LSD1 acts as an epigenetic barrier against glucocorticoid-induced atrophy and exercise-induced hypertrophy in skeletal muscle

Abstract

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 ERR{gamma}, 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. Graphical abstract. LSD1 serves as an "epigenetic barrier" that defines stress sensitivities in the skeletal muscleLSD1 attenuates glucocorticoid (GC)-induced atrophy in the fast fiber-dominant muscles, in collaboration with Foxk1, an anti-autophagic transcription factor. On the other hand, LSD1 attenuates endurance exercise-induced hypertrophy in the slow fiber-dominant muscles, by inhibiting ERR{gamma}, a transcription factor that promotes oxidative metabolism genes. The loss of LSD1 remarkably sensitized the muscles to GC and endurance exercise.