Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Free Radic Biol Med. 2010 Nov 30;49(10):1487-93. doi: 10.1016/j.freeradbiomed.2010.08.010. Epub 2010 Aug 11.
The role of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) redox signaling has not been characterized in human skeletal muscle despite an extensive delineation of oxidative stress in the etiology of aging and sarcopenia. We assessed whether the age-associated decline in antioxidant response is due, at least in part, to dysfunction in Nrf2-Keap1 redox signaling. We also evaluated whether an active lifestyle can conserve skeletal muscle cellular redox status via activation of Nrf2-Keap1 signaling. Here we show that a recreationally active lifestyle is associated with the activation of upstream modulators that induce the Nrf2-mediated antioxidant response cascade in skeletal muscle of the elderly. Conversely, a sedentary lifestyle is negatively associated with these adaptations mainly because of dysregulation of Nrf2-Keap1 redox signaling that renders the intracellular environment prone to reactive oxygen species-mediated toxicity. Our results indicate that an active lifestyle is an important determinant of cellular redox status. We propose that the metabolic induction of Nrf2-Keap1 redox signaling promises to be a viable therapy for attenuating oxidative stress-mediated damage in skeletal muscle associated with physical inactivity.
尽管氧化应激在衰老和肌肉减少症的发病机制中得到了广泛的描述，但核因子红细胞 2 p45 相关因子 2 (Nrf2) 和 Kelch 样 ECH 相关蛋白 1 (Keap1) 氧化还原信号在人体骨骼肌中的作用尚未得到阐明。我们评估了抗氧化反应的年龄相关性下降是否至少部分归因于 Nrf2-Keap1 氧化还原信号的功能障碍。我们还评估了积极的生活方式是否可以通过激活 Nrf2-Keap1 信号来维持骨骼肌细胞的氧化还原状态。在这里，我们发现，有规律的休闲活动与激活上游调节剂有关，这些调节剂可诱导老年人骨骼肌中 Nrf2 介导的抗氧化反应级联。相反，久坐不动的生活方式与这些适应性呈负相关，主要是因为 Nrf2-Keap1 氧化还原信号的失调，使细胞内环境容易受到活性氧介导的毒性。我们的结果表明，积极的生活方式是细胞氧化还原状态的重要决定因素。我们提出，Nrf2-Keap1 氧化还原信号的代谢诱导有望成为一种可行的治疗方法，可减轻与缺乏身体活动相关的骨骼肌中氧化应激介导的损伤。
