Sarcolipin overexpression impairs myogenic differentiation in Duchenne muscular dystrophy

Nandita Niranjan, Satvik Mareedu, Yimin Tian, Kasun Kodippili, Nadezhda Fefelova, Antanina Voit, Lai Hua Xie, Dongsheng Duan, Gopal J. Babu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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+ (Cai 2+) 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 Cai 2+ 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 Cai 2+ mishandling, which subsequently contributes to poor myogenic differentiation. Accordingly, reducing SLN expression can improve the Cai 2+ cycling and differentiation of dystrophic myoblasts. These findings provide cellular-level supports for targeting SLN expression as a therapeutic strategy for DMD.

Original languageEnglish (US)
Pages (from-to)C813-C824
JournalAmerican Journal of Physiology - Cell Physiology
Volume317
Issue number4
DOIs
StatePublished - 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Keywords

  • Calcium
  • Differentiation
  • Duchenne muscular dystrophy
  • Myoblast fusion
  • Sarcolipin

Fingerprint Dive into the research topics of 'Sarcolipin overexpression impairs myogenic differentiation in Duchenne muscular dystrophy'. Together they form a unique fingerprint.

Cite this