A collaborative study led by Prof. LIU Guanghui from the Institute of Zoology of the Chinese Academy of Sciences and Dr. WANG Si from Xuanwu Hospital, Capital Medical University, has unveiled a novel molecular mechanism that could delay age-related skeletal muscle decline. Published in Nature Metabolism, the study highlights the role of the "longevity protein" SIRT5 in mitigating skeletal muscle aging and proposes a potential gene therapy strategy to counteract this process.

Skeletal muscle plays a pivotal role in maintaining physical function and energy metabolism. However, aging is often accompanied by a progressive loss of muscle mass and function, leading to reduced mobility, increased susceptibility to falls and fractures, and a higher risk of chronic diseases. Despite its significant impact on health, effective interventions to combat skeletal muscle aging remain limited. This study sheds light on how SIRT5, a member of the sirtuin family of proteins, can delay muscle aging by modulating inflammatory pathways through its interaction with the protein kinase TBK1.

Using a primate model of skeletal muscle aging, the researchers identified hallmark features of muscle aging, including reduced muscle fiber size, shifts in fiber type composition, increased inflammatory responses, and a decline in muscle stem cell populations. They discovered that the downregulation of SIRT5 is a critical molecular alteration in aged skeletal muscle. Through genetic and biochemical analyses, the researchers demonstrated that SIRT5 desuccinylates TBK1, thereby inhibiting the activation of downstream pro-inflammatory signaling pathways and slowing the progression of muscle aging.

Building on these findings, the researchers developed a gene therapy approach using a lentiviral vector to overexpress SIRT5 in aged mice. Notably, after five weeks of treatment, the mice exhibited improvements in physical performance, increased muscle fiber size, reduced inflammation, and a rejuvenated gene expression profile. These results suggest that SIRT5 overexpression holds promise as a therapeutic strategy to reverse skeletal muscle aging and prevent age-related muscle disorders.

This study not only elucidates the molecular mechanisms driving skeletal muscle aging but also identifies SIRT5 as a potential therapeutic target.

Fiber-type distribution in aged cynomolgus monkey skeletal muscle (Image by LIU Guanghui's lab)