A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1‐mediated oxidative stress. (13th April 2021)

• Record Type: Journal Article
• Authors: Damal Villivalam, Sneha; Ebert, Scott M; Lim, Hee Woong; Kim, Jinse; You, Dongjoo; Jung, Byung Chul; Palacios, Hector H; Tcheau, Tabitha; Adams, Christopher M; Kang, Sona
• Is Part Of: EMBO journal. Volume 40:Number 9(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-04-13
• Subjects: DNA methylation -- exercise -- oxidative stress; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020106491
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: Exercise significantly alters the DNA methylation profile of skeletal muscle, yet little is known about the underlying function of the DNA methylation machinery during exercise performance. Skeletal muscle DNA methyltransferase 3 (DNMT3) is necessary to maintain mitochondrial function and oxidative capacity, and support endurance exercise by suppressing Aldh1l1 transcription. DNMT3A expression is increased in the oxidative soleus muscle during exercise. Muscle‐specific Dnmt3a knockout mice display a reduced tolerance to endurance exercise. Dnmt3a knockout soleus muscle overproduces ROS and exhibits mitochondrial dysfunction. Aldh1l1 is a direct target gene of DNMT3A mediating mitochondrial dysfunction in red oxidative muscle. Aldh1l1 knockdown partially restores exercise intolerance of Dnmt3a knockout mice. Abstract : Skeletal muscle‐expressed DNA methyltransferase 3 maintains mitochondrial function and oxidative capacity by suppressing Aldh1l1 transcription.