Targeting cPLA₂ derived lipid hydroperoxides as a potential intervention for sarcopenia.

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.

SUBMITTER: Pharaoh G 

PROVIDER: S-EPMC7435184 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature