title: Sarcolemma instability during mechanical activity in Largemyd cardiac myocytes with loss of dystroglycan extracellular matrix receptor function.
abstract: The abnormal glycosylation and loss of extracellular matrix receptor function of the protein dystroglycan (DG) lead to the development of muscular dystrophy and cardiomyopathy. Dystroglycan is an important receptor for extracellular matrix proteins, such as laminin, in the basement membrane surrounding muscle. Large(myd) mice have a null mutation in a gene encoding the glycosyltransferase LARGE that results in abnormal glycosylation of α-DG and phenotypes similar to those in human α-DG glycosylation-deficient muscular dystrophy. Here, we show that Large(myd) hearts with the loss of DG extracellular matrix receptor function display a cardiomyopathy characterized by myocyte damage in patches of cells positive for membrane impermeant dyes. To examine the cellular mechanisms, we show that isolated adult cardiac myocytes from Large(myd) mice retain normal laminin-dependent cell adhesion, cell surface laminin deposition and basement membrane assembly. However, although isolated adult cardiac myocytes with the loss of α-DG glycosylation adhere normally to laminin substrates both passively and in the presence of mechanical activity, Large(myd) myocytes rapidly take up membrane impermeant dye following cyclical cell stretching. Therefore, while other cell surface laminin receptors are likely responsible for myocardial cell adhesion to the basement membrane, DG has a unique function of stabilizing the cardiac myocyte plasma membrane during repetitive mechanical activity by tightly binding the transmembrane dystrophin-glycoprotein complex to the extracellular matrix. This function of DG to stabilize the myocyte membrane during normal physiologic cell length changes is likely critical for the prevention of the myocardial damage and subsequent remodeling observed in α-DG glycosylation-deficient muscular dystrophies.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-0622, USA.
authors.forename: Zhyldyz
authors.initials: Z
authors.lastname: Kabaeva
authors.forename: Kailyn E
authors.initials: KE
authors.lastname: Meekhof
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Michele
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D049030:Dystroglycans / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism*
chemical_list: D011956:Receptors, Cell Surface; C052131:extracellular matrix receptor; D049030:Dystroglycans