Lipogenesis mitigates dysregulated sarcoplasmic reticulum calcium uptake in muscular dystrophy

Christopher W. Paran, Kai Zou, Patrick J. Ferrara, Haowei Song, John Turk, Katsuhiko Funai

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Muscular dystrophy is accompanied by a reduction in activity of sarco/endoplasmic reticulum Ca2 +-ATPase (SERCA) that contributes to abnormal Ca2 + homeostasis in sarco/endoplasmic reticulum (SR/ER). Recent findings suggest that skeletal muscle fatty acid synthase (FAS) modulates SERCA activity and muscle function via its effects on SR membrane phospholipids. In this study, we examined muscle's lipid metabolism in mdx mice, a mouse model for Duchenne muscular dystrophy (DMD). De novo lipogenesis was ~ 50% reduced in mdx muscles compared to wildtype (WT) muscles. Gene expressions of lipogenic and other ER lipid-modifying enzymes were found to be differentially expressed between wildtype (WT) and mdx muscles. A comprehensive examination of muscles' SR phospholipidome revealed elevated phosphatidylcholine (PC) and PC/phosphatidylethanolamine (PE) ratio in mdx compared to WT mice. Studies in primary myocytes suggested that defects in key lipogenic enzymes including FAS, stearoyl-CoA desaturase-1 (SCD1), and Lipin1 are likely contributing to reduced SERCA activity in mdx mice. Triple transgenic expression of FAS, SCD1, and Lipin1 (3TG) in mdx myocytes partly rescued SERCA activity, which coincided with an increase in SR PE that normalized PC/PE ratio. These findings implicate a defect in lipogenesis to be a contributing factor for SERCA dysfunction in muscular dystrophy. Restoration of muscle's lipogenic pathway appears to mitigate SERCA function through its effects on SR membrane composition.

Original languageEnglish
Pages (from-to)1530-1538
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1851
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • Calcium
  • Lipogenesis
  • Membrane phospholipid
  • Muscular dystrophy
  • Sarcoplasmic reticulum

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