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
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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