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.
Elife. 2023 Jan 25;12:e84618. doi: 10.7554/eLife.84618.
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.
骨骼肌对环境信号表现出显著的可塑性，对快肌纤维和慢肌纤维有应激依赖性影响。尽管应激诱导的基因表达是环境适应的基础，但转录和表观遗传因子如何调节肌肉中纤维类型特异性反应尚不清楚。在这里，我们表明黄素依赖的赖氨酸特异性去甲基酶 1（LSD1）在出生后骨骼肌中对糖皮质激素和运动的反应有差异控制。使用骨骼肌特异性 LSD1 敲除小鼠和体外方法，我们发现 LSD1 缺失加剧了糖皮质激素诱导的快肌纤维占优势的肌肉萎缩，抗自噬转录因子 Foxk1 的核保留减少。此外，LSD1 耗竭通过诱导促进氧化代谢基因表达的转录因子 ERRγ，增强了慢肌纤维占优势的肌肉的耐力运动诱导的肥大。因此，LSD1 作为一种“表观遗传障碍”，在应激条件下优化纤维类型特异性反应和肌肉质量。我们的研究结果表明，LSD1 调节剂为应激诱导的肌病（如肌肉减少症、恶病质和废用性萎缩）提供了新的治疗和预防策略。
