy have increased cardiovascular morbidity and mortality. However, many have doubted the effectiveness of LV mass assessment because it is difficult...

  15. Congenital Heart Information Network

    Science.gov (United States)

    ... and Uwe Baemayr for The Congenital Heart Information Network Exempt organization under Section 501(c)3. Copyright ©1996 - 2016 C.H.I.N. All rights reserved TX4-390-685 Original site design and HTML by Panoptic Communications

  16. Heart Disease and Stroke

    Centers for Disease Control (CDC) Podcasts

    2013-09-03

    In this podcast, Dr. Tom Frieden, CDC Director, discusses the number one killer in the United States - heart disease and stroke.  Created: 9/3/2013 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 3/6/2014.

  17. Congenital heart disease

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    970296 Evaluating the degree of pulmonary vascularlesions in congenital heart disease with selective pul-monary angiography. PAN Shiwei(潘世伟), et al.Fuwai Hosp, CAMS & PUMC, Beijing, 100037. Chin JCardiol 1997; 25(1): 39-41. Objective: To evaluate the degree of pulmonary vas-

  18. [Echinococcosis of the heart].

    Science.gov (United States)

    Rein, R; Niggemann, B; Runge, M

    1996-06-01

    Human disease caused by echinococcus granulosus is rare in Northern Europe, but is seen increasingly due to migration of labour and of tourism to endemic areas e. g. Southern Europe and the Middle East. Echinococcosis of the heart occurs in only 0.5 to 2% of cases of echinococcosis. Diagnosis is difficult because of the long latency between infection and manifestation of disease, and also because symptoms are unspecific. It is a diagnosis "to think of". Apart from a thorough history serological tests and medical imaging (ultrasound, X-rays, computed tomography) are used in the diagnosis of echinococcosis. Surgery is the preferred therapy, if not feasible medical treatment with benzimidazoles (Albendazole and Mebendazole) is effective. We describe a case of echinococcosis of the heart as the only manifestation of the disease: a 34-year-old male Turkish patient came in severe cardiac shock due to cardiac tamponade to the emergency department. Immediate heart surgery revealed a pericardium filled with cysts of echinococcus granulosus, infiltrating the left ventricle of the heart (Figure 1). The cysts were removed and the patient was put on a 2-year course of Mebendazole. The patient is free of relapse for more than 6 years now and he is considered to be cured.

  19. Feedback on heart attack.

    Science.gov (United States)

    Pearce, Lynne

    2016-04-13

    The Royal Brompton & Harefield NHS Foundation Trust in London is the largest heart and lung centre in the UK. This article explores a project carried out by nurses at the trust looking at the experiences of having an acute myocardial infarction, and how patients felt about taking part in a research study.

  20. The Danish heart register

    DEFF Research Database (Denmark)

    Abildstrøm, Steen Z; Madsen, Mette

    2011-01-01

    Introduction: The Danish Heart Register (DHR) is a clinical database of invasive procedures within cardiology. Content: All providers of these procedures have been obliged to report to DHR since 2000. DHR is used to monitor the activity and quality of the procedures and serves as a data source...

  1. Educating the Heart

    Science.gov (United States)

    Schwartz, Sherry

    2007-01-01

    Japan's elementary and junior high schools have a formal, nationally mandated moral curriculum called Kokoro-no-kyoiku--education of the heart. Japanese educators include moral growth as an integral part of one's intellectual growth and believe that democratic societies must promote virtuous decision making. Moral education in Japan nurtures the…

  2. Unlock Their Lonely Hearts.

    Science.gov (United States)

    Fu, Danling

    1998-01-01

    Argues that, for new immigrant children, literacy education that challenges students to speak and engage in meaningful work (not worksheets and handwriting practice) is the key to initiating them into American culture, to helping them feel this country is their home, and to unlocking their lonely hearts. Focuses on the special problems of Chinese…

  3. Types of Heart Block

    Science.gov (United States)

    ... P wave as it normally would. If an electrical signal is blocked before it reaches the ventricles, they won't contract and pump blood to the lungs and the rest of the body. Second-degree heart block is divided into two ...

  4. Stress and Heart Health

    Science.gov (United States)

    ... also zap your energy, wreak havoc on your sleep and make you feel cranky, forgetful and out of control. A stressful situation sets off a chain of events. Your body releases adrenaline, a hormone that temporarily causes your breathing and heart rate to speed up and your blood pressure to ...

  5. Exercise and Your Heart.

    Science.gov (United States)

    National Heart and Lung Inst. (DHHS/NIH), Bethesda, MD.

    This pamphlet presents information on the effects of physical activity on the heart and practical guidelines for starting and staying on an exercise program. The following topics are discussed: (1) the benefits of getting sufficient exercise; (2) possible risks in exercising compared to benefits; (3) when to seek doctor's advice and prevention of…

  6. Mental Health and Heart Health

    Science.gov (United States)

    ... Recognition & Awards Healthy Workplace Food and Beverage Toolkit Mental Health and Heart Health Updated:Nov 10,2015 For years, doctors thought the connection between mental health and heart health was strictly behavioral – such as ...

  7. What Is a Heart Murmur?

    Science.gov (United States)

    ... Holes in the Heart How the Heart Works Patent Ductus Arteriosus Stress Testing Tetralogy of Fallot Rate This Content: Updated: December 9, 2016 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA OIG CONTACT ...

