Targeting cPLA 2 derived lipid hydroperoxides as a potential intervention for sarcopenia

Sci Rep. 2020 Aug 18;10(1):13968. doi: 10.1038/s41598-020-70792-7.

Abstract

Defects in neuromuscular innervation contribute significantly to the age-related decline in muscle mass and function (sarcopenia). Our previous studies demonstrated that denervation induces muscle mitochondrial hydroperoxide production (H2O2 and lipid hydroperoxides (LOOHs)). Here we define the relative contribution of mitochondrial electron transport chain (ETC) derived H2O2 versus cytosolic phospholipase A2 (cPLA2) derived LOOHs in neurogenic muscle atrophy. We show that denervation increases muscle cPLA2 protein content, activity, and metabolites downstream of cPLA2 including LOOHs. Increased scavenging of mitochondrial H2O2 does not protect against denervation atrophy, suggesting ETC generated H2O2 is not a critical player. In contrast, inhibition of cPLA2 in vivo mitigates LOOH production and muscle atrophy and maintains individual muscle fiber size while decreasing oxidative damage. Overall, we show that loss of innervation in several muscle atrophy models including aging induces generation of LOOHs produced by arachidonic acid metabolism in the cPLA2 pathway contributing to loss of muscle mass.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cytosol / metabolism
  • Electron Transport Chain Complex Proteins / metabolism
  • Hydrogen Peroxide / metabolism
  • Lipid Peroxides / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Mitochondrial Membranes / metabolism
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / pathology
  • Oxidative Stress / drug effects
  • Phospholipases A2 / metabolism*
  • Sarcopenia / metabolism
  • Sarcopenia / therapy*

Substances

  • Electron Transport Chain Complex Proteins
  • Lipid Peroxides
  • Hydrogen Peroxide
  • Phospholipases A2