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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dystrophin-glycoprotein complex (DGC) is a multisubunit complex that connects the cytoskeleton of a muscle fiber to its surrounding extracellular matrix. Mutations in the DGC disrupt the complex and lead to muscular dystrophy. There are a few naturally occurring animal models of DGC-associated muscular dystrophy (e.g. the dystrophin-deficient mdx mouse, dystrophic golden retriever dog, HFMD cat and the delta-sarcoglycan-deficient BIO 14.6 cardiomyopathic hamster) that share common genetic protein abnormalities similar to those of the human disease. However, the naturally occurring animal models only partially resemble human disease. In addition, no naturally occurring mouse models associated with loss of other DGC components are available. This has encouraged the generation of genetically engineered mouse models for DGC-linked muscular dystrophy. Not only have analyses of these mice led to a significant improvement in our understanding of the pathogenetic mechanisms for the development of muscular dystrophy, but they will also be immensely valuable tools for the development of novel therapeutic approaches for these incapacitating diseases.
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PMID:Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models. 1207 80

Muscular dystrophies are a clinically and genetically heterogeneous group of disorders that show myofiber degeneration and regeneration. Identification of animal models of muscular dystrophy has been instrumental in research on the pathogenesis, pathophysiology, and treatment of these disorders. We review our understanding of the functional status of dystrophic skeletal muscle from selected animal models with a focus on 1) the mdx mouse model of Duchenne muscular dystrophy, 2) the Bio 14.6 delta-sarcoglycan-deficient hamster model of limb-girdle muscular dystrophy, and 3) transgenic null mutant murine lines of sarcoglycan (alpha, beta, delta, and gamma) deficiencies. Although biochemical data from these models suggest that the dystrophin-sarcoglycan-dystroglycan-laminin network is critical for structural integrity of the myofiber plasma membrane, emerging studies of muscle physiology suggest a more complex picture, with specific functional deficits varying considerably from muscle to muscle and model to model. It is likely that changes in muscle structure and function, downstream of the specific, primary biochemical deficiency, may alter muscle contractile properties.
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PMID:Functional characteristics of dystrophic skeletal muscle: insights from animal models. 1213 45

The dystrophin glycoprotein complex (DGC) is found at the plasma membrane of muscle cells, where it provides a link between the cytoskeleton and the extracellular matrix. A subcomplex within the DGC, the sarcoglycan complex, associates with dystrophin and mediates muscle membrane stability. Mutations in sarcoglycan genes lead to muscular dystrophy and cardiomyopathy in both humans and mice. In invertebrates, there are three sarcoglycan genes, while in mammals there are additional sarcoglycan genes that probably arose from gene duplication events. We identified a novel mammalian sarcoglycan, zeta-sarcoglycan, that is highly related to gamma-sarcoglycan and delta-sarcoglycan. We generated a zeta-sarcoglycan-specific antibody and found that zeta-sarcoglycan associated with other members of the sarcoglycan complex at the plasma membrane. Additionally, zeta-sarcoglycan was reduced at the membrane in muscular dystrophy, consistent with a role in mediating membrane stability. zeta-Sarcoglycan was also found as a component of the vascular smooth muscle sarcoglycan complex. Together, these data demonstrate that zeta-sarcoglycan is an integral component of the sarcoglycan complex and, as such, is important in the pathogenesis of muscular dystrophy.
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PMID:Zeta-sarcoglycan, a novel component of the sarcoglycan complex, is reduced in muscular dystrophy. 1218 67

Disruption of the dystrophin-glycoprotein complex caused by genetic defects of dystrophin or sarcoglycans results in muscular dystrophy and/or cardiomyopathy in humans and animal models. However, the key early molecular events leading to myocyte degeneration remain elusive. Here, we observed that the growth factor-regulated channel (GRC), which belongs to the transient receptor potential channel family, is elevated in the sarcolemma of skeletal and/or cardiac muscle in dystrophic human patients and animal models deficient in dystrophin or delta-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from delta-sarcoglycan-deficient BIO14.6 hamsters revealed that GRC is activated in response to myocyte stretch and is responsible for enhanced Ca2+ influx and resultant cell damage as measured by creatine phosphokinase efflux. We found that cell stretch increases GRC translocation to the sarcolemma, which requires entry of external Ca2+. Consistent with these findings, cardiac-specific expression of GRC in a transgenic mouse model produced cardiomyopathy due to Ca2+ overloading, with disease expression roughly parallel to sarcolemmal GRC levels. The results suggest that GRC is a key player in the pathogenesis of myocyte degeneration caused by dystrophin-glycoprotein complex disruption.
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PMID:A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel. 1279 81