  8. Hispanics and Heart Disease, Stroke

    Science.gov (United States)

    ... Thromboembolism Aortic Aneurysm More Hispanics and Heart Disease, Stroke Updated:Aug 30,2016 Heart disease is the No. 1 killer for all Americans and stroke is the fifth leading cause of death. Hispanics ...

  9. Diabetes, Heart Disease, and Stroke

    Science.gov (United States)

    ... Disease, & Other Dental Problems Diabetes & Sexual & Urologic Problems Diabetes, Heart Disease, and Stroke Having diabetes means that ... help to stop. What is the link between diabetes, heart disease, and stroke? Over time, high blood ...

  10. How Is Heart Failure Diagnosed?

    Science.gov (United States)

    ... your heart pumps blood when it beats. Doppler Ultrasound A Doppler ultrasound uses sound waves to measure ... when your heart is working hard and beating fast. During stress testing , you exercise to make your ...

  11. Dental Health and Heart Health

    Science.gov (United States)

    ... Check Meal Certification Program Nutrition Requirements Heart-Check Professional Resources Contact the Heart-Check Certification Program Simple Cooking and Recipes Dining Out Choosing a Restaurant Deciphering the Menu Ordering Your Meal Eating Fast ...

  12. FastStats: Heart Disease

    Science.gov (United States)

    ... this? Submit What's this? Submit Button NCHS Home Heart Disease Recommend on Facebook Tweet Share Compartir Data are ... the U.S. Morbidity Number of adults with diagnosed heart disease: 28.4 million Percent of adults with diagnosed ...

  13. Adults with Congenital Heart Defects

    Science.gov (United States)

    ... Disease Venous Thromboembolism Aortic Aneurysm More Web Booklet: Adults With Congenital Heart Defects Updated:Aug 29,2017 ... the list below to learn more. Web Booklet: Adults With Congenital Heart Defects Introduction Introduction: Adults with ...

  14. Heart Disease: Symptoms, Diagnosis, Treatment

    Science.gov (United States)

    ... Past Issues Cover Story Heart Health Heart Disease: Symptoms, Diagnosis, Treatment Past Issues / Winter 2009 Table of Contents ... to view a larger version of the image Symptoms It is very important to learn the signs ...

  15. Hypoplastic left heart syndrome

    Directory of Open Access Journals (Sweden)

    Thiagarajan Ravi

    2007-05-01

    Full Text Available Abstract Hypoplastic left heart syndrome(HLHS refers to the abnormal development of the left-sided cardiac structures, resulting in obstruction to blood flow from the left ventricular outflow tract. In addition, the syndrome includes underdevelopment of the left ventricle, aorta, and aortic arch, as well as mitral atresia or stenosis. HLHS has been reported to occur in approximately 0.016 to 0.036% of all live births. Newborn infants with the condition generally are born at full term and initially appear healthy. As the arterial duct closes, the systemic perfusion becomes decreased, resulting in hypoxemia, acidosis, and shock. Usually, no heart murmur, or a non-specific heart murmur, may be detected. The second heart sound is loud and single because of aortic atresia. Often the liver is enlarged secondary to congestive heart failure. The embryologic cause of the disease, as in the case of most congenital cardiac defects, is not fully known. The most useful diagnostic modality is the echocardiogram. The syndrome can be diagnosed by fetal echocardiography between 18 and 22 weeks of gestation. Differential diagnosis includes other left-sided obstructive lesions where the systemic circulation is dependent on ductal flow (critical aortic stenosis, coarctation of the aorta, interrupted aortic arch. Children with the syndrome require surgery as neonates, as they have duct-dependent systemic circulation. Currently, there are two major modalities, primary cardiac transplantation or a series of staged functionally univentricular palliations. The treatment chosen is dependent on the preference of the institution, its experience, and also preference. Although survival following initial surgical intervention has improved significantly over the last 20 years, significant mortality and morbidity are present for both surgical strategies. As a result pediatric cardiologists continue to be challenged by discussions with families regarding initial decision

  16. Modelling heart rate kinetics.

    Science.gov (United States)

    Zakynthinaki, Maria S

    2015-01-01

    The objective of the present study was to formulate a simple and at the same time effective mathematical model of heart rate kinetics in response to movement (exercise). Based on an existing model, a system of two coupled differential equations which give the rate of change of heart rate and the rate of change of exercise intensity is used. The modifications introduced to the existing model are justified and discussed in detail, while models of blood lactate accumulation in respect to time and exercise intensity are also presented. The main modification is that the proposed model has now only one parameter which reflects the overall cardiovascular condition of the individual. The time elapsed after the beginning of the exercise, the intensity of the exercise, as well as blood lactate are also taken into account. Application of the model provides information regarding the individual's cardiovascular condition and is able to detect possible changes in it, across the data recording periods. To demonstrate examples of successful numerical fit of the model, constant intensity experimental heart rate data sets of two individuals have been selected and numerical optimization was implemented. In addition, numerical simulations provided predictions for various exercise intensities and various cardiovascular condition levels. The proposed model can serve as a powerful tool for a complete means of heart rate analysis, not only in exercise physiology (for efficiently designing training sessions for healthy subjects) but also in the areas of cardiovascular health and rehabilitation (including application in population groups for which direct heart rate recordings at intense exercises are not possible or not allowed, such as elderly or pregnant women).

