The Role of Sarcospan in Cardiac Sarcolemma Organization and Function

Abstract

Mutations in the dystrophin gene cause loss of dystrophin and the entire glycoprotein complex (DGC) that protects muscle cells from contraction-induced damage. Therapeutic interventions for Duchenne muscular dystrophy (DMD) have targeted small protein components of the DGC, like sarcospan (SSPN), to stabilize the membrane complex. Previously, we showed that increased SSPN expression in a DMD mouse model (mdx3.0) attenuates skeletal muscle pathology in DMD by increasing DGC interactions and cellular-adhesion. However, the effects of SSPN overexpression on cardiomyopathy in the mdx mouse remains unknown. SSPN overexpression in WT (WT3.0) and mdx background enhanced levels of DGC at the cardiac sarcolemma and attenuated DMD cardiac tissue pathology. Furthermore, anatomical and molecular studies showed that overexpression of SSPN reduced EBD uptake, CK-MB, cardiac myopathy markers such as atrial natriuretic peptide (ANP) and reduced left ventricular (LV) mass. These findings support the concept that alterations in sarcospan expression contributes to cardiac dysfunction and re-introduction of sarcospan could be used as a molecular target to prevent or attenuate cardiomyopathy associated with DMD. NRSA GM07104 NRSA T32AR059033 CureDuchenne Fellowship William Townsend Porter Pre-doctoral Fellowship from the American Physiological Society NIH/NIAMS- R01 AR048179 and UL1TR000124