Oyabu Mamoru, Ohira Yuto, Fujita Mariko, Yoshioka Kiyoshi, Kawaguchi Runa, Kubo Atsushi, Hatazawa Yukino, Yukitoshi Hinako, Ortuste Quiroga Huascar Pedro, Horii Naoki, Miura Fumihito, Araki Hiromitsu, Okano Masaki, Hatada Izuho, Gotoh Hitoshi, Yoshizawa Tatsuya, Fukada So-Ichiro, Ogawa Yoshihiro, Ito Takashi, Ishihara Kengo, Ono Yusuke, Kamei Yasutomi
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan.
Institute for Research on Productive Aging (IRPA), Tokyo, Japan.
iScience. 2025 Mar 3;28(4):112144. doi: 10.1016/j.isci.2025.112144. eCollection 2025 Apr 18.
Mammalian aging is reportedly driven by the loss of epigenetic information; however, its impact on skeletal muscle aging remains unclear. This study shows that aging mouse skeletal muscle exhibits increased DNA methylation, and overexpression of DNA methyltransferase 3a (Dnmt3a) induces an aging-like phenotype. Muscle-specific Dnmt3a overexpression leads to an increase in central nucleus-positive myofibers, predominantly in fast-twitch fibers, a shift toward slow-twitch fibers, elevated inflammatory and senescence markers, mitochondrial OXPHOS complex I reduction, and decreased basal autophagy. Dnmt3a overexpression resulted in reduced muscle mass and strength and impaired endurance exercise capacity with age, accompanied by an enhanced inflammatory signature. In addition, Dnmt3a overexpression reduced not only sensitivity to starvation-induced muscle atrophy but also the restorability from muscle atrophy. These findings suggest that increased DNA methylation disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces muscle metabolic elasticity.
据报道，哺乳动物的衰老由表观遗传信息的丧失所驱动；然而，其对骨骼肌衰老的影响仍不明确。本研究表明，衰老小鼠的骨骼肌表现出DNA甲基化增加，并且DNA甲基转移酶3a（Dnmt3a）的过表达会诱导出类似衰老的表型。肌肉特异性Dnmt3a过表达导致中央核阳性肌纤维增加，主要在快肌纤维中，向慢肌纤维转变，炎症和衰老标志物升高，线粒体氧化磷酸化复合体I减少，基础自噬降低。随着年龄增长，Dnmt3a过表达导致肌肉质量和力量下降以及耐力运动能力受损，并伴有炎症特征增强。此外，Dnmt3a过表达不仅降低了对饥饿诱导的肌肉萎缩的敏感性，还降低了肌肉萎缩后的恢复能力。这些发现表明，DNA甲基化增加会破坏骨骼肌稳态，促进类似衰老的表型，并降低肌肉代谢弹性。