Limb-girdle muscular dystrophy types 2E and F are characterized by skeletal muscle weakness and often cardiomyopathy and are due to mutations in the genes encoding beta- and delta-sarcoglycan. We previously demonstrated that loss of sarcoglycans in smooth muscle leads to constrictions of the microvasculature that contributes to the cardiac phenotype. It is unclear how vasculature abnormalities affect skeletal muscle. We injected recombinant beta- or delta-sarcoglycan adenoviruses into skeletal muscles of corresponding null mice. We hypothesized that the adenoviruses would not transduce vascular smooth muscle, and we would only target skeletal muscle. Indeed, sustained expression of intact sarcoglycan-sarcospan complex was noted at the sarcolemma, neuromuscular junction, myotendinous junction, and in peripheral nerve, but not in vascular smooth muscle. Gene transfer of the corresponding deleted sarcoglycan gene preserved sarcolemmal integrity, prevented pathological dystrophy and hypertrophy, and protected against exercised-induced damage. We conclude that vascular dysfunction is not a primary cause of beta- and delta-sarcoglycan-deficient muscular dystrophy. In addition, we show successful functional rescue of entire muscles after adenovirus-mediated gene delivery. Thus, virus-mediated gene transfer of sarcoglycans to skeletal muscle in combination with pharmacological prevention of cardiomyopathy constitute promising therapeutic strategies for limb-girdle muscular dystrophies.
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PMID:Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy. 1285 63

Mutations in the dystrophin glycoprotein complex, and in particular the sarcoglycan subcomplex, lead to cardiomyopathy and muscular dystrophy. Mice with mutations in gamma-sarcoglycan or delta-sarcoglycan develop cardiomyopathy that is characterized by focal regions of tissue damage. These focally damaged regions constitute 0-5% of cardiac tissue. In cardiomyopathy arising from sarcoglycan mutations, we found that endothelial nitric oxide synthase (eNOS) was significantly increased in focally damaged cardiac myocytes. In addition, we noted that nitric oxide (NO) was also increased in regions of tissue damage and altered membrane permeability. In sarcoglycan mutant mice, regionally increased cardiac NO was associated with hypersensitivity to carbachol and decreased sensitivity to adrenergic stimulation. Inhibition of NO production in sarcoglycan mutant mice was associated with improved recovery after carbachol and isoproterenol infusion. These data provide a mechanism where regional, focal cardiac damage creates pathologic gradients of NO. Moreover, inhibition of nitric oxide synthase corrects defects that arise from pathologic NO gradients.
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PMID:Functional nitric oxide synthase mislocalization in cardiomyopathy. 1487 47

Cardiomyopathy is primary degenerative disease of myocardium, which leads to cardiac failure and lethal arrhythmia. An appropriate model animal of a particular disease is, in general, greatly helpful for better understanding of its pathogenesis. In 1962, a naturally occurring mutant line of Syrian hamster named BIO1.50 was reported, which inherited cardiomyopathy and muscular dystrophy as autosomal recessive mode with 100% penetrance. To date, several sublines of cardiomyopathic hamsters (CM hamsters) have been derived. The genomic deletion of delta-sarcoglycan, a member of dystrophin-associated proteins, was demonstrated to be the common genetic cause of CM hamsters in 1997. Over the past 40 years, hundreds of papers have been published on the pathophysiological aspects of CM hamsters. The aim of this paper is to annotate every one of the CM hamsters with its historical background and then summarize the previous findings on CM hamsters with special focus on electrical and ionic properties. This review article is expected to serve as a basis to build up a new paradigm for the pathogenesis of cardiac failure and severe arrhythmia.
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PMID:Electrical and ionic abnormalities in the heart of cardiomyopathic hamsters: in quest of a new paradigm for cardiac failure and lethal arrhythmia. 1512 23

