A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice

VO2peak is a key health benefit of aerobic exercise; however, chronic hyperglycemia is associated with persistently low VO2peak due to an impaired adaptive response to training. Here, we show that reducing blood glucose with a carbohydrate-restricted, high fat ketogenic diet can restore aerobic exercise adaptation in male mice with hyperglycemia. Hyperglycemic mice received standard high-carbohydrate chow (CHOW), which sustains high blood glucose; or a ketogenic diet (KETO), which normalizes blood glucose levels. After aerobic exercise training, improvements in VO2peak are blunted in CHOW, but restored by KETO. Increased VO2peak in KETO is associated with enhanced aerobic remodeling of skeletal muscle, including a more oxidative fiber-type and increased capillary density. Moreover, KETO induces exercise-independent effects on muscle mitochondrial remodeling and substrate selection, significantly increasing fatty acid oxidation and down-regulating glucose metabolism. We identify a ketogenic diet as a potential therapy to improve aerobic exercise adaptation in the growing population with hyperglycemia. A ketogenic diet in male mice with hyperglycemia normalized blood glucose and enhanced improvements in cardiorespiratory fitness and aerobic remodeling of skeletal muscle with aerobic exercise training, compared to mice consuming regular chow.