Constitutive mTORC1 activation in skeletal muscle increases inflammation but is not sufficient to impair glucose tolerance.

Aberrant mechanistic target of rapamycin complex 1 (mTORC1) signaling in skeletal muscle has been implicated in aging and insulin resistance; however, it is not known whether chronic mTORC1 activation directly causes glucose intolerance. We tested the hypothesis that constitutive mTORC1 activation in mouse skeletal muscle impairs glucose homeostasis. Six-month-old female and male mice with tamoxifen-inducible, muscle-specific knockout of the DEP domain containing 5, GATOR1 subcomplex subunit gene (Depdc5), a key component of the GAP activity toward rag 1 (GATOR1) complex and negative regulator of mTORC1, were fed normal chow or Western diet (WD; 45% fat, 17% sucrose) for 12 wk. Depdc5 knockout (KO) increased mTORC1 signaling and altered autophagy markers. WD increased body and fat mass and impaired glucose tolerance independent of genotype. KO had minimal effects on fasting glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), glycosylated hemoglobin (HbA1c), or oral glucose tolerance, although female KO mice showed a modest increase in WD-induced weight gain and fasting glucose. Mitochondrial respiration and content were unchanged by KO or WD. KO increased mitochondrial H2O2 production capacity but did not drive clear signs of oxidative stress. Transcriptomic analysis revealed robust KO-driven upregulation of genes related to cell division and immune pathways. Consistent with this, KO increased TNF-α and IL-6 protein expression and shifted macrophage polarization toward an M2-like phenotype without altering total macrophage content. Collectively, these findings indicate that chronic activation of mTORC1 in skeletal muscle promotes inflammatory remodeling but is insufficient to impair systemic glucose homeostasis, even under dietary stress.NEW & NOTEWORTHY Chronic skeletal muscle mTORC1 hyperactivation is widely assumed to drive insulin resistance and metabolic decline, yet direct causal evidence remains limited. Using adult-onset Depdc5 deletion to constitutively activate mTORC1 via GATOR1 disruption, we show that this is insufficient to impair glucose homeostasis even under a Western diet challenge. Strikingly, glucose tolerance and mitochondrial respiration remained preserved despite inflammation and immune transcriptional reprogramming-challenging the prevailing model of mTORC1-driven metabolic dysfunction in muscle.