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- W3026604987 abstract "Abstract Exercise interventions alter the DNA methylation profile in skeletal muscle, yet little is known about the role of the DNA methylation machinery in exercise capacity. In this study, we found that in oxidative red muscle, DNMT3A expression increases greatly following a bout of endurance exercise. Mice lacking Dnmt3a in skeletal muscle fibers had reduced tolerance to endurance exercise, accompanied by reduced oxidative capacity and reduced mitochondrial counts. Moreover, during exercise, the knockout muscles overproduced reactive oxygen species (ROS), which are major contributors to muscle dysfunction. In mechanistic terms, we demonstrated that Aldh1l1 is a key target of repression by DNMT3A in red muscles. DNMT3A directly regulated the Aldh1l1 transcription by binding to the Aldh1l1 promoter region and altering DNA methylation and histone modification. Enforcing ALDH1L1 expression, leading to elevated NADPH, led to overproduction of ROS by the NADPH oxidase complex (NOX) in myotubes, ultimately resulting in mitochondrial defects. Moreover, both genetic inhibition of ALDH1L1 and pharmacological inhibition of NOX rescued oxidative stress and mitochondrial decline in Dnmt3a -deficient myotubes, confirming the essential role of ALDH1L1-dependent ROS generation as a downstream effector of DNMT3A loss of function. Together, our results reveal that DNMT3A in skeletal muscle plays a pivotal role in endurance exercise by controlling intracellular oxidative stress." @default.
- W3026604987 created "2020-05-29" @default.
- W3026604987 creator A5000562543 @default.
- W3026604987 creator A5002719297 @default.
- W3026604987 creator A5006637134 @default.
- W3026604987 creator A5057229639 @default.
- W3026604987 creator A5065276262 @default.
- W3026604987 creator A5066038957 @default.
- W3026604987 creator A5086156809 @default.
- W3026604987 creator A5091496107 @default.
- W3026604987 date "2020-05-19" @default.
- W3026604987 modified "2023-10-01" @default.
- W3026604987 title "Skeletal muscle DNMT3A plays a necessary role in endurance exercise by regulating oxidative capacity of red muscles" @default.
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