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

The mouse has become the principal animal model for studying biologic processes in mammals. Major advances in transgene and gene targeting technology enabled manipulation of the mouse genome in a predictable fashion. Mutant mouse strains provide important insights into the molecular mechanisms underlying normal and disordered cardiac conduction and sudden cardiac death. A variety of mouse strains harboring gene mutations leading to inherited developmental disorders have been designed. Structural protein abnormalities, connexin protein defects, and ion channelopathies associated with human clinical phenotypes, including congenital heart disease, cardiomyopathies, long QT syndrome, and muscular dystrophy, have been engineered into the mouse genome, creating models of human electrophysiologic disease. Functional analyses of the underlying molecular mechanisms of resultant phenotypes require appropriate and sophisticated experimental methodology. In this review, genetic mouse models pertinent to human arrhythmogenic disorders and their application to present-day ex vivo and in vivo murine electrophysiologic technology at the whole organ and animal levels are discussed.
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PMID:Cardiac electrophysiology in genetically engineered mice. 1074 60

Claudin-5 is a transmembrane cell junction protein that is a component of tight junctions in endothelial cell layers. We have previously shown that claudin-5 also localizes to lateral membranes of murine cardiomyocytes at their junction with the extracellular matrix. Claudin-5 levels are specifically reduced in myocytes from a mouse model of muscular dystrophy with cardiomyopathy. To establish whether claudin-5 is similarly specifically reduced in human cardiomyopathy, we compared the levels of claudin-5 with other cell junction proteins in 62 cardiomyopathic end-stage explant samples. We show that claudin-5 levels are reduced in at least 60% of patient samples compared with non-failing controls. Importantly, claudin-5 reductions can be independent of connexin-43, a gap junction protein previously reported to be reduced in failing heart samples. Other cell junction proteins including alpha-catenin, beta-catenin, gamma-catenin, desmoplakin, and N-cadherin are reduced in only a small number of failing samples and only in combination with reduced claudin-5 or connexin-43 levels. We also show that reduced claudin-5 levels can be present independently from dystrophin alterations, which are known to be capable of causing and resulting from cardiomyopathy. These data are the first to show alterations of a tight junction protein in human cardiomyopathy samples and suggest that claudin-5 may participate in novel mechanisms in the pathway to end-stage heart failure.
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PMID:Claudin-5 levels are reduced in human end-stage cardiomyopathy. 1851 42

The lack of dystrophin in mdx mice leads to cycles of muscle degeneration and regeneration processes. Various strategies have been proposed in order to reduce the muscle-wasting component of muscular dystrophy, including implementation of an exercise programme. The aim of this study was to examine how low-intensity endurance exercise affects the degeneration-regeneration process in dystrophic muscle of male mdx mice. Mice were subjected to low-intensity endurance exercise by running on a motorized Rota-Rod for 5 days/week for 6 weeks. Histomorphological analysis showed a significant reduction of measured inflammatory-necrotic areas in both gastrocnemius and quadriceps muscle of exercised mdx mice as compared to matched sedentary mdx mice. The degenerative-regenerative process was also evaluated by examining the protein levels of connexin 39 (Cx39), a specific gene expressed in injured muscles. Cx39 was not detected in sedentary wild type mice, whereas it was found markedly increased in sedentary mdx mice, revealing active muscle degeneration-regeneration process. These Cx39 protein levels were significantly reduced in muscles of mdx mice exercised for 30 and 40 days, revealing together with histomorphological analysis a strong reduction of degeneration process in mice subjected to low-intensity endurance exercise. Muscles of exercised mdx mice did not show significant changes in force and fatigue resistance as compared to sedentary mdx mice. Overall in this study we found that specific low-intensity endurance exercise induces a beneficial effect probably by reducing the degeneration of dystrophic muscle.
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PMID:Recovery of damaged skeletal muscle in mdx mice through low-intensity endurance exercise. 2386 81

Aberrant opening of nonjunctional connexin hemichannels at the plasma membrane is associated with many diseases, including ischemia and muscular dystrophy. Proper control of hemichannel opening is essential to maintain cell viability and is achieved by physiological levels of extracellular Ca2+, which drastically reduce hemichannel activity. Here we examined the role of conserved charged residues that form electrostatic networks near the extracellular entrance of the connexin pore, a region thought to be involved in gating rearrangements of hemichannels. Molecular dynamics simulations indicate discrete sites for Ca2+ interaction and consequent disruption of salt bridges in the open hemichannels. Experimentally, we found that disruption of these salt bridges by mutations facilitates hemichannel closing. Two negatively charged residues in these networks are putative Ca2+ binding sites, forming a Ca2+-gating ring near the extracellular entrance of the pore. Accessibility studies showed that this Ca2+-bound gating ring does not prevent access of ions or small molecules to positions deeper into the pore, indicating that the physical gate is below the Ca2+-gating ring. We conclude that intra- and intersubunit electrostatic networks at the extracellular entrance of the hemichannel pore play critical roles in hemichannel gating reactions and are tightly controlled by extracellular Ca2+ Our findings provide a general mechanism for Ca2+ gating among different connexin hemichannel isoforms.
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PMID:Mechanism of gating by calcium in connexin hemichannels. 2787 96