Zhao Qian, Jing Ying, Jiang Xiaoyu, Zhang Xin, Liu Feifei, Huang Haoyan, Zhang Zhihua, Wang Haijun, Sun Shuhui, Ma Shuai, Zhang Weiqi, Yu Yang, Fu Xiaobing, Zhao Guoguang, Qu Jing, Wang Si, Liu Guang-Hui
Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China.
Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, China.
Nat Metab. 2025 Mar;7(3):556-573. doi: 10.1038/s42255-025-01235-8. Epub 2025 Mar 14.
Ageing-induced skeletal muscle deterioration contributes to sarcopenia and frailty, adversely impacting the quality of life in the elderly. However, the molecular mechanisms behind primate skeletal muscle ageing remain largely unexplored. Here, we show that SIRT5 expression is reduced in aged primate skeletal muscles from both genders. SIRT5 deficiency in human myotubes hastens cellular senescence and intensifies inflammation. Mechanistically, we demonstrate that TBK1 is a natural substrate for SIRT5. SIRT5 desuccinylates TBK1 at lysine 137, which leads to TBK1 dephosphorylation and the suppression of the downstream inflammatory pathway. Using SIRT5 lentiviral vectors for skeletal muscle gene therapy in male mice enhances physical performance and alleviates age-related muscle dysfunction. This study sheds light on the molecular underpinnings of skeletal muscle ageing and presents the SIRT5-TBK1 pathway as a promising target for combating age-related skeletal muscle degeneration.
衰老引起的骨骼肌退化会导致肌肉减少症和身体虚弱，对老年人的生活质量产生不利影响。然而，灵长类动物骨骼肌衰老背后的分子机制在很大程度上仍未被探索。在这里，我们表明，SIRT5在老年灵长类动物两性骨骼肌中的表达均降低。人类肌管中SIRT5的缺乏会加速细胞衰老并加剧炎症。从机制上讲，我们证明TBK1是SIRT5的天然底物。SIRT5使TBK1的赖氨酸137去琥珀酰化，导致TBK1去磷酸化并抑制下游炎症途径。在雄性小鼠中使用SIRT5慢病毒载体进行骨骼肌基因治疗可增强身体机能并减轻与年龄相关的肌肉功能障碍。这项研究揭示了骨骼肌衰老的分子基础，并提出SIRT5-TBK1途径是对抗与年龄相关的骨骼肌退化的一个有希望的靶点。