  17. Modelling heart rate kinetics.

    Directory of Open Access Journals (Sweden)

    Maria S Zakynthinaki

    Full Text Available The objective of the present study was to formulate a simple and at the same time effective mathematical model of heart rate kinetics in response to movement (exercise. Based on an existing model, a system of two coupled differential equations which give the rate of change of heart rate and the rate of change of exercise intensity is used. The modifications introduced to the existing model are justified and discussed in detail, while models of blood lactate accumulation in respect to time and exercise intensity are also presented. The main modification is that the proposed model has now only one parameter which reflects the overall cardiovascular condition of the individual. The time elapsed after the beginning of the exercise, the intensity of the exercise, as well as blood lactate are also taken into account. Application of the model provides information regarding the individual's cardiovascular condition and is able to detect possible changes in it, across the data recording periods. To demonstrate examples of successful numerical fit of the model, constant intensity experimental heart rate data sets of two individuals have been selected and numerical optimization was implemented. In addition, numerical simulations provided predictions for various exercise intensities and various cardiovascular condition levels. The proposed model can serve as a powerful tool for a complete means of heart rate analysis, not only in exercise physiology (for efficiently designing training sessions for healthy subjects but also in the areas of cardiovascular health and rehabilitation (including application in population groups for which direct heart rate recordings at intense exercises are not possible or not allowed, such as elderly or pregnant women.

  18. Modelling Heart Rate Kinetics

    Science.gov (United States)

    Zakynthinaki, Maria S.

    2015-01-01

    The objective of the present study was to formulate a simple and at the same time effective mathematical model of heart rate kinetics in response to movement (exercise). Based on an existing model, a system of two coupled differential equations which give the rate of change of heart rate and the rate of change of exercise intensity is used. The modifications introduced to the existing model are justified and discussed in detail, while models of blood lactate accumulation in respect to time and exercise intensity are also presented. The main modification is that the proposed model has now only one parameter which reflects the overall cardiovascular condition of the individual. The time elapsed after the beginning of the exercise, the intensity of the exercise, as well as blood lactate are also taken into account. Application of the model provides information regarding the individual’s cardiovascular condition and is able to detect possible changes in it, across the data recording periods. To demonstrate examples of successful numerical fit of the model, constant intensity experimental heart rate data sets of two individuals have been selected and numerical optimization was implemented. In addition, numerical simulations provided predictions for various exercise intensities and various cardiovascular condition levels. The proposed model can serve as a powerful tool for a complete means of heart rate analysis, not only in exercise physiology (for efficiently designing training sessions for healthy subjects) but also in the areas of cardiovascular health and rehabilitation (including application in population groups for which direct heart rate recordings at intense exercises are not possible or not allowed, such as elderly or pregnant women). PMID:25876164

  19. Give your heart a workout

    Science.gov (United States)

    ... to your health care provider before starting an exercise program. The Benefits of Exercise Exercise helps your heart in several ways. Burns ... is the best type for your heart. Aerobic exercise is any activity that uses ... faster. To benefit your heart, experts recommend getting at least 30 ...

  20. Heart murmurs and other sounds

    Science.gov (United States)

    ... ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College ... team. Related MedlinePlus Health Topics Congenital Heart Defects Heart Valve Diseases Browse the Encyclopedia A.D.A.M., Inc. ...

  1. Chelation for Coronary Heart Disease

    Science.gov (United States)

    ... V W X Y Z Chelation for Coronary Heart Disease Share: © AHA Coronary heart disease is a leading cause of death among both ... health approach . The use of disodium EDTA for heart disease has not been approved by the U.S. Food ...

  2. What Is Coronary Heart Disease?

    Science.gov (United States)

    ... from the NHLBI on Twitter. What Is Coronary Heart Disease? Español Coronary heart disease (CHD) is a disease in which a waxy ... medical procedures can help prevent or treat coronary heart disease. These treatments may reduce the risk of related ...

  3. Ejection Fraction Heart Failure Measurement

    Science.gov (United States)

    ... Disease Venous Thromboembolism Aortic Aneurysm More Ejection Fraction Heart Failure Measurement Updated:Feb 15,2017 The ejection fraction ( ... failure This content was last reviewed April 2015. Heart Failure • Home • About Heart Failure • Causes and Risks for ...

  4. Aging, telomeres and heart failure

    NARCIS (Netherlands)

    Wong, Liza S. M.; van der Harst, Pim; de Boer, Rudolf A.; Huzen, Jardi; van Gilst, Wiek H.; van Veldhuisen, Dirk J.

    2010-01-01

    During normal aging, the heart undergoes functional, morphological and cellular changes. Although aging per se does not lead to the expression of heart failure, it is likely that age-associated changes lower the threshold for the manifestation of signs and symptoms of heart failure. In patients, the

  5. Heart failure - fluids and diuretics

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000112.htm Heart failure - fluids and diuretics To use the sharing features on ... at Home When you have heart failure, your heart does not pump out enough blood. This causes fluids to build up in your body. If you ...

  6. What Is a Total Artificial Heart?

    Science.gov (United States)

    ... the NHLBI on Twitter. What Is a Total Artificial Heart? A total artificial heart (TAH) is a device ... outside power source. Normal Heart and CardioWest Total Artificial Heart Figure A shows the normal structure and location ...

