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(Circulation Research. 2009;105:984.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Dystroglycan Matrix Receptor Function in Cardiac Myocytes Is Important for Limiting Activity-Induced Myocardial Damage

Daniel E. Michele, Zhyldyz Kabaeva, Sarah L. Davis, Robert M. Weiss, Kevin P. Campbell

From the Departments of Molecular and Integrative Physiology (D.E.M., Z.K.) and Internal Medicine (D.E.M.), University of Michigan, Ann Arbor; and Departments of Molecular Physiology and Biophysics (S.L.D., K.P.C.), Neurology (K.P.C.), and Internal Medicine (R.M.W., K.P.C.) and Howard Hughes Medical Institute (S.L.D., K.P.C.), University of Iowa, Iowa City.

Correspondence to Daniel Michele, PhD, Assistant Professor, Department of Molecular and Integrative Physiology, Department of Internal Medicine, University of Michigan, 7732C Medical Science II, 1301 E Catherine St, Ann Arbor, MI 48109-0622. E-mail dmichele{at}umich.edu

Rationale: Genetic mutations in a number of putative glycosyltransferases lead to the loss of glycosylation of dystroglycan and loss of its laminin-binding activity in genetic forms of human muscular dystrophy. Human patients and glycosylation defective myd mice develop cardiomyopathy with loss of dystroglycan matrix receptor function in both striated and smooth muscle.

Objective: To determine the functional role of dystroglycan in cardiac muscle and smooth muscle in the development of cardiomyopathy in muscular dystrophies.

Methods and Results: Using cre/lox–mediated gene targeting, we show here that loss of dystroglycan function in ventricular cardiac myocytes is sufficient to induce a progressive cardiomyopathy in mice characterized by focal cardiac fibrosis, increase in cardiac mass, and dilatation ultimately leading to heart failure. In contrast, disruption of dystroglycan in smooth muscle is not sufficient to induce cardiomyopathy. The specific loss of dystroglycan function in cardiac myocytes causes the accumulation of large, clustered patches of myocytes with membrane damage, which increase in number in response to exercise-induced cardiac stress, whereas exercised mice with normal dystroglycan expression accumulate membrane damage limited to individual myocytes.

Conclusions: Our findings suggest dystroglycan function as an extracellular matrix receptor in cardiac myocytes plays a primary role in limiting myocardial damage from spreading to neighboring cardiac myocytes, and loss of dystroglycan matrix receptor function in cardiac muscle cells is likely important in the development of cardiomyopathy in glycosylation-deficient muscular dystrophies.

Key Words: heart failure • cardiomyopathy • adhesion molecules • muscular dystrophy