Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
Kan Etoh
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
Daiki Seko
Department of Muscle Development and Regeneration, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; Department of Molecular Bone Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Skeletal muscle exhibits remarkable plasticity in response to environmental cues, with stress-dependent effects on the fast-twitch and slow-twitch fibers. Although stress-induced gene expression underlies environmental adaptation, it is unclear how transcriptional and epigenetic factors regulate fiber type-specific responses in the muscle. Here, we show that flavin-dependent lysine-specific demethylase-1 (LSD1) differentially controls responses to glucocorticoid and exercise in postnatal skeletal muscle. Using skeletal muscle-specific LSD1-knockout mice and in vitro approaches, we found that LSD1 loss exacerbated glucocorticoid-induced atrophy in the fast fiber-dominant muscles, with reduced nuclear retention of Foxk1, an anti-autophagic transcription factor. Furthermore, LSD1 depletion enhanced endurance exercise-induced hypertrophy in the slow fiber-dominant muscles, by induced expression of ERRγ, a transcription factor that promotes oxidative metabolism genes. Thus, LSD1 serves as an ‘epigenetic barrier’ that optimizes fiber type-specific responses and muscle mass under the stress conditions. Our results uncover that LSD1 modulators provide emerging therapeutic and preventive strategies against stress-induced myopathies such as sarcopenia, cachexia, and disuse atrophy.
