FOXO1‐induced Atrophy Changes in Phospholipid Profiles of Skeletal Muscle
Authors: Senoo Nanami , Miyoshi Noriyuki , Kobayashi Eri , Morita Akihito , Kamei Yasutomi , Miura Shinji 
Published: November 2023

Exercise training influences phospholipid fatty acid composition in skeletal muscle and these changes are associated with physiological phenotypes. Recently we have found that peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α), a nuclear receptor coactivator, affected lipid profiles in skeletal muscle and increased several phospholipid species in glycolytic muscle, namely phosphatidylcholine (PC) (18:0/22:6) and phosphatidylethanolamine (PE) (18:0/22:6). We also found that exercise training increased PC (18:0/22:6) and PE (18:0/22:6) in glycolytic muscle and that PGC‐1α was required for these alterations. On the other hand, a decrease in docosahexaenoic acid [22:6 (n‐3)] from the skeletal muscle phospholipid fraction was observed in dystrophic mdx mice, suggesting changes of phospholipid fatty acid composition related with physiological phenotypes of skeletal muscle. However, the molecular mechanism of this influence on compositional changes is poorly understood. Forkhead box protein O1 (FOXO1) is a transcriptional factor that plays an important role in regulation of skeletal muscle mass. Because we have demonstrated that muscle‐specific overexpression of FOXO1 is sufficient to cause skeletal muscle atrophy in vivo, we speculated that FOXO1 contribute to the atrophy‐mediated change in phospholipid fatty acid composition. To determine the role of FOXO1, we performed lipidomics analyses of skeletal muscle from genetically modified mice that overexpress FOXO1 in skeletal muscle. After lipid extraction from EDL or soleus by Bligh and Dyer method, the lipid samples were injected into LC‐MS and determined peaks were re‐analyzed by MS/MS for identification of lipid species. Using these data, principal component analysis was done to classified the changes of lipid species depending on muscle fiber type and FOXO1 expression. As a result, we observed that PC and PE containing specific fatty acid species changed in both of EDL and soleus derived from mice that overexpress FOXO1 in skeletal muscle. From these results, it was suggested that FOXO1 expression changed fatty acid composition of PC and PE and these changes might be involved in the physiological phenotype of muscle atrophy.Support or Funding InformationThis study was supported by the Council for Science, Technology and Innovation (CSTI), Cross‐ministerial Strategic Innovation Promotion Program (SIP, No.14533567), and “Technologies for creating next‐generation agriculture, forestry and fisheries” (funding agency: Bio‐oriented Technology Research Advancement Institution, NARO), The Tojuro Iijima Foundation for Food Science and Technology (Chiba, Japan), Grants‐in‐Aid for Scientific Research (KAKENHI, No. 26282184, 26560400, 21300240) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT, Tokyo), The Uehara Memorial Foundation (Tokyo, Japan), The Kao Research Council for the Study of Healthcare Science (Tokyo, Japan, No. A‐31006), and University of Shizuoka Grant for Scientific and Educational Research.