Dystroglycan matrix receptor function in cardiac myocytes is important for limiting activity-induced myocardial damage.
BACKGROUND
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.


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.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-0622, USA. dmichele@umich.edu
Daniel E
DE
Michele
Zhyldyz
Z
Kabaeva
Sarah L
SL
Davis
Robert M
RM
Weiss
Kevin P
KP
Campbell
D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology
D049030:Dystroglycans; D016695:Glycosyltransferases