Abstract
To investigate mechanisms in the pathogenesis of cardiomyopathy associated with mutations of the dystrophin-glycoprotein complex, we analyzed genetically engineered mice deficient for either alpha-sarcoglycan (Sgca) or delta-sarcoglycan (Sgcd). We found that only Sgcd null mice developed cardiomyopathy with focal areas of necrosis as the histological hallmark in cardiac and skeletal muscle. Absence of the sarcoglycan-sarcospan (SG-SSPN) complex in skeletal and cardiac membranes was observed in both animal models. Loss of vascular smooth muscle SG-SSPN complex was only detected in Sgcd null mice and associated with irregularities of the coronary vasculature. Administration of a vascular smooth muscle relaxant prevented onset of myocardial necrosis. Our data indicate that disruption of the SG-SSPN complex in vascular smooth muscle perturbs vascular function, which initiates cardiomyopathy and exacerbates muscular dystrophy.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cardiomyopathy, Dilated / genetics*
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Cardiomyopathy, Dilated / metabolism
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Cardiomyopathy, Dilated / pathology
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Carrier Proteins / physiology*
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Coronary Vessels / pathology
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Cytoskeletal Proteins / deficiency
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / physiology*
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Macromolecular Substances
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Membrane Proteins / physiology*
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Mice
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Mice, Knockout
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Muscle, Smooth, Vascular / metabolism*
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Muscle, Smooth, Vascular / pathology
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Muscular Dystrophy, Animal / genetics*
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Muscular Dystrophy, Animal / metabolism
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Muscular Dystrophy, Animal / pathology
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Myocardium / pathology
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Necrosis
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Neoplasm Proteins*
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Physical Conditioning, Animal / adverse effects
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Sarcoglycans
Substances
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Carrier Proteins
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Cytoskeletal Proteins
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Macromolecular Substances
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Membrane Glycoproteins
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Membrane Proteins
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Neoplasm Proteins
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Sarcoglycans
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Sspn protein, mouse