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; Gopal J Babu

doi:10.1038/s41467-017-01146-7

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

Journal article

Open access

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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, …

Nature communications, Vol.8(1), pp.1068-14

10/20/2017

DOI: https://doi.org/10.1038/s41467-017-01146-7

PMCID: PMC5648780

PMID: 29051551

Abstract

Animals

Cardiomyopathies - genetics

Cardiomyopathies - physiopathology

Disease Models, Animal

Dystrophin - genetics

Dystrophin - metabolism

Gene Expression Regulation - genetics

Gene Silencing

Genetic Therapy

Mice

Mice, Inbred mdx

Mice, Knockout

Muscle Proteins - genetics

Muscle Proteins - metabolism

Muscular Dystrophy, Duchenne - genetics

Muscular Dystrophy, Duchenne - physiopathology

Muscular Dystrophy, Duchenne - therapy

Proteolipids - genetics

Proteolipids - metabolism

RNA Interference

Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics

Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism

Utrophin - genetics

Utrophin - metabolism

Sarcolipin (SLN) is an inhibitor of the sarco/endoplasmic reticulum (SR) Ca 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.

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Title: Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice
Creators: Antanina Voit - Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA
Vishwendra Patel - Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA
Ronald Pachon - Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA
Vikas Shah - Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA
Mohammad Bakhutma - Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA
Erik Kohlbrenner - Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
Joseph J McArdle - Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA
Louis J Dell'Italia - Department of Medicine, University of Alabama at Birmingham, and Birmingham VA Medical Center, Birmingham, AL, 35294, USA
Jerry R Mendell - Department of Pediatrics and Department of Neurology, Ohio State University Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
Lai-Hua Xie - Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA
Roger J Hajjar - Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
Dongsheng Duan - Department of Molecular Microbiology and Immunology, Neurology, Bioengineering, Biomedical Sciences, The University of Missouri, Columbia, MO, 65212, USA
Diego Fraidenraich - Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA
Gopal J Babu - Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA. babugo@njms.rutgers.edu
Publication Details: Nature communications, Vol.8(1), pp.1068-14
Date published: 10/20/2017
Grant note: R01 HL097979 / NHLBI NIH HHS R01 AR069107 / NIAMS NIH HHS R01 AR070517 / NIAMS NIH HHS
Academic Unit: Cell Biology and Molecular Medicine (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031666231104646