Dystroglycan Matrix Receptor Function in Cardiac Myocytes Is Important for Limiting Activity-Induced Myocardial Damage
- 6 November 2009
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 105 (10), 984-993
- https://doi.org/10.1161/circresaha.109.199489
Abstract
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.Keywords
This publication has 28 references indexed in Scilit:
- Sarcolemma-localized nNOS is required to maintain activity after mild exerciseNature, 2008
- Combined Deficiency of Dystrophin and β1 Integrin in the Cardiac Myocyte Causes Myocardial Dysfunction, Fibrosis and CalcificationCirculation Research, 2008
- Emergent Dilated Cardiomyopathy Caused by Targeted Repair of Dystrophic Skeletal MuscleMolecular Therapy, 2008
- Fibrosis, not cell size, delineates β-myosin heavy chain reexpression during cardiac hypertrophy and normal aging in vivoProceedings of the National Academy of Sciences of the United States of America, 2006
- Calcific Aortic Valve Stenosis in Old Hypercholesterolemic MiceCirculation, 2006
- Dystroglycan: a multifunctional adaptor proteinBiochemical Society Transactions, 2005
- Functional nitric oxide synthase mislocalization in cardiomyopathyJournal of Molecular and Cellular Cardiology, 2004
- Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophyNature, 2002
- Post-translational disruption of dystroglycan–ligand interactions in congenital muscular dystrophiesNature, 2002
- Disruption of the β-Sarcoglycan Gene Reveals Pathogenetic Complexity of Limb-Girdle Muscular Dystrophy Type 2EMolecular Cell, 2000