The Role of Delta Sarcoglycan in Dystrophin-Glycoprotein Complex Function in Cardiac Muscle.

Abstract

Delta sarcoglycan (δSG) is a highly conserved member of the sarcoglycan complex and the dystrophin-glycoprotein complex (DGC) in muscle cells. The DGC is a multimeric complex at the lateral sarcolemma in muscle that acts as a functional linkage between the cytoskeleton and the extracellular matrix. Muscle undergoes consistent strain through stretch and contraction and the DGC is hypothesized to help protect sarcolemmal integrity during mechanical activity. The role of δSG in the function of the DGC is not well understood. Mutations in the SGCD (coding the δSG protein) gene that are recessively inherited disturb the normal assembly of the DGC resulting in absence of not only δSG, but also the entire sarcoglycan complex and a reduction of dystrophin at the plasma membrane, resulting in limb-girdle muscular dystrophy 2F (LGMD2F). In general, LGMD2F patients have skeletal muscle dystrophy that is on the milder end of the clinical spectrum but patients are at risk for early death from cardiomyopathy. A surprising and unique feature of δSG is that dominantly inherited mutations within the δSG gene have been linked to dilated cardiomyopathy (DCM) with no accompanying skeletal muscle phenotype. The lack of skeletal muscle dystrophy indicates the likely presence of an intact and functional DGC within skeletal muscle. In this thesis, I tested the overall working hypothesis that dominant mutations in the extracellular domain of δSG alter protein structure or post-translational modifications causing DGC dysfunction and lead to disrupted mechanical stability of cardiac myocytes. I show here that DCM-linked δSG mutants R97Q and R71T, when expressed integrate into the plasma membrane and do not disturb the natural localization and assembly of the DGC indicating a likely dominant negative mechanism of action. When submitted to mechanical strain cardiac myocytes expressing δSG mutant R97Q or R71T have compromised sarcolemmal integrity indicating that δSG plays a functional role in the protection of the plasma membrane by the DGC during mechanical activity.