A Ketogenic Diet Improves Aerobic Capacity in Hyperglycemic Mice by Sex-Dependent Mechanisms

Hyperglycemia is associated with lower aerobic exercise capacity (VO2peak) in humans and rodent models. We tested whether reducing blood glucose levels with a dietary intervention can restore VO2peak in hyperglycemic mice. Male and female CD-1 mice were injected with low dose streptozotocin (STZ) to induce moderate hyperglycemia (>200 mg/dL). Hyperglycemic mice were randomized to receive a standard diet (STZ-CHOW) or a ketogenic diet (STZ-KETO). KETO significantly reduced blood glucose in STZ-treated mice. Next, both groups underwent similar volumes of exercise training by voluntary wheel running, or remained sedentary for 8 wks. In males, VO2peak during maximal exercise testing was similar in sedentary mice, regardless of diet. However, with training, VO2peak was significantly improved in STZ-KETO, but not STZ-CHOW males (see Figure). In females, KETO significantly increased VO2peak in sedentary mice, with no additional increase in response to training. Improved VO2peak with KETO in females was associated with a 50% increase in skeletal muscle mitochondrial ATP synthase protein. In contrast, ATP synthase was not regulated by diet in males. Our data demonstrate that a ketogenic diet can improve VO2peak in mice with hyperglycemia. In males, improved VO2peak with KETO was exercise-dependent, while in females, the beneficial effects of KETO on VO2peak and mitochondrial content were exercise-independent. Disclosure P.Pattamaprapanont: None. M.Formato: None. R.Nogueira soares: None. S.J.Lessard: None.