  7. Heart Surgery: MedlinePlus Health Topic

    Science.gov (United States)

    ... Is a Pediatric Heart Surgeon? (American Academy of Pediatrics) Also in Spanish Patient Handouts Aortic valve surgery - open (Medical Encyclopedia) ... Spanish Open heart surgery (Medical Encyclopedia) Also in Spanish ... heart surgery Pediatric heart surgery - discharge Sternal exploration or closure Related ...

  8. Heart Failure in Children and Adolescents

    Science.gov (United States)

    ... the heart to beat too slow or too fast. Sometimes one of the heart valves does not open properly causing pressure to back up inside the heart chambers. Rarely, severe chest trauma may damage the heart. Children with muscular dystrophy ...

  9. What Is a Pediatric Heart Surgeon?

    Science.gov (United States)

    ... Text Size Email Print Share What is a Pediatric Heart Surgeon? Page Content Article Body If your ... require heart surgery. What Kind of Training Do Pediatric Heart Surgeons Have? Pediatric heart surgeons are medical ...

  10. Heart Disease Affects Women of All Ages

    Science.gov (United States)

    Skip Navigation Bar Home Current Issue Past Issues Heart Disease Affects Women of All Ages Past Issues / Winter ... weeks of a heart attack. For Women with Heart Disease: About 6 million American women have coronary heart ...

  11. Heart rate reduction in coronary artery disease and heart failure.

    Science.gov (United States)

    Ferrari, Roberto; Fox, Kim

    2016-08-01

    Elevated heart rate is known to induce myocardial ischaemia in patients with coronary artery disease (CAD), and heart rate reduction is a recognized strategy to prevent ischaemic episodes. In addition, clinical evidence shows that slowing the heart rate reduces the symptoms of angina by improving microcirculation and coronary flow. Elevated heart rate is an established risk factor for cardiovascular events in patients with CAD and in those with chronic heart failure (HF). Accordingly, reducing heart rate improves prognosis in patients with HF, as demonstrated in SHIFT. By contrast, data from SIGNIFY indicate that heart rate is not a modifiable risk factor in patients with CAD who do not also have HF. Heart rate is also an important determinant of cardiac arrhythmias; low heart rate can be associated with atrial fibrillation, and high heart rate after exercise can be associated with sudden cardiac death. In this Review, we critically assess these clinical findings, and propose hypotheses for the variable effect of heart rate reduction in cardiovascular disease.

  12. Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of α1-syntrophin and α-dystrobrevin in skeletal muscles of mdx mice.

    Science.gov (United States)

    Koo, Taeyoung; Malerba, Alberto; Athanasopoulos, Takis; Trollet, Capucine; Boldrin, Luisa; Ferry, Arnaud; Popplewell, Linda; Foster, Helen; Foster, Keith; Dickson, George

    2011-11-01

    Duchenne muscular dystrophy is a severe X-linked inherited muscle wasting disorder caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vectors have been extensively used to deliver genes efficiently for dystrophin expression in skeletal muscles. To overcome limited packaging capacity of AAV vectors (damage in the mdx mice compared with MD1. These results suggest that the incorporation of helix 1 of the coiled-coil motif in the CT domain of dystrophin to the microdystrophins will substantially improve their efficiency in restoring muscle function in patients with Duchenne muscular dystrophy.

  13. Heart fields and cardiac morphogenesis.

    Science.gov (United States)

    Kelly, Robert G; Buckingham, Margaret E; Moorman, Antoon F

    2014-10-01

    In this review, we focus on two important steps in the formation of the embryonic heart: (i) the progressive addition of late differentiating progenitor cells from the second heart field that drives heart tube extension during looping morphogenesis, and (ii) the emergence of patterned proliferation within the embryonic myocardium that generates distinct cardiac chambers. During the transition between these steps, the major site of proliferation switches from progenitor cells outside the early heart to proliferation within the embryonic myocardium. The second heart field and ballooning morphogenesis concepts have major repercussions on our understanding of human heart development and disease. In particular, they provide a framework to dissect the origin of congenital heart defects and the regulation of myocardial proliferation and differentiation of relevance for cardiac repair.

  14. The Heart of Matter

    CERN Document Server

    Godbole, Rohini M

    2010-01-01

    In this article I trace the development of the human understanding of the "Heart of Matter" from early concepts of "elements" (or alternatively "Panchmahabhootas") to the current status of "quarks" and "leptons" as the fundamental constituents of matter, interacting together via exchange of the various force carrier particles called "gauge bosons" such as the photon, W/Z-boson etc. I would like to show how our understanding of the fundamental constituents of matter has gone hand in hand with our understanding of the fundamental forces in nature. I will also outline how the knowledge of particle physics at the "micro" scale of less than a Fermi(one millionth of a nanometer), enables us to offer explanations of Cosmological observations at the "macro" scale. Consequently these observations, may in turn, help us address some very fundamental questions of the Physics at the "Heart of the Matter".

