Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe "Físico" s/n, 35017, Las Palmas de Gran Canaria, Spain.
Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira, Las Palmas de Gran Canaria, 35017, Spain; Complejo Hospitalario Universitario Insular-Materno Infantil de Las Palmas de Gran Canaria, Clinical Genetics Unit, 35016, Las Palmas de Gran Canaria, Spain.
Redox Biol. 2020 Sep;36:101627. doi: 10.1016/j.redox.2020.101627. Epub 2020 Jun 30.
The Nrf2 transcription factor is induced by reactive oxygen and nitrogen species and is necessary for the adaptive response to exercise in mice. It remains unknown whether Nrf2 signalling is activated by exercise in human skeletal muscle. Here we show that Nrf2 signalling is activated by exercise to exhaustion with similar responses in normoxia (PO: 143 mmHg) and severe acute hypoxia (PO: 73 mmHg). CaMKII and AMPKα phosphorylation were similarly induced in both conditions. Enhanced Nrf2 signalling was achieved by raising Nrf2 total protein and Ser Nrf2 phosphorylation, accompanied by a reduction of Keap1. Keap1 protein degradation is facilitated by the phosphorylation of p62/SQSTM1 at Ser by AMPK, which targets Keap1 for autophagic degradation. Consequently, the Nrf2-to-Keap1 ratio was markedly elevated and closely associated with a 2-3-fold increase in Catalase protein. No relationship was observed between Nrf2 signalling and SOD1 and SOD2 protein levels. Application of ischaemia immediately at the end of exercise maintained these changes, which were reverted within 1 min of recovery with free circulation. While SOD2 did not change significantly during either exercise or ischaemia, SOD1 protein expression was marginally downregulated and upregulated during exercise in normoxia and hypoxia, respectively. We conclude that Nrf2/Keap1/Catalase pathway is rapidly regulated during exercise and recovery in human skeletal muscle. Catalase emerges as an essential antioxidant enzyme acutely upregulated during exercise and ischaemia. Post-exercise ischaemia maintains Nrf2 signalling at the level reached at exhaustion and can be used to avoid early post-exercise recovery, which is O-dependent.
Nrf2 转录因子被活性氧和氮物种诱导，是小鼠对运动适应反应所必需的。目前尚不清楚 Nrf2 信号是否在人类骨骼肌中通过运动激活。在这里，我们表明，Nrf2 信号在常氧（PO：143mmHg）和严重急性低氧（PO：73mmHg）下的衰竭运动中被激活，具有相似的反应。在这两种情况下，CaMKII 和 AMPKα 的磷酸化也被类似地诱导。增强的 Nrf2 信号是通过提高 Nrf2 总蛋白和 Ser Nrf2 磷酸化来实现的，同时降低了 Keap1。AMPK 磷酸化 p62/SQSTM1 的 Ser 可促进 Keap1 的自噬降解，从而促进 Keap1 蛋白的降解。因此，Nrf2 与 Keap1 的比值显著升高，与 Catalase 蛋白增加 2-3 倍密切相关。未观察到 Nrf2 信号与 SOD1 和 SOD2 蛋白水平之间存在关系。运动结束时立即施加缺血可维持这些变化，恢复后 1 分钟内循环恢复时这些变化被逆转。虽然在运动或缺血过程中 SOD2 没有显著变化，但 SOD1 蛋白表达在常氧和低氧运动中分别略有下调和上调。我们的结论是，Nrf2/Keap1/Catalase 途径在人类骨骼肌的运动和恢复过程中迅速调节。Catalase 作为一种重要的抗氧化酶，在运动和缺血期间被急性上调。运动后缺血将 Nrf2 信号维持在衰竭时达到的水平，并可用于避免早期运动恢复，这是 O 依赖性的。
