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Updated: May 22, 2026
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Loss of calcium-dependent phospholipase A2 contributes to multi-omic changes in mouse denervated skeletal muscle
Agnieszka Czyżowska-Froemling1, Hongyang Xu1, Kylene Harold1
1Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
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.
Insights
Genetic deletion of calcium-dependent phospholipase A2 (cPLA2) did not protect against muscle atrophy in mice. Despite altered oxylipin profiles and lower hydroperoxide generation, cPLA2 knockout did not mitigate denervation-induced muscle wasting.
Area of Science:
- Muscle physiology
- Molecular biology
- Biochemistry
Background:
- Sarcopenia, the age-related loss of skeletal muscle mass and strength, is significantly driven by denervation.
- Calcium-dependent phospholipase A2 (cPLA2) plays a role in releasing fatty acids that generate bioactive oxylipins.
- Oxylipins are implicated as signaling molecules in various physiological and pathological processes.
Purpose of the Study:
- To investigate the role of cPLA2 in denervation-induced muscle atrophy.
- To determine if genetic deletion of cPLA2 protects against muscle atrophy by altering hydroperoxide and oxylipin generation.
- To examine the impact of cPLA2 deficiency on the transcriptome and lipidome of denervated muscle.
Main Methods:
- Utilized a sciatic nerve transection model in wildtype and cPLA2 knockout (KO) mice.
- Analyzed oxylipin content, including specific HDoHE, HEPE, and EpOME variants, in gastrocnemius muscle.
- Performed transcriptomic analysis to identify differentially expressed genes and pathways.
- Assessed levels of glycolytic intermediates and other metabolites.
Main Results:
- Genetic deletion of cPLA2 resulted in significantly higher levels of certain oxylipins (4,10,11,13,14-HDoHE, 12-HEPE, 9,10-EpOME, 12,13-EpOME) in denervated muscle compared to wildtype.
- Denervation led to reductions in glycolytic intermediates, with alpha-hydroxy-glutarate and glucose-6-phosphate being lower in cPLA2 KO mice.
- Transcriptomic analysis revealed differential expression in G-protein coupled receptor signaling pathways between wildtype and cPLA2 KO mice.
- Contrary to the hypothesis, genetic deletion of cPLA2 did not mitigate denervation-induced muscle atrophy, despite reduced hydroperoxide generation.
Conclusions:
- Genetic deletion of cPLA2 does not protect against denervation-induced muscle atrophy in mice.
- The absence of cPLA2 leads to an unexpected increase in specific oxylipin species in denervated muscle.
- Altered hydroperoxide generation and specific oxylipin profiles in cPLA2-deficient muscle do not confer protection against atrophy.
- Further research is needed to elucidate the complex role of cPLA2 and its metabolites in muscle denervation and atrophy.
