Delta sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in delta sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in delta sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant delta sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant delta sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type delta sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant delta sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching cardiac myocytes expressing mutant delta sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal delta sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of delta sarcoglycan. Therefore, appropriate glycosylation of delta sarcoglycan may also be necessary for proper delta sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in delta sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of delta sarcoglycan-associated DCM.
- dilated cardiomyopathy
- delta sarcoglycan
- dystrophin-glycoprotein complex
- mechanical strain
- Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology