Rapamycin Treatment Induces Lipidomic and Metabolic Changes in Skeletal Muscle of Aged Mice with Hyperactive mTORC1

Mechanistic Target of Rapamycin Complex I (mTORC1) kinase activity plays a central role in regulating muscle protein synthesis in response to amino acids, growth factors, energy availability, and mechanical stimuli. In our previous studies, we observed that mice with chronically active muscle mTORC1, via an inducible skeletal muscle-specific DEPDC5 knockout (mKO) model, exhibited muscle hypertrophy and increased mitochondrial respiration. However, these mice showed no significant improvements in muscle quality or function. This study aimed to investigate the lipidomic and metabolic changes in the skeletal muscle of 27-month-old DEPDC5 mKO mice and DEPDC5 mKO mice treated with rapamycin after five months of gene deletion. We hypothesized that DEPDC5 mKO in old mice would have deleterious effects on muscle metabolism which could be reversed with rapamycin treatment. Our lipidomic analysis revealed a large significant shift in the lipidome between DEPDC5 mKO and DEPDC5 mKO with rapamycin mice. Notably, males exhibited larger shifts in the lipidome compared to females. There was a significant increase in DEPDC5 mKO with rapamycin group including diacylglycerols (DG), cholesterol esters (CE), lyso-phosphatidylethanolamines (LPE) and a decrease in phosphatidylcholines (PC) and phosphatidylglycerols (PG) in comparison to DEPDC5 mKO (p-adjusted < 0.05). In contrast, the analysis of the muscle metabolome showed smaller differences between DEPDC5 mKO and DEPDC5 mKO with rapamycin, although male mice displayed more pronounced changes (p-adjusted < 0.05). Additionally, there was a significant increase in arginine and proline metabolism in DEPDC5 mKO with rapamycin group (p-adjusted < 0.05). We conclude that rapamycin treatment in older mice with hyperactive mTORC1 induced significant changes in the skeletal muscle lipidome and amino acid metabolism. These findings provide valuable insights into the metabolic adaptations of older mice driven by mTORC1 activity and its inhibition in skeletal muscle. NIH R56AG051267; NIH P30AG013319; CPRIT RP190682 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.