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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 ERR\u03b3, a transcription factor that promotes oxidative metabolism genes. Thus, LSD1 serves as an \u2018epigenetic barrier\u2019 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.<\/jats:p>","DOI":"10.7554\/elife.84618","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T05:18:41Z","timestamp":1673587121000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.84618","source":"Crossref","is-referenced-by-count":15,"title":["LSD1 defines the fiber type-selective responsiveness to environmental stress in skeletal muscle"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8679-948X","authenticated-orcid":true,"given":"Hirotaka","family":"Araki","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02cgss904","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University","place":["Kumamoto, 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