Targeting cPLA2 derived lipid hydroperoxides as a potential intervention for sarcopenia

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 (H 2 O 2 and lipid hydroperoxides (LOOHs)). Here we define the relative contribution of mitochondrial electron transport chain (ETC) derived H 2 O 2 versus cytosolic phospholipase A 2 (cPLA 2 ) derived LOOHs in neurogenic muscle atrophy. We show that denervation increases muscle cPLA 2 protein content, activity, and metabolites downstream of cPLA 2 including LOOHs. Increased scavenging of mitochondrial H 2 O 2 does not protect against denervation atrophy, suggesting ETC generated H 2 O 2 is not a critical player. In contrast, inhibition of cPLA 2 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 cPLA 2 pathway contributing to loss of muscle mass.