Sarcolipin overexpression impairs myogenic differentiation in Duchenne muscular dystrophy

Author:

Niranjan Nandita1,Mareedu Satvik1,Tian Yimin1,Kodippili Kasun2,Fefelova Nadezhda1,Voit Antanina1,Xie Lai-Hua1,Duan Dongsheng2345,Babu Gopal J.1ORCID

Affiliation:

1. Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey

2. Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri

3. Department of Neurology, University of Missouri, Columbia, Missouri

4. Department of Biomedical, Biological & Chemical Engineering, University of Missouri, Columbia, Missouri

5. Department of Biomedical Sciences, University of Missouri, Columbia, Missouri

Abstract

Reduction in the expression of sarcolipin (SLN), an inhibitor of sarco(endo)plasmic reticulum (SR) Ca2+-ATPase (SERCA), ameliorates severe muscular dystrophy in mice. However, the mechanism by which SLN inhibition improves muscle structure remains unclear. Here, we describe the previously unknown function of SLN in muscle differentiation in Duchenne muscular dystrophy (DMD). Overexpression of SLN in C2C12 resulted in decreased SERCA pump activity, reduced SR Ca2+ load, and increased intracellular Ca2+ ([Formula: see text]) concentration. In addition, SLN overexpression resulted in altered expression of myogenic markers and poor myogenic differentiation. In dystrophin-deficient dog myoblasts and myotubes, SLN expression was significantly high and associated with defective [Formula: see text] cycling. The dystrophic dog myotubes were less branched and associated with decreased autophagy and increased expression of mitochondrial fusion and fission proteins. Reduction in SLN expression restored these changes and enhanced dystrophic dog myoblast fusion during differentiation. In summary, our data suggest that SLN upregulation is an intrinsic secondary change in dystrophin-deficient myoblasts and could account for the [Formula: see text] mishandling, which subsequently contributes to poor myogenic differentiation. Accordingly, reducing SLN expression can improve the [Formula: see text] cycling and differentiation of dystrophic myoblasts. These findings provide cellular-level supports for targeting SLN expression as a therapeutic strategy for DMD.

Funder

HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases

Jesse's Journey: The foundation for Gene and Cell Therapy

Jackson Freel DMD Research Fund

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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