  15. Heart, lipids and hormones

    Directory of Open Access Journals (Sweden)

    Peter Wolf

    2017-05-01

    Full Text Available Cardiovascular disease is the leading cause of death in general population. Besides well-known risk factors such as hypertension, impaired glucose tolerance and dyslipidemia, growing evidence suggests that hormonal changes in various endocrine diseases also impact the cardiac morphology and function. Recent studies highlight the importance of ectopic intracellular myocardial and pericardial lipid deposition, since even slight changes of these fat depots are associated with alterations in cardiac performance. In this review, we overview the effects of hormones, including insulin, thyroid hormones, growth hormone and cortisol, on heart function, focusing on their impact on myocardial lipid metabolism, cardiac substrate utilization and ectopic lipid deposition, in order to highlight the important role of even subtle hormonal changes for heart function in various endocrine and metabolic diseases.

  16. [Hypertension and heart].

    Science.gov (United States)

    Hennersdorf, Marcus G; Strauer, Bodo E

    2006-03-22

    The term hypertensive heart disease covers the entities left ventricular hypertrophy, microangiopathy, diastolic and systolic dysfunction, und increased risk of arrhythmias. From the pathophysiological point of view this is caused by hypertrophy of cardiac myocytes, interstitial fibrosis and media hypertrophy of the arterioles. As an earliest sign of hypertensive heart disease a microangiopathy can be diagnosed. Also a diastolic dysfunction can be found as an early change. In further persisting arterial hypertension left ventricular hypertrophy develops (often asymmetric), and later a systolic dysfunction. Clinically, the patients suffer from angina pectoris, dyspnea and rhythm disorders. Left ventricular hypertrophy is associated with an increased risk of ventricular malignant arrhythmias. Thus, the main therapeutic principle should be antihypertensive therapy with the goal of regression of hypertrophy and, as a consequence, a decreased mortality risk.

  17. Ischaemic heart disease

    DEFF Research Database (Denmark)

    Hansen, Louise Houlberg; Mikkelsen, Søren

    2013-01-01

    Purpose. Correct prehospital diagnosis of ischaemic heart disease (IHD) may accelerate and improve the treatment. We sought to evaluate the accuracy of prehospital diagnoses of ischemic heart diseases assigned by physicians. Methods. The Mobile Emergency Care Unit (MECU) in Odense, Denmark...... to the relevant ward. Of these patients, 40,0% had their preliminary diagnosis of IHD confirmed. 14,1% of all patients admitted to the hospital were diagnosed with nonheart conditions. Preliminary diagnoses of STEMI had an accuracy of 87,5%. Conclusions. The preliminary IHD diagnoses assigned by the MECU...... physicians were acceptable. In case of STEMI patients the diagnostic accuracy was excellent. In this study there was an apparent overtriage....

  18. "Head versus heart"

    Directory of Open Access Journals (Sweden)

    Paul Rozin

    2007-08-01

    Full Text Available Most American respondents give ``irrational,'' magical responses in a variety of situations that exemplify the sympathetic magical laws of similarity and contagion. In most of these cases, respondents are aware that their responses (usually rejections, as of fudge crafted to look like dog feces, or a food touched by a sterilized, dead cockroach are not ``scientifically'' justified, but they are willing to avow them. We interpret this, in some sense, as ``heart over head.'' We report in this study that American adults and undergraduates are substantially less likely to acknowledge magical effects when the judgments involve money (amount willing to pay to avoid an ``unpleasant'' magical contact than they are when using preference or rating measures. We conclude that in ``head-heart'' conflicts of this type, money tips the balance towards the former, or, in other words, that money makes the mind less magical.

  19. Heart Imaging System

    Science.gov (United States)

    1993-01-01

    Johnson Space Flight Center's device to test astronauts' heart function in microgravity has led to the MultiWire Gamma Camera, which images heart conditions six times faster than conventional devices. Dr. Jeffrey Lacy, who developed the technology as a NASA researcher, later formed Proportional Technologies, Inc. to develop a commercially viable process that would enable use of Tantalum-178 (Ta-178), a radio-pharmaceutical. His company supplies the generator for the radioactive Ta-178 to Xenos Medical Systems, which markets the camera. Ta-178 can only be optimally imaged with the camera. Because the body is subjected to it for only nine minutes, the radiation dose is significantly reduced and the technique can be used more frequently. Ta-178 also enables the camera to be used on pediatric patients who are rarely studied with conventional isotopes because of the high radiation dosage.

  20. Heart and radiation

    Directory of Open Access Journals (Sweden)

    Lauro Martins Júnior

    2011-12-01

    Full Text Available ABSTRATC The heart exposition to ionizing radiation may produce lesions in cardiac structures, acute (in most of cases benign and reversible, or months and even years later. There is a direct relationship of severity of lesions with radiation doses. The clinical picture receives a new denomination: radiation induced cardiopathy. The more frequent use of radiation in diagnosis and therapeutics increases the importance of their knowledge and especially their prevention.

  1. Thyroid and the Heart

    OpenAIRE

    A Karas; Obrezan, A.

    2009-01-01

    The cardiovascular signs and symptoms of thyroid disease are some of the most clinically relevant findings that accompany both hyperthyroidism and hypothyroidism. On the basis of the understanding of the mechanisms of thyroid hormone action on the heart and cardiovascular system, it is possible to explain the changes in cardiac output, cardiac contractility, blood pressure and rhythm disturbances that result from thyroid dysfunction. In the present review will integrate what is known about th...

