Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness

Abstract

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 modulating muscle pyruvate utilization to ameliorate obesity and type 2 diabetes.

Blocking mitochondrial pyruvate import causes energy wasting via futile lipid cycling in brown fat

“…Further studies by Zou et al showed that whole body heterozygous MPC1 knock-out mice have reduced body weight and increased expression of genes associated with lipolysis and fatty acid oxidation [31]. Additionally studies in C2C12 cells and muscle specific MPC1 KO mice have increased fatty acid oxidation [14,32]. This is in agreement with our results showing increased lipid droplet consumption and fatty acid oxidation in brown adipocytes treated with an MPC inhibitor.…”

The Mitochondrial Ca2+ Uptake and the Fine-Tuning of Aerobic Metabolism

“…This triggered enhanced FA oxidation and Cori cycling, with an overall increase in energy expenditure. Thus, skeletal-muscle restricted MPC deletion accelerated fat mass loss when mice were fed again with a chow diet after high-fat diet-induced obesity (Sharma et al, 2019). Altogether these studies support a model in which impaired mitochondrial Ca 2+ uptake and mitochondrial pyruvate entry inhibition lead to similar defects in glucose oxidation, which result in overlapping local and systemic metabolic adaptations.…”

The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

“…During T2D, decreased glucose uptake by skeletal muscle significantly drives chronic hyperglycemia [83]. Skeletal muscle-specific MPC knockout in mice (MPC SkmKO) leads to increased glucose uptake in muscle and increased lactate release [84], thus increasing the Cori cycle as explained above. Furthermore, FA oxidation appears to be increased in MPC-deficient cells.…”