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

VOpeak is a key health benefit of aerobic exercise; however, chronic hyperglycemia is associated with persistently low VOpeak due to an impaired adaptive response to training. Here, we tested whether reducing blood glucose with a low-carbohydrate/high-fat "ketogenic" diet could restore aerobic exercise adaptation in a mouse model of hyperglycemia. Hyperglycemia was induced by streptozotocin (STZ) and mice were stratified to standard chow (STZ-CHOW), or a ketogenic diet (STZ-KETO), which rapidly normalized blood glucose. After aerobic exercise training, improvements in VOpeak were blunted in STZ-CHOW, but exercise response was restored in STZ-KETO. Improved VOpeak in STZ-KETO was associated with enhanced aerobic remodeling of skeletal muscle, including a more oxidative fiber-type and increased capillary density, along with restoration of circulating angiogenic markers. Moreover, KETO induced exercise-independent effects on muscle mitochondrial remodeling and mitochondrial dynamics, significantly increasing fatty acid oxidation. Our results identify a ketogenic diet as a potential therapy to improve aerobic exercise response in the growing population with hyperglycemia due to diabetes and other metabolic conditions.