Cardiomyopathy in muscular dystrophies

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DESCRIPTION (provided by applicant): The long term objective of this work is to understand the mechanisms of genetically defined inherited cardiomyopathies in order to shed light on common mechanisms and devise therapies for cardiovascular disease in humans. This proposal is focused on cardiomyopathies that occur in muscular dystrophies associated with defects in the dystrophin-glycoprotein complex (DGC). Cardiomyopathy is an increasingly significant, but understudied, clinical problem in muscular dystrophy patients, often resulting in premature death. Dystroglycan is the central transmembrane protein within the DGC, binding both dystrophin, which binds the intracellular cytoskeleton, and proteins in the extracellular matrix. The DGC is expressed in both cardiac myocytes and vascular smooth muscle but the contributions of each tissue to cardiomyopathy are highly debated. The abnormal glycosylation of dystroglycan leads to a loss of function of dystroglycan as an extracellular matrix receptor and is believed to be responsible for several forms of human muscular dystrophy with associated cardiomyopathy. The overall hypothesis is that the disrupted mechanical link from the cytoskeleton to the extracellular matrix through dystroglycan in cardiac myocytes is the central mechanism directly causing glycosylation-deficient muscular dystrophy associated cardiomyopathy. The specific aims are to: 1) Investigate the primacy of cardiac disruption of dystroglycan, and the relative contributions of skeletal and smooth muscle disruption, to the severity of cardiomyopathy and the mechanical function of the heart. 2) Identify the cell intrinsic mechanisms by which dystroglycan disruption affects muscle cell structure/function in order to identify targets for therapeutic intervention. Glycosylation deficient and dystroglycan gene targeted mice will be used to test the causal and tissue specific role of dystroglycan in cardiomyopathies associated with glycosylation-deficient muscular dystrophies. Experiments in cardiac muscle cells will identify the cell intrinsic mechanisms of myocyte dysfunction that underlie the cardiomyopathy caused by deficiency of functional dystroglycan, and will provide a platform for testing therapeutic interventions aimed at those mechanisms. Because alterations in the DGC are also seen in several other forms of muscular dystrophy and genetic or acquired human cardiomyopathies, this work should contribute broadly to our understanding of human muscular dystrophies and heart disease.