UCLA

Duchenne Muscular Dystrophy (DMD) is a fatal neuromuscular disorder resulting from the loss of dystrophin protein and subsequent loss of the dystrophin-glycoprotein complex (DGC). Although there are new therapeutic options, there still is no cure for the disease. The delay in finding a cure can be partly due to the lack of an appropriate mouse model that recapitulates the pathology seen in DMD patients. Compared to the popular DMD mouse model, B10.mdx, the D2.mdx murine model presents a more severe muscle disease pathology, more closely matching DMD patients. Our project shows that sarcospan overexpression in D2.mdx mice stabilizes the muscle membrane by upregulating the presence of adhesion complex proteins. Sarcospan increases the expression of utrophin, a homolog of dystrophin and a component of the utrophin-glycoprotein complex, compensating for the dystrophin loss in the DGC. Further, quantitative and proteomic analysis reveals an increase in the amount of matrisomal proteins that supports our hypothesis of an upregulation of adhesion complex proteins in D2.mdxTG mice. When examining collagen distribution and abundance changes, we note a restoration of fibrillar collagen solubility, which may account for increased muscle fiber size homogeneity and decreased central nucleation. In conclusion, sarcospan overexpression ameliorates the pathophysiology of the severe mouse model of DMD by strengthening the myofiber membrane and decreasing insoluble collagen linked to fibrosis.