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.
Dnmt3a overexpression disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces metabolic elasticity.
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作者: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
期刊: | iScience | 影响因子: | 4.100 |
时间: | 2025 | 起止号: | 2025 Mar 3; 28(4):112144 |
doi: | 10.1016/j.isci.2025.112144 |
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