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<p>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.</p>

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SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1

  • 期刊论文

  • 发表日期：

    2025年3月14日

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  • 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

摘要

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.