Kitaoka Yu, Tamura Yuki, Takahashi Kenya, Takeda Kohei, Takemasa Tohru, Hatta Hideo
Department of Human Sciences, Kanagawa University, Yokohama, Japan.
Department of Exercise Physiology, Nippon Sport Science University, Tokyo, Japan.
Physiol Rep. 2019 Feb;7(3):e13998. doi: 10.14814/phy2.13998.
Oxidative stress and mitochondrial dysfunction are associated with the aging process. However, the role of nuclear factor erythroid 2 -related factor 2 (Nrf2) in skeletal muscle during aging remains to be clarified. In the current study, we assessed whether the lack of Nrf2, which is known as a master regulator of redox homeostasis, promotes age-related mitochondrial dysfunction and muscle atrophy in skeletal muscle. Here, we demonstrated that mitochondrial 4-hydroxynonenal and protein carbonyls, markers of oxidative stress, were robustly elevated in aged Nrf2 knockout (KO) mice because of the decreased expression of Nrf2-target antioxidant genes. Mitochondrial respiration declined with aging; however, there was no difference between Nrf2 KO and age-matched WT mice. Similarly, cytochrome c oxidase activity was lower in aged WT and Nrf2 KO mice compared with young WT mice. The expression of Mfn1 and Mfn2 mRNA was lower in aged Nrf2 KO muscle. Mitochondrial reactive oxygen species production per oxygen consumed was elevated in aged Nrf2 KO mice. There was no effect of Nrf2 KO on muscle mass normalized to body weight. These results suggest that Nrf2 deficiency exacerbates age-related mitochondrial oxidative stress but does not affect the decline of respiratory function in skeletal muscle.
氧化应激和线粒体功能障碍与衰老过程相关。然而，核因子红细胞2相关因子2（Nrf2）在衰老过程中骨骼肌中的作用仍有待阐明。在本研究中，我们评估了作为氧化还原稳态主要调节因子的Nrf2的缺失是否会促进骨骼肌中与年龄相关的线粒体功能障碍和肌肉萎缩。在此，我们证明，由于Nrf2靶抗氧化基因表达降低，氧化应激标志物线粒体4-羟基壬烯醛和蛋白质羰基在老年Nrf2基因敲除（KO）小鼠中显著升高。线粒体呼吸随衰老而下降；然而，Nrf2基因敲除小鼠与年龄匹配的野生型（WT）小鼠之间没有差异。同样，与年轻野生型小鼠相比，老年野生型和Nrf2基因敲除小鼠的细胞色素c氧化酶活性较低。老年Nrf2基因敲除肌肉中Mfn1和Mfn2 mRNA的表达较低。老年Nrf2基因敲除小鼠每消耗一分子氧产生的线粒体活性氧增加。Nrf2基因敲除对体重标准化后的肌肉质量没有影响。这些结果表明，Nrf2缺乏会加剧与年龄相关的线粒体氧化应激，但不影响骨骼肌呼吸功能的下降。
