Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice

• DOI: 10.1038/s41467-017-01146-7
• Publication Date: 2017-10-16T15:53:31Z
• Authors: Antanina Voit; Vishwendra Patel; Ronald Pachon; Vikas Shah; Mohammad Bakhutma; Erik Kohlbrenner; Joseph J. McArdle; Louis J. Dell’Italia; Jerry R. Mendell; Lai-Hua Xie; Roger J. Hajjar; Dongsheng Duan; Diego Fraidenraich; Gopal J. Babu
• Keywords: Mice, Knockout; 0303 health sciences; Utrophin; Science; Proteolipids; Q; Muscle Proteins; Genetic Therapy; Article; Sarcoplasmic Reticulum Calcium-Transporting ATPases; 3. Good health; Dystrophin; Muscular Dystrophy, Duchenne; Disease Models, Animal; Mice; 03 medical and health sciences; Gene Expression Regulation; Mice, Inbred mdx; Animals; RNA Interference; Gene Silencing; Cardiomyopathies

AbstractSarcolipin (SLN) is an inhibitor of the sarco/endoplasmic reticulum (SR) Ca2+ATPase (SERCA) and is abnormally elevated in the muscle of Duchenne muscular dystrophy (DMD) patients and animal models. Here we show that reducing SLN levels ameliorates dystrophic pathology in the severe dystrophin/utrophin double mutant (mdx:utr−/−) mouse model of DMD. Germline inactivation of one allele of the SLN gene normalizes SLN expression, restores SERCA function, mitigates skeletal muscle and cardiac pathology, improves muscle regeneration, and extends the lifespan. To translate our findings into a therapeutic strategy, we knock down SLN expression in 1-month oldmdx:utr−/−mice via adeno-associated virus (AAV) 9-mediated RNA interference. The AAV treatment markedly reduces SLN expression, attenuates muscle pathology and improves diaphragm, skeletal muscle and cardiac function. Taken together, our findings suggest that SLN reduction is a promising therapeutic approach for DMD.