Loss of Muscle MTCH2 Increases Whole-Body Energy Utilization and Protects from Diet-Induced Obesity

Mitochondrial carrier homolog 2 (MTCH2) is a repressor of mitochondrial oxidative phosphorylation (OXPHOS), and its locus is associated with increased BMI in humans. Here, we demonstrate that mice deficient in muscle MTCH2 are protected from diet-induced obesity and hyperinsulinemia and that they demonstrate increased energy expenditure. Deletion of muscle MTCH2 also increases mitochondrial OXPHOS and mass, triggers conversion from glycolytic to oxidative fibers, increases capacity for endurance exercise, and increases heart function. Moreover, metabolic profiling of mice deficient in muscle MTCH2 reveals a preference for carbohydrate utilization and an increase in mitochondria and glycolytic flux in muscles. Thus, MTCH2 is a critical player in muscle biology, modulating metabolism and mitochondria mass as well as impacting whole-body energy homeostasis. [Display omitted] •MTCH2 acts as a repressor of muscle mitochondrial metabolism and size•Loss of MTCH2 increases muscle metabolism, energy expenditure, and heart function•Mice deficient in muscle MTCH2 demonstrate an increased capacity for endurance exercise•Mice deficient in muscle MTCH2 are protected from diet-induced obesity The MTCH2 locus is associated with increased obesity in humans. Buzaglo-Azriel et al. show that muscle MTCH2 deficiency in mice provides protection from a high-fat diet and that this protection is most likely due to increased muscle metabolism, leading to elevated whole-body energy demand and heat production.