  2. "Head versus heart"

    OpenAIRE

    2007-01-01

    Most American respondents give ``irrational,'' magical responses in a variety of situations that exemplify the sympathetic magical laws of similarity and contagion. In most of these cases, respondents are aware that their responses (usually rejections, as of fudge crafted to look like dog feces, or a food touched by a sterilized, dead cockroach) are not ``scientifically'' justified, but they are willing to avow them. We interpret this, in some sense, as ``heart over head.'' We report in this ...

  3. Pediatric heart transplantation

    OpenAIRE

    Schweiger, Martin; Stiasny, Brian; Dave, Hitendu; Cavigelli-Brunner, Anna; Balmer, Christian; Kretschmar, Oliver; Bürki, Christoph; Klauwer, Dietrich; Hübler, Michael

    2015-01-01

    Pediatric heart transplantation (pHTx) represents a small (14%) but very important and particular part in the field of cardiac transplantation. This treatment has lifelong impact on children. To achieve the best short and especially long-term survival with adequate quality of life, which is of crucial importance for this young patient population, one has to realize and understand the differences with adult HTx. Indication for transplantation, waitlist management including ABO incompatible (AB...

  4. Coronary heart disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008277 Relationship between pulse wave velocity and the NYHA classification of coronary insufficiency.SUN Weiping(孙卫平),et al.Dept Cardiol,Tongji Hosp Tongji Univ,Shanghai 200065.Chin J Intern Med 2008;47(5):382-384.Objective To investigate the relationship between brachial-ankle pulse wave velocity(baPWV)and different stage of cardiac dysfunction.Methods 253 consecutive patients with coronary atherosclerotic heart disease

  5. Biological heart valves.

    Science.gov (United States)

    Ciubotaru, Anatol; Cebotari, Serghei; Tudorache, Igor; Beckmann, Erik; Hilfiker, Andres; Haverich, Axel

    2013-10-01

    Cardiac valvular pathologies are often caused by rheumatic fever in young adults, atherosclerosis in elderly patients, or by congenital malformation of the heart in children, in effect affecting almost all population ages. Almost 300,000 heart valve operations are performed worldwide annually. Tissue valve prostheses have certain advantages over mechanical valves such as biocompatibility, more physiological hemodynamics, and no need for life-long systemic anticoagulation. However, the major disadvantage of biological valves is related to their durability. Nevertheless, during the last decade, the number of patients undergoing biological, rather than mechanical, valve replacement has increased from half to more than three-quarters for biological implants. Continuous improvement in valve fabrication includes development of new models and shapes, novel methods of tissue treatment, and preservation and implantation techniques. These efforts are focused not only on the improvement of morbidity and mortality of the patients but also on the improvement of their quality of life. Heart valve tissue engineering aims to provide durable, "autologous" valve prostheses. These valves demonstrate adaptive growth, which may avoid the need of repeated operations in growing patients.

  6. Heart rate variability and heart rate recovery as prognostic factors

    OpenAIRE

    GRAD, COSMIN

    2015-01-01

    Background and aim Heart rate (HR) can appear static and regular at rest, during exercise or recovery after exercise. However, HR is constantly adjusted due to factors such as breathing, blood pressure control, thermoregulation and the renin-angiotensin system, leading to a more dynamic response that can be quantified using HRV (heart rate variability). HRV is defined as the deviation in time between successive normal heart beat and is a noninvasive method to measure the total variation in a ...

  7. The heart and the liver

    DEFF Research Database (Denmark)

    Møller, Søren; Dümcke, Christine Winkler; Krag, Aleksander

    2009-01-01

    against the heart failure. Transjugular intrahepatic portosystemic shunt insertion and liver transplantation affect cardiac function in portal hypertensive patients and cause stress to the cirrhotic heart, with a risk of perioperative heart failure. The risk and prevalence of coronary artery disease......Cardiac failure affects the liver and liver dysfunction affects the heart. Chronic and acute heart failure can lead to cardiac cirrhosis and cardiogenic ischemic hepatitis. These conditions may impair liver function and treatment should be directed towards the primary heart disease and seek...... are increasing in cirrhotic patients and since perioperative mortality is high, careful evaluation of such patients with dobutamine stress echocardiography, coronary angiography and myocardial perfusion imaging is required prior to liver transplantation. Future research should focus on beneficial effects...

  8. Nuclear cardiology and heart failure

    Energy Technology Data Exchange (ETDEWEB)

    Giubbini, Raffaele; Bertagna, Francesco [University of Brescia, Department of Nuclear Medicine, Brescia (Italy); Milan, Elisa [Ospedale Di Castelfranco Veneto, Nuclear Medicine Unit, Castelfranco Veneto (Italy); Mut, Fernando; Dondi, Maurizio [International Atomic Energy Agency, Nuclear Medicine Section, Division of Human Health, Vienna (Austria); Metra, Marco [University of Brescia, Department of Cardiology, Brescia (Italy); Rodella, Carlo [Health Physics Department, Spedali Civili di Brescia, Brescia (Italy)

    2009-12-15

    The prevalence of heart failure in the adult population is increasing. It varies between 1% and 2%, although it mainly affects elderly people (6-10% of people over the age of 65 years will develop heart failure). The syndrome of heart failure arises as a consequence of an abnormality in cardiac structure, function, rhythm, or conduction. Coronary artery disease is the leading cause of heart failure and it accounts for this disorder in 60-70% of all patients affected. Nuclear techniques provide unique information on left ventricular function and perfusion by gated-single photon emission tomography (SPECT). Myocardial viability can be assessed by both SPECT and PET imaging. Finally, autonomic dysfunction has been shown to increase the risk of death in patients with heart disease and this may be applicable to all patients with cardiac disease regardless of aetiology. MIBG scanning has a very promising prognostic value in patients with heart failure. (orig.)

