FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging

Nat Commun. 2020 Nov 9;11(1):5661. doi: 10.1038/s41467-020-19501-6.

Abstract

Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Cell Line
  • Endoplasmic Reticulum Stress / physiology*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fatty Acid Binding Protein 3 / genetics
  • Fatty Acid Binding Protein 3 / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Lipidomics
  • Membrane Fluidity
  • Membrane Lipids / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Myoblasts / pathology
  • Myoblasts / physiology
  • Phospholipids / metabolism
  • Protein Serine-Threonine Kinases
  • Sarcopenia
  • Up-Regulation

Substances

  • Eukaryotic Initiation Factor-2
  • Fabp3 protein, mouse
  • Fatty Acid Binding Protein 3
  • Membrane Lipids
  • Phospholipids
  • Protein Serine-Threonine Kinases
  • eIF2alpha kinase, mouse