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A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1‐mediated oxidative stress
Author(s) -
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
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106491
Subject(s) - biology , oxidative stress , myogenesis , reactive oxygen species , skeletal muscle , dna damage , gene knockdown , microbiology and biotechnology , nadph oxidase , oxidative phosphorylation , epigenetics , mitochondrion , endocrinology , biochemistry , dna , gene
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.