A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1-mediated oxidative stress
A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1-mediated oxidative stress
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DOI：
10.15252/embj.2020106491
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发表时间：
2021-04-13
期刊：
影响因子：
11.4
通讯作者：
Kang, Sona
中科院分区：
文献类型：
--
作者：
Damal Villivalam, Sneha;Ebert, Scott M.;Kang, Sona
运动可以改变骨骼肌DNA甲基化，但对DNA甲基化机制在运动能力中的作用知之甚少。在这里，我们表明，DNMT3A在氧化红肌肉中的表达在一轮耐力运动后大大增加。肌肉特异性Dnmt3a敲除小鼠对耐力运动的耐受性降低，伴随着氧化能力和线粒体呼吸的降低。此外，Dnmt3a缺乏的肌肉过度产生活性氧（ROS），这是肌肉功能障碍的主要原因。从机制上讲，我们表明，DNMT3A抑制Aldh1l1转录结合到其启动子区，改变其表观遗传学的档案。ALDH1L1的强制表达升高NADPH水平，这导致通过NADPH氧化酶复合物的作用过量产生ROS，最终导致肌管中的线粒体缺陷。因此，ALDH1L1通路的抑制可以从肌管中的Dnmt3a缺陷中拯救氧化应激和线粒体功能障碍。最后，我们表明，在体内敲低Aldh1l1在很大程度上挽救运动不耐受Dnmt3a缺陷小鼠。总之，我们确定骨骼肌中的DNMT3A通过控制细胞内氧化应激在耐力运动中起着关键作用。
Exercise can alter the skeletal muscle DNA methylome, yet little is known about the role of the DNA methylation machinery in exercise capacity. Here, we show that DNMT3A expression in oxidative red muscle increases greatly following a bout of endurance exercise. Muscle-specific Dnmt3a knockout mice have reduced tolerance to endurance exercise, accompanied by reduction in oxidative capacity and mitochondrial respiration. Moreover, Dnmt3a-deficient muscle overproduces reactive oxygen species (ROS), the major contributors to muscle dysfunction. Mechanistically, we show that DNMT3A suppresses the Aldh1l1 transcription by binding to its promoter region, altering its epigenetic profile. Forced expression of ALDH1L1 elevates NADPH levels, which results in overproduction of ROS by the action of NADPH oxidase complex, ultimately resulting in mitochondrial defects in myotubes. Thus, inhibition of ALDH1L1 pathway can rescue oxidative stress and mitochondrial dysfunction from Dnmt3a deficiency in myotubes. Finally, we show that in vivo knockdown of Aldh1l1 largely rescues exercise intolerance in Dnmt3a-deficient mice. Together, we establish that DNMT3A in skeletal muscle plays a pivotal role in endurance exercise by controlling intracellular oxidative stress.