Washington University in St. Louis

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Metabolomics to elucidate novel biochemical mechanisms of disease
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Impaired Skeletal Muscle Mitochondrial Pyruvate Uptake Rewires Glucose Metabolism to Drive Whole-Body Leanness

Sharma A, Oonthonpan L, Sheldon RD, Rauckhorst AJ, Zhu Z, Tompkins SC, Cho K, Gray LR, Scerbo DA, Pewa AD, Cushing EM, Dyle MC, Cox JE, Adams CM, Davies BS, Shields RK, Norris AW, Patti GJ, Zingman LV, and Taylor EB
Impaired Skeletal Muscle Mitochondrial Pyruvate Uptake Rewires Glucose Metabolism to Drive Whole-Body Leanness
eLife, 8:e45873, 2019
doi:10.7554/eLife.45873

Metabolic cycles are a fundamental element of cellular and organismal function. Among the most critical in higher organisms is the Cori Cycle, the systemic cycling between lactate and glucose. Here, skeletal muscle-specific Mitochondrial Pyruvate Carrier (MPC) deletion in mice diverted pyruvate into circulating lactate. This switch disinhibited muscle fatty acid oxidation and drove Cori Cycling that contributed to increased energy expenditure. Loss of muscle MPC activity led to strikingly decreased adiposity with complete muscle mass and strength retention. Notably, despite decreasing muscle glucose oxidation, muscle MPC disruption increased muscle glucose uptake and whole-body insulin sensitivity. Furthermore, chronic and acute muscle MPC deletion accelerated fat mass loss on a normal diet after high fat diet-induced obesity. Our results illuminate the role of the skeletal muscle MPC as a whole-body carbon flux control point. They highlight the potential utility of decreasing muscle pyruvate utilization to ameliorate obesity and type 2 diabetes.

Washington University, Departments of Chemistry, Genetics, and Medicine. Saint Louis, Missouri 63110 USA