SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1

IF 18.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Nature metabolism Pub Date : 2025-03-14 DOI:10.1038/s42255-025-01235-8

Qian Zhao, Ying Jing, Xiaoyu Jiang, Xin Zhang, Feifei Liu, Haoyan Huang, Zhihua Zhang, Haijun Wang, Shuhui Sun, Shuai Ma, Weiqi Zhang, Yang Yu, Xiaobing Fu, Guoguang Zhao, Jing Qu, Si Wang, Guang-Hui Liu

{"title":"SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1","authors":"Qian Zhao, Ying Jing, Xiaoyu Jiang, Xin Zhang, Feifei Liu, Haoyan Huang, Zhihua Zhang, Haijun Wang, Shuhui Sun, Shuai Ma, Weiqi Zhang, Yang Yu, Xiaobing Fu, Guoguang Zhao, Jing Qu, Si Wang, Guang-Hui Liu","doi":"10.1038/s42255-025-01235-8","DOIUrl":null,"url":null,"abstract":"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. SIRT5 protects against primate skeletal muscle ageing through TBK1 desuccinylation, which inhibits the downstream inflammatory and senescent phenotypes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 3","pages":"556-573"},"PeriodicalIF":18.9000,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature metabolism","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s42255-025-01235-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}

引用次数: 0

Abstract

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. SIRT5 protects against primate skeletal muscle ageing through TBK1 desuccinylation, which inhibits the downstream inflammatory and senescent phenotypes.

Abstract Image

查看原文本刊更多论文

SIRT5通过TBK1去琥珀酰化防止灵长类骨骼肌老化

衰老引起的骨骼肌退化导致肌肉减少和虚弱，对老年人的生活质量产生不利影响。然而，灵长类动物骨骼肌老化背后的分子机制仍未被充分探索。在这里，我们发现SIRT5在老年灵长类动物的骨骼肌中表达减少。人肌管SIRT5缺乏会加速细胞衰老并加剧炎症。在机制上，我们证明TBK1是SIRT5的天然底物。SIRT5在赖氨酸137处使TBK1去琥珀酰化，从而导致TBK1去磷酸化并抑制下游炎症途径。利用SIRT5慢病毒载体对雄性小鼠进行骨骼肌基因治疗，可提高运动能力，减轻年龄相关性肌肉功能障碍。这项研究揭示了骨骼肌老化的分子基础，并提出SIRT5-TBK1途径是对抗年龄相关骨骼肌退化的有希望的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Nature metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

27.50

自引率

2.40%

发文量

170

期刊介绍： Nature Metabolism is a peer-reviewed scientific journal that covers a broad range of topics in metabolism research. It aims to advance the understanding of metabolic and homeostatic processes at a cellular and physiological level. The journal publishes research from various fields, including fundamental cell biology, basic biomedical and translational research, and integrative physiology. It focuses on how cellular metabolism affects cellular function, the physiology and homeostasis of organs and tissues, and the regulation of organismal energy homeostasis. It also investigates the molecular pathophysiology of metabolic diseases such as diabetes and obesity, as well as their treatment. Nature Metabolism follows the standards of other Nature-branded journals, with a dedicated team of professional editors, rigorous peer-review process, high standards of copy-editing and production, swift publication, and editorial independence. The journal has a high impact factor, has a certain influence in the international area, and is deeply concerned and cited by the majority of scholars.