Abstract 2289: Dystroglycan Function in Cardiac Myocytes is Required for Prevention of Cardiac Myocyte Sarcolemma Damage
Genetic mutations in several putative glycosyltransferases lead to several forms of human congenital and limb girdle muscular dystrophy. Human patients and glycosylation defective myd mice develop cardiomyopathy in addition to muscular dystrophy. Myd mice show very significant reduction in life span compared to wild type littermates (median survival 33 wks and 110 wks, respectively). Although the exact reason is unknown, respiratory failure or heart failure are major contributors of early death in human patients. A convergent feature of glycosylation deficient muscular dystrophy is abnormal glycosylation of the protein dystroglycan, which leads to loss of its function in striated and smooth muscle, and in the central nervous system. To dissect the contribution of dystroglycan function to the heart disease in myd mice, the dystroglycan gene was ablated specifically in cardiac muscle or vascular smooth muscle of mice. Loss of dystroglycan function in ventricular cardiac myocytes was not sufficient to cause the early mortality that was observed in myd mice less than 1 year of age. However, at 50 weeks of age mice with loss of dystroglycan function in cardiac myocytes showed significant focal fibrosis, cardiac hypertrophy and dilation, and systolic dysfunction. To assess the origin of fibrosis, we injected mice, at younger age (22–27 wks) prior to the development of observable fibrosis, with Evan’s blue dye. We found that cardiac myocyte specific dystroglycan knockout mice show distinct patches of Evan’s blue dye uptake that vary in size and distribution suggesting cell membrane damage. These data suggest that loss of dystroglycan in the heart causes focal cardiac myocyte death with subsequent replacement by fibrotic tissue, resulting in the cardiac fibrosis and cardiac dysfunction we observe at later ages. Therefore, recurrent focal myocyte death due to cell membrane damage resulting from loss of dystroglycan function in cardiac myocytes is likely an underlying mechanism of heart failure in glycosylation deficient muscular dystrophy.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).