Hypoxia preconditioning promotes endurance exercise capacity of mice by activating skeletal muscle Nrf2.

Elite endurance athletes are used to train under hypoxic/high altitude conditions, which can elicit certain stress responses in skeletal muscle and helps to improve their physical performance. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the cellular redox homoeostasis and metabolism in skeletal muscle, playing important roles in adaptation to various stresses. In this study, Nrf2 knockout (KO) and wild-type (WT) mice were pre-conditioned to 48 hours of hypoxia exposure (11.2% oxygen), and the effects of hypoxia preconditioning (HP) on exercise capacity and exercise-induced changes of antioxidant status, energetic metabolism and mitochondrial adaptation in skeletal muscle were evaluated. Nrf2 KO and WT mice were exposed to normoxia or hypoxia for 48 hours before taking incremental treadmill exercise to exhaustion under hypoxia. The skeletal muscles were collected immediately after the incremental treadmill exercise to evaluate the impacts of HP and Nrf2 on the exercise-induced changes. The results indicate absence of Nrf2 did not affect the exercise capacity, though the mRNA expression of certain muscular genes involved in antioxidant, glycogen and fatty acid catabolism was decreased in Nrf2 KO mice. However, the 48-hour HP enhanced exercise capacity in WT mice but not in Nrf2 KO mice, and the exercise capacity of WT mice was significantly higher than that of Nrf2 KO mice. These findings suggest the HP promotes exercise capacity of mice with the participation of Nrf2 signal in skeletal muscle.