Several studies have demonstrated the existence of pluripotent bone marrow-derived stem cells capable of homing to injured cardiac and skeletal muscle; however, there has been little evidence demonstrating the induction of tissue-specific endogenous genes in donor stem cells following engraftment. A new study in this issue reports an intriguing finding that raises additional concerns relating to stem cell plasticity and stem cell therapy in an already heated and controversial field. The study demonstrates that wild-type bone marrow-derived side population stem cells are indeed readily incorporated into both skeletal and cardiac muscle when transplanted into mice that lack delta-sarcoglycan -- a model of cardiomyopathy and muscular dystrophy. However, these cells fail to express sarcoglycan and thus to repair the tissue, which suggests that this stem cell population has limited potential for cardiac and skeletal muscle regeneration.
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PMID:Fusion of bone marrow-derived stem cells with striated muscle may not be sufficient to activate muscle genes. 1557 90

Pluripotent bone marrow-derived side population (BM-SP) stem cells have been shown to repopulate the hematopoietic system and to contribute to skeletal and cardiac muscle regeneration after transplantation. We tested BM-SP cells for their ability to regenerate heart and skeletal muscle using a model of cardiomyopathy and muscular dystrophy that lacks delta-sarcoglycan. The absence of delta-sarcoglycan produces microinfarcts in heart and skeletal muscle that should recruit regenerative stem cells. Additionally, sarcoglycan expression after transplantation should mark successful stem cell maturation into cardiac and skeletal muscle lineages. BM-SP cells from normal male mice were transplanted into female delta-sarcoglycan-null mice. We detected engraftment of donor-derived stem cells into skeletal muscle, with the majority of donor-derived cells incorporated within myofibers. In the heart, donor-derived nuclei were detected inside cardiomyocytes. Skeletal muscle myofibers containing donor-derived nuclei generally failed to express sarcoglycan, with only 2 sarcoglycan-positive fibers detected in the quadriceps muscle from all 14 mice analyzed. Moreover, all cardiomyocytes with donor-derived nuclei were sarcoglycan-negative. The absence of sarcoglycan expression in cardiomyocytes and skeletal myofibers after transplantation indicates impaired differentiation and/or maturation of bone marrow-derived stem cells. The inability of BM-SP cells to express this protein severely limits their utility for cardiac and skeletal muscle regeneration.
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PMID:Transplanted hematopoietic stem cells demonstrate impaired sarcoglycan expression after engraftment into cardiac and skeletal muscle. 1557 85

Sixteen different forms of limb-girdle muscular dystrophies (LGMDs) have emerged from recent molecular genetic studies, six forms with a dominant trait and ten forms with a recessive trait. Among 1,420 Japanese patients with muscular dystrophy analyzed at NCNP, LGMD is the secondly largest category (19%) following dystrophinopathy (56%). Within LGMDs, the occurrence of LGMD2A (calpainopathy), LGMD2B (dysferlinopathy), and LGMD2C-F (sarcoglycanopathy) is 26%, 18%, and 6.6%, respectively, however, causative genes have not been specified in about 50% of the LGMD patients. LGMD2A patients show atrophy prominent in shoulder and pelvic girdle muscles without calf muscle hypertrophy, and abundant lobulated fibers in muscle biopsy. Four major mutations unique to the Japanese population, have been identified. Pathogenesis attributes to a loss of proteolytic activity of mutant calpain-3. Dysferlin, the defective protein in LGMD2B, is a ferlin family molecule possessing six C2 domains probably mediating the resealing mechanism of the damaged sarcolemma. Mutations in the dysferlin gene result in Miyoshi distal myopathy and distal anterior compartment myopathy other than LGMD2B. Among four sarcoglyconopathies, LGMD2D is the most common form, whereas LGMD2F has not yet been reported. In sarcoglycan-deficient skeletal muscle, matrix metalloproteinases may be involved in the beta-dystroglycan processing which underlies the pathogenesis of sarcoglycanopathy.
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PMID:[Limb-girdle muscular dystrophy; update]. 1565 52


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