Duchenne muscular dystrophy (DMD), the most common form of dystrophy, is caused by mutations in the dystrophin gene that result in loss of dystrophin protein and the entire dystrophin-glycoprotein complex, which protects the sarcolemma of muscle cells from contraction-induced injury. DMD is characterized by severe muscle weakness and wasting that leads to life-threatening cardiac and respiratory dysfunction in the early twenties. Progress has been made to enhance the quality of life of affected individuals; however, deterioration of cardiac function progresses to dilated cardiomyopathy with subsequent heart failure and is the primary cause of mortality in DMD individuals. The current application is focused on understanding the cardiac mechanisms associated with muscular dystrophy and testing new treatments that are known to ameliorate DMD skeletal muscle disease. Our research group has pioneered several key discoveries related to the function of sarcospan, an integral component of the dystrophin-glycoprotein complex. We have demonstrated that mild sarcospan over-expression in skeletal muscle of mdx mice, which possess a mutation in the murine dystrophin gene, rescues muscular dystrophy by stabilizing expression of a complex of proteins called the utrophin-glycoprotein complex that is functionally analogous to the dystrophin-glycoprotein complex. In fact, our studies are revealing a chaperone-like function for sarcospan in determining the cell surface expression of laminin-binding adhesion complexes (i.e. dystrophin-glycoprotein complex, utrophin-glycoprotein complex, and ?7?1 integrin) that are known to ameliorate disease in DMD mouse models. Sarcospan activates the Akt signaling pathway that promotes muscle growth and regeneration, providing further benefit to dystrophic muscle. The proposed experiments will test whether introduction of sarcospan into heart muscles ameliorates cardiomyopathy associated with muscular dystrophy. Our studies will examine laminin-binding in DMD associated cardiomyopathy and reveal whether sarcospan affects laminin-binding receptors that regulate cardiomyocyte adhesion. In our preliminary data, we reveal a new cardiac phenotype in sarcospan-deficient mice and we will investigate whether sarcospan is cardioprotective to multiple cardiac challenges. The outcomes of the proposal will change our understanding of DMD cardiac pathogenesis and provide necessary insight for development of sarcospan-based treatments.
Our proposal will determine whether application of sarcospan treatment for Duchenne Muscular Dystrophies will affect cardiomyopathy disease progression in relevant murine models. We will investigate molecular mechanisms of cardiomyopathy in regulating adhesion and determine whether sarcospan is cardioprotective.
| Gibbs, Elizabeth M; Crosbie-Watson, Rachelle H (2017) A Simple and Low-cost Assay for Measuring Ambulation in Mouse Models of Muscular Dystrophy. J Vis Exp : |
