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

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 and Gopal J. Babu ()
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Antanina Voit: The State University of New Jersey
Vishwendra Patel: The State University of New Jersey
Ronald Pachon: The State University of New Jersey
Vikas Shah: The State University of New Jersey
Mohammad Bakhutma: The State University of New Jersey
Erik Kohlbrenner: Icahn School of Medicine at Mount Sinai
Joseph J. McArdle: The State University of New Jersey
Louis J. Dell’Italia: University of Alabama at Birmingham, and Birmingham VA Medical Center
Jerry R. Mendell: Ohio State University Research Institute at Nationwide Children’s Hospital
Lai-Hua Xie: The State University of New Jersey
Roger J. Hajjar: Icahn School of Medicine at Mount Sinai
Dongsheng Duan: The University of Missouri
Diego Fraidenraich: The State University of New Jersey
Gopal J. Babu: The State University of New Jersey

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Sarcolipin (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 old mdx: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.

Date: 2017
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DOI: 10.1038/s41467-017-01146-7

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