A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1-mediated oxidative stress
Autor: | Jinse Kim, Hector Palacios, Tabitha Tcheau, Hee-Woong Lim, Byung Chul Jung, Scott M. Ebert, Sneha Damal Villivalam, Christopher M. Adams, Sona Kang, Dongjoo You |
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Rok vydání: | 2020 |
Předmět: |
Oxidative phosphorylation
Exercise intolerance Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Cell Line DNA Methyltransferase 3A 03 medical and health sciences Gene Knockout Techniques Mice 0302 clinical medicine Endurance training medicine Animals DNA (Cytosine-5-)-Methyltransferases Muscle Skeletal Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences Reactive oxygen species Oxidoreductases Acting on CH-NH Group Donors General Immunology and Microbiology Myogenesis Sequence Analysis RNA General Neuroscience Gene Expression Profiling Skeletal muscle Articles Cell biology Mitochondria Muscle Rats Oxidative Stress medicine.anatomical_structure chemistry Knockout mouse embryonic structures Physical Endurance medicine.symptom Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress |
Zdroj: | EMBO J |
ISSN: | 1460-2075 |
Popis: | 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. |
Databáze: | OpenAIRE |
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