Abstract 2203 Muscle Metabolic Profile Following Acute Exercise in Mice with Constitutively Active mTORC1

An increase in Mechanistic Target Of Rapamycin Complex I (mTORC1) kinase activity stimulates muscle protein synthesis in response to amino acids, growth factors, energy, and mechanical stimuli. We previously found muscle hypertrophy and increased mitochondrial respiration in resting mice with chronically active mTORC1 (i.e., an inducible skeletal muscle specific DEPDC5 knockout (KO) model), but no improvement in muscle quality and function. The effect of acute exercise on chronically active mTORC1 in skeletal muscle is unknown. The purpose of this study was to determine the metabolic profile of skeletal muscle in DEPDC5 KO and wild-type (WT) male and female mice following 1-hour of treadmill exercise. Targeted metabolomics was performed on quadricep muscle, with a total of 272 polar metabolites being detected. Pathway analysis found significant differences between KO and WT mice in pyrimidine, phenylalanine, glycine, serine, and threonine metabolism independent of sex (P<0.05). Additionally, in male mice, KO and WT, showed significant differences in pathways related to pyruvate, glycolysis/gluconeogenesis, and beta-alanine metabolism, whereas in female mice, KO and WT had differences in pathways involving cysteine, methionine, and tyrosine metabolism (P<0.05). Purines and pyrimidines were most responsible for the differences between the groups. We conclude that chronic activation of mTORC1 in skeletal muscle alters several metabolic pathways that may impact muscle function and sarcopenia. NIA R56AG052267; NIA P30AG024832; CPRIT RP190682.