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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Don, 2017. "Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01146-7
    DOI: 10.1038/s41467-017-01146-7
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    Cited by:

    1. Caterina Marchioretti & Giulia Zanetti & Marco Pirazzini & Gaia Gherardi & Leonardo Nogara & Roberta Andreotti & Paolo Martini & Lorenzo Marcucci & Marta Canato & Samir R. Nath & Emanuela Zuccaro & Ma, 2023. "Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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