Loss of calcium-dependent phospholipase A2 contributes to multi-omic changes in mouse denervated skeletal muscle

Age-related loss of innervation in skeletal muscle is a key driver of sarcopenia. We investigated the role of calcium-dependent phospholipase A₂ (cPLA₂) in denervation-atrophy. cPLA₂ mediates the release of polyunsaturated fatty acid substrates, and the oxidation of the free fatty acids generates oxylipins, which are bioactive signaling facilitators. We hypothesized that loss of cPLA₂ would protect against muscle atrophy by altering hydroperoxide and oxylipin generation, thereby modifying the transcriptome and lipidome of denervated muscle to mitigate atrophy. We used a sciatic nerve transection model in wildtype and cPLA₂ knockout (KO) mice to test this hypothesis. Surprisingly, oxylipin content was significantly higher in 4,10,11,13,14-HDoHE, 12-HEPE, 9,10-EpOME, and 12,13-EpOME in gastrocnemius muscle from mice with genetic deletion of cPLA₂ compared to wildtype controls. We observed reductions in several glycolytic intermediates after denervation such as fructose-6-phosphate, glucose-6-phosphate, fructose-1,6-bisphosphate, and phosphoenol pyruvate. Both alpha-hydroxy-glutarate and glucose-6-phosphate were lower in muscle from mice lacking cPLA₂. Transcriptomic analysis showed that G-protein coupled receptor signaling was differentially expressed when comparing wildtype and cPLA₂ KO mice. In contrast to the protective effects previously reported with inhibition of cPLA₂, we found that genetic deletion of cPLA₂ did not mitigate denervation-induced muscle atrophy despite having lower hydroperoxide generation in gastrocnemius muscle.