  9. Fluid dynamics of heart development.

    Science.gov (United States)

    Santhanakrishnan, Arvind; Miller, Laura A

    2011-09-01

    The morphology, muscle mechanics, fluid dynamics, conduction properties, and molecular biology of the developing embryonic heart have received much attention in recent years due to the importance of both fluid and elastic forces in shaping the heart as well as the striking relationship between the heart's evolution and development. Although few studies have directly addressed the connection between fluid dynamics and heart development, a number of studies suggest that fluids may play a key role in morphogenic signaling. For example, fluid shear stress may trigger biochemical cascades within the endothelial cells of the developing heart that regulate chamber and valve morphogenesis. Myocardial activity generates forces on the intracardiac blood, creating pressure gradients across the cardiac wall. These pressures may also serve as epigenetic signals. In this article, the fluid dynamics of the early stages of heart development is reviewed. The relevant work in cardiac morphology, muscle mechanics, regulatory networks, and electrophysiology is also reviewed in the context of intracardial fluid dynamics.

  10. Reduced Heart Rate Volatility

    Science.gov (United States)

    Grogan, Eric L.; Morris, John A.; Norris, Patrick R.; France, Daniel J.; Ozdas, Asli; Stiles, Renée A.; Harris, Paul A.; Dawant, Benoit M.; Speroff, Theodore

    2004-01-01

    Objective: To determine if using dense data capture to measure heart rate volatility (standard deviation) measured in 5-minute intervals predicts death. Background: Fundamental approaches to assessing vital signs in the critically ill have changed little since the early 1900s. Our prior work in this area has demonstrated the utility of densely sampled data and, in particular, heart rate volatility over the entire patient stay, for predicting death and prolonged ventilation. Methods: Approximately 120 million heart rate data points were prospectively collected and archived from 1316 trauma ICU patients over 30 months. Data were sampled every 1 to 4 seconds, stored in a relational database, linked to outcome data, and de-identified. HR standard deviation was continuously computed over 5-minute intervals (CVRD, cardiac volatility–related dysfunction). Logistic regression models incorporating age and injury severity score were developed on a test set of patients (N = 923), and prospectively analyzed in a distinct validation set (N = 393) for the first 24 hours of ICU data. Results: Distribution of CVRD varied by survival in the test set. Prospective evaluation of the model in the validation set gave an area in the receiver operating curve of 0.81 with a sensitivity and specificity of 70.1 and 80.0, respectively. CVRD predict death as early as 24 hours in the validation set. Conclusions: CVRD identifies a subgroup of patients with a high probability of dying. Death is predicted within first 24 hours of stay. We hypothesize CVRD is a surrogate for autonomic nervous system dysfunction. PMID:15319726

  11. Yoga and the heart

    Directory of Open Access Journals (Sweden)

    Rahul Mehrotra

    2016-01-01

    Full Text Available The concept of "Yoga" is currently gaining a lot of popularity worldwide owing to its various health benefits and other advantages such as safety and ease of practice. There is considerable evidence accumulating related to its benefits on health, especially cardiovascular health. There is, however, a lot of confusion related to the term "Yoga" in the various studies as it comprises several different practices. More good quality studies are needed utilizing different components of "Yoga" investigating their effects on cardiovascular disease. There is also a change in the understanding of the role of the heart in the human body.

  12. Mechanism of artificial heart

    CERN Document Server

    Yamane, Takashi

    2016-01-01

    This book first describes medical devices in relation to regenerative medicine before turning to a more specific topic: artificial heart technologies. Not only the pump mechanisms but also the bearing, motor mechanisms, and materials are described, including expert information. Design methods are described to enhance hemocompatibility: main concerns are reduction of blood cell damage and protein break, as well as prevention of blood clotting. Regulatory science from R&D to clinical trials is also discussed to verify the safety and efficacy of the devices.

  13. Heart Disease Detection Using Wavelets

    Science.gov (United States)

    González S., A.; Acosta P., J. L.; Sandoval M., M.

    2004-09-01

    We develop a wavelet based method to obtain standardized gray-scale chart of both healthy hearts and of hearts suffering left ventricular hypertrophy. The hypothesis that early bad functioning of heart can be detected must be tested by comparing the wavelet analysis of the corresponding ECD with the limit cases. Several important parameters shall be taken into account such as age, sex and electrolytic changes.

  14. Depression and Coronary Heart Disease

    OpenAIRE

    2012-01-01

    There are exciting findings in the field of depression and coronary heart disease. Whether diagnosed or simply self-reported, depression continues to mark very high risk for a recurrent acute coronary syndrome or for death in patients with coronary heart disease. Many intriguing mechanisms have been posited to be implicated in the association between depression and heart disease, and randomized controlled trials of depression treatment are beginning to delineate the types of depression manage...

  15. Heart rates during competitive orienteering.

    OpenAIRE

    Bird, S R; Bailey, R.; Lewis, J.

