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We investigated the role of calcium\u2010dependent phospholipase A\n                    <jats:sub>2<\/jats:sub>\n                    (cPLA\n                    <jats:sub>2<\/jats:sub>\n                    ) in denervation\u2010atrophy. cPLA\n                    <jats:sub>2<\/jats:sub>\n                    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 cPLA\n                    <jats:sub>2<\/jats:sub>\n                    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 cPLA\n                    <jats:sub>2<\/jats:sub>\n                    knockout (KO) mice to test this hypothesis. Surprisingly, oxylipin content was significantly higher in 4,10,11,13,14\u2010HDoHE, 12\u2010HEPE, 9,10\u2010EpOME, and 12,13\u2010EpOME in gastrocnemius muscle from mice with genetic deletion of cPLA\n                    <jats:sub>2<\/jats:sub>\n                    compared to wildtype controls. We observed reductions in several glycolytic intermediates after denervation such as fructose\u20106\u2010phosphate, glucose\u20106\u2010phosphate, fructose\u20101,6\u2010bisphosphate, and phosphoenol pyruvate. Both alpha\u2010hydroxy\u2010glutarate and glucose\u20106\u2010phosphate were lower in muscle from mice lacking cPLA\n                    <jats:sub>2<\/jats:sub>\n                    . Transcriptomic analysis showed that G\u2010protein coupled receptor signaling was differentially expressed when comparing wildtype and cPLA\n                    <jats:sub>2<\/jats:sub>\n                    KO mice. In contrast to the protective effects previously reported with inhibition of cPLA\n                    <jats:sub>2<\/jats:sub>\n                    , we found that genetic deletion of cPLA\n                    <jats:sub>2<\/jats:sub>\n                    did not mitigate denervation\u2010induced muscle atrophy despite having lower hydroperoxide generation in gastrocnemius muscle.\n                  <\/jats:p>","DOI":"10.14814\/phy2.70906","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T08:06:45Z","timestamp":1779350805000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of calcium\u2010dependent phospholipase\n                    <scp>A2<\/scp>\n                    contributes to multi\u2010omic changes in mouse denervated skeletal 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