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

Czyżowska‐Froemling, Agnieszka, Xu, Hongyang, Harold, Kylene, Thomason, Jessica, Kneuper, Kara, Duggan, Elizabeth, Pranay, Atul, Zhu, Jie, Agbaga, Martin‐Paul, Georgescu, Constantin, Tyrrell, Victoria, O'Donnell, Valerie ORCID: https://orcid.org/0000-0003-4089-8460, Humphries, Ken, Van Remmen, Holly and Brown, Jacob L. 2026. Loss of calcium‐dependent phospholipase A2 contributes to multi‐omic changes in mouse denervated skeletal muscle. Physiological Reports 14 (10) , e70906. 10.14814/phy2.70906

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley
ISSN:	2051-817X
Date of First Compliant Deposit:	29 May 2026
Date of Acceptance:	30 April 2026
Last Modified:	29 May 2026 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/187279

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