    1993-01-01

    This study investigated the heart rate profiles of 16 experienced, competitive orienteers (aged 15-62 years) during three competitive events. Each competitor was assessed over three different types of course which were classified as: fast run (FR), slow run (SR) and highly physical (HP). The results showed that all subjects recorded heart rates that were between 140 and 180 beats min-1 for the majority of each event (irrespective of age or course type). The heart rate data indicated that the ...

  16. [Cholinergic system of the heart].

    Science.gov (United States)

    Kučera, Matej; Hrabovská, Anna

    2015-12-01

    The cholinergic system of the heart can be either of neuronal or non-neuronal origin. The neuronal cholinergic system in the heart is represented by preganglionic parasympathetic pathways, intracardiac parasympathetic ganglia and postganglionic parasympathetic neurons projecting to the atria, SA node and AV node. The non-neuronal cholinergic system consists of cardiomyocytes that have complete equipment for synthesis and secretion of acetylcholine. Current knowledge suggests that the non-neuronal cholinergic system in the heart affects the regulation of the heart during sympathetic activation. The non-neuronal cholinergic system of the heart plays also a role in the energy metabolism of cardimyocites. Acetylcholine of both neuronal and non-neuronal origin acts in the heart through muscarinic and nicotinic receptors. The effect of acetylcholine in the heart is terminated by cholinesterases acetylcholinesterase and butyrylcholinesterase. Recently, papers suggest that the increased cholinergic tone in the heart by cholinesterase inhibitors has a positive effect on some cardiovascular disorders such as heart failure. For this reason, the cholinesterase inhibitors might be used in the treatment of certain cardiovascular disorders in the future.

  17. New medications for heart failure.

    Science.gov (United States)

    Gordin, Jonathan S; Fonarow, Gregg C

    2016-08-01

    Heart failure is common and results in substantial morbidity and mortality. Current guideline-based therapies for heart failure with reduced ejection fraction, including beta blockers, angiotensin converting enzyme (ACE) inhibitors, and aldosterone antagonists aim to interrupt deleterious neurohormonal pathways and have shown significant success in reducing morbidity and mortality associated with heart failure. Continued efforts to further improve outcomes in patients with heart failure with reduced ejection fraction have led to the first new-in-class medications approved for heart failure since 2005, ivabradine and sacubitril/valsartan. Ivabradine targets the If channels in the sinoatrial node of the heart, decreasing heart rate. Sacubitril/valsartan combines a neprilysin inhibitor that increases levels of beneficial vasodilatory peptides with an angiotensin receptor antagonist. On a background of previously approved, guideline-directed medical therapies for heart failure, these medications have shown improved clinical outcomes ranging from decreased hospitalizations in a select group of patients to a reduction in all-cause mortality across all pre-specified subgroups. In this review, we will discuss the previously established guideline-directed medical therapies for heart failure with reduced ejection fraction, the translational research that led to the development of these new therapies, and the results from the major clinical trials of ivabradine and sacubitril/valsartan. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Cardiomyocytic apoptosis and heart failure

    Institute of Scientific and Technical Information of China (English)

    Quanzhou Feng

    2008-01-01

    Heart failure is a major disease seriously threatening human health.Once left ventricular dysfunction develops,cardiac function usually deteriorates and progresses to congestive heart failure in several months or years even if no factors which accelerate the deterioration repeatedly exist.Mechanism through which cardiac function continually deteriorates is still unclear.Cardiomyocytic apoptosis can occur in acute stage of ischemic heart diseases and the compensated stage of cardiac dysfunction.In this review,we summarize recent advances in understanding the role of cardiomyocytic apoptosis in heart failure.

  19. Mushroom and Rape Heart Soup

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    100 grams mushrooms12 rape hearts5 grams salt2 grams MSG20 grams (2 tbsp) cooking oilWash mushrooms and slice. Clean the rape hearts, and cross-cut stem ends.Heat oil in a wok, and stir-fry the rape hearts for the short time it takes till their color changes. Add 750 grams (1 1/2 cups) of water. When boiling, add salt, MSG, and mushroom slices. Bring to the boil once more. Serve.Features: clear and refreshing.Effect: Nourishes the heart and stomach.

  20. High Altitude and Heart

    Directory of Open Access Journals (Sweden)

    Murat Yalcin

    2011-04-01

    Full Text Available Nowadays, situations associated with high altitude such as mountaineering, aviation increasingly draw the attention of people. Gas pressure decreases and hypoxia is encountered when climbing higher. Physiological and pathological responses of human body to different heights are different. Therefore, physiological and pathological changes that may occur together with height and to know the clinical outcomes of these are important . Acute mountain sickness caused by high altitude and high altitude cerebral edema are preventable diseases with appropriate precautions. Atmospheric oxygen decreasing with height, initiates many adaptive mechanisms. These adaptation mechanisms and acclimatization vary widely among individuals because of reasons such as environmental factors, exercise and cold. High altitude causes different changes in the cardiovascular system with various mechanisms. Although normal individuals easily adapt to these changes, this situation can lead to undesirable results in people with heart disease. For this reason, it should be known the effective evaluation of the people with known heart disease before traveling to high altitude and the complications due to the changes with height and the recommendations can be made to these patients. [TAF Prev Med Bull 2011; 10(2.000: 211-222