Elevated mTORC1 Signaling in Skeletal Muscle Alters Mitochondrial Dynamics and H2O2 Production and Exacerbates Diet-Induced Hyperglycemia

Authors

Erik D. Marchant, The University of Texas Health Science Center at San AntonioFollow
Hanna Kalenta, The University of Texas Health Science Center at San AntonioFollow
Sean P. Kilroe, The University of Texas Health Science Center at San AntonioFollow
Jacquelyn May, The University of Texas Health Science Center at San AntonioFollow
Blake B. Rasmussen, The University of Texas Health Science Center at San AntonioFollow

Abstract

The mechanisms underlying skeletal muscle insulin resistance are not completely understood, but altered signaling through mTORC1 is associated with insulin resistance. PURPOSE: Determine if the disruption of the GATOR1 complex and subsequent mTORC1 hyperactivation is sufficient to drive insulin resistance in skeletal muscle with or without a western diet. METHODS: Muscle-specific DEPDC5 (a component of GATOR1) knockout mice or littermate controls were administered a western diet or control synthetic chow for 12 weeks and assessed for fasting glucose and insulin, oral glucose tolerance, and mitochondrial dynamics and function (respiration and H₂O₂ production). RESULTS: Western diet increased fasting glucose by 32 mg/dL (p<0.001) and impaired glucose tolerance (33% increase in area under the curve; p<0.0001), both of which appeared worse in knockout mice (13% and 7%, respectively), though this was not statistically different from western diet alone. Additionally, western diet increased HbA1c by about 5% (p=0.10), and reduced grip strength by 12% (p<0.05). Markers of mitochondrial dynamics and mitophagy were altered in knockout mice (increased OPA1, DRP1, and Beclin-1; decreased Parkin; p<0.05). Neither genotype nor diet affected mitochondrial respiration, apart from a 30% increase in complex IV maximal activity in knockout mice (p=0.09). However, knockout mice fed a western diet exhibited an approximately 2-fold increase in mitochondrial H₂O₂ production compared to controls across a range of physiological relevant energy states (p<0.05). CONCLUSION: Feeding mice a western diet impairs glycemic control even in the absence of altered mitochondrial respiration, and increased mTORC1 signaling in skeletal muscle exacerbates the negative effects of western diet, potentially by altering mitochondrial dynamics and increasing mitochondrial H₂O₂ production.

Recommended Citation

Marchant, Erik D.; Kalenta, Hanna; Kilroe, Sean P.; May, Jacquelyn; and Rasmussen, Blake B. (2025) "Elevated mTORC1 Signaling in Skeletal Muscle Alters Mitochondrial Dynamics and H2O2 Production and Exacerbates Diet-Induced Hyperglycemia," International Journal of Exercise Science: Conference Proceedings: Vol. 2: Iss. 17, Article 21.
Available at: https://digitalcommons.wku.edu/ijesab/vol2/iss17/21