Sarcolipin in Duchenne Muscular Dystrophy

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PROJECT SUMMARY Duchenne muscular dystrophy (DMD) is the most common lethal muscle wasting disease caused by dystrophin deficiency. There is no effective treatment exists for this disease. The current therapeutic strategies aimed to either replace or compensate for the lack of dystrophin also face major challenges such as targeting cardiac and respiratory tissues and fibrosis. Therefore, recent studies are focused to prevent directly the consequences of dystrophic process. Identification of such alternative therapies could complement the existing strategies and enhance the effectiveness of treatment for this lethal disease. Abnormal intracellular Ca2+ overload is an important, early pathogenic event that initiates and perpetuates disease progression in DMD. We recently found that sarcolipin (SLN), a potent inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), is significantly increased in the skeletal and cardiac muscles of mouse models of DMD. Similar to rodents, SLN levels are high in myoblasts and muscles of a canine model of DMD and in muscle biopsies of DMD patients. In muscle cells, SERCA accounts for ≥ 70% of Ca2+ removal from the cytosol during excitation- contraction coupling. Therefore in dystrophic muscles, chronic inhibition of SERCA by high-levels of SLN could majorly contribute to the abnormal elevation of cytosolic Ca2+. Accordingly, reducing SLN expression is anticipated to improve SERCA function, restore intracellular Ca2+ homeostasis and reduce dystrophic pathology. Towards this goal, we genetically ablated SLN expression in mouse models of DMD. Preliminary studies suggest that reduction in SLN expression is sufficient to improve SERCA function and mitigate DMD. Here, we propose to evaluate the potential mechanisms by which SLN reduction mitigates skeletal muscle pathology and cardiomyopathy in mouse models of DMD. In addition, we propose to determine whether targeting SLN expression mitigate DMD in preclinical settings. We will specifically test the following hypotheses: 1) SLN overexpression limits skeletal muscle regeneration in DMD, 2) Reduction in SLN expression can improve cardiac SERCA function and prevent cardiomyopathy, and 3) Postnatal AAV mediated SLN gene silencing therapy can ameliorate DMD. The outcomes of these studies will identify SLN as a potential therapeutic target for the treatment of DMD and associated cardiomyopathy.