School of Sport Science, Beijing Sport University, Beijing, China.
State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing, China.
J Appl Physiol (1985). 2019 Nov 1;127(5):1267-1277. doi: 10.1152/japplphysiol.00347.2019. Epub 2019 Sep 5.
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 cellular redox homeostasis 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 preconditioned to 48 h 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 knockout (KO) and wild-type (WT) mice were exposed to normoxia or hypoxia for 48 h 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 the absence of Nrf2 did not affect exercise capacity, although the mRNA expression of certain muscular genes involved in antioxidant, glycogen and fatty acid catabolism was decreased in Nrf2 KO mice. However, 48-h 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 HP promotes exercise capacity of mice with the participation of the Nrf2 signal in skeletal muscle. Hypoxia preconditioning (HP) activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signal, which was involved in HP-elicited adaptation responses to hypoxia, oxidative, and metabolic stresses in skeletal muscle. On the other hand, Nrf2 deficiency abolished the enhanced exercise capacity after the 48-h HP. Our results indicate that Nrf2 plays an essential role in the exercise capacity-enhancing effect of HP, possibly by modulating muscular antioxidative responses, the mRNA expression of muscular genes involved in glycogen and fatty acid metabolism, as well as mitochondrial biogenesis, and through the cross talk with AMPK and hypoxia-inducible factor-1α signaling.
精英耐力运动员习惯于在低氧/高原条件下训练，这会在骨骼肌中引起一定的应激反应，并有助于提高他们的身体表现。核因子红细胞 2 相关因子 2（Nrf2）调节骨骼肌中的细胞氧化还原平衡和代谢，在适应各种应激方面发挥重要作用。在这项研究中，Nrf2 敲除（KO）和野生型（WT）小鼠预先暴露于 48 小时的低氧环境（11.2%氧气）中，评估了低氧预处理（HP）对运动能力以及运动引起的抗氧化状态、能量代谢和骨骼肌线粒体适应的影响。Nrf2 敲除（KO）和野生型（WT）小鼠在低氧下进行递增跑步机运动至力竭之前，先在常氧或低氧下暴露 48 小时。在递增跑步机运动后立即采集骨骼肌，以评估 HP 和 Nrf2 对运动引起的变化的影响。结果表明，Nrf2 的缺失并不影响运动能力，尽管 Nrf2 KO 小鼠中某些与抗氧化、糖原和脂肪酸分解代谢有关的肌肉基因的 mRNA 表达降低。然而，48 小时的 HP 增强了 WT 小鼠的运动能力，但不能增强 Nrf2 KO 小鼠的运动能力，并且 WT 小鼠的运动能力明显高于 Nrf2 KO 小鼠。这些发现表明，HP 通过骨骼肌中的 Nrf2 信号参与，促进了 WT 小鼠的运动能力。低氧预处理（HP）激活了核因子红细胞 2 相关因子 2（Nrf2）信号，该信号参与了 HP 引起的低氧、氧化和代谢应激在骨骼肌中的适应反应。另一方面，Nrf2 缺失消除了 48 小时 HP 后运动能力的增强。我们的结果表明，Nrf2 在 HP 增强运动能力的效应中起着至关重要的作用，可能通过调节肌肉抗氧化反应、参与糖原和脂肪酸代谢的肌肉基因的 mRNA 表达以及线粒体生物发生，以及通过与 AMPK 和低氧诱导因子-1α信号的相互作用。
