SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1.

Summary

SIRT5 expression declines with age in primate skeletal muscle. SIRT5 desuccinylates TBK1 (K137), dampening inflammatory signaling and preserving function; SIRT5 gene therapy improves performance and mitigates age-related muscle dysfunction in mice.

Key Findings

• SIRT5 expression is reduced in aged primate skeletal muscle from both sexes.
• TBK1 is a SIRT5 substrate; desuccinylation at K137 reduces TBK1 phosphorylation and downstream inflammatory signaling.
• SIRT5 deficiency accelerates senescence and inflammation in human myotubes.
• Skeletal muscle-directed SIRT5 gene therapy improves physical performance and alleviates age-related dysfunction in mice.

Clinical Implications

Although preclinical, targeting the SIRT5–TBK1 pathway could inform future interventions to prevent or treat sarcopenia and frailty.

Limitations

• Preclinical models; human interventional data are lacking
• Gene therapy experiments reported in male mice; sex-specific efficacy requires further study

Future Directions

Evaluate pharmacologic SIRT5 modulation, test translational biomarkers of TBK1 succinylation/dephosphorylation, and conduct early-phase trials targeting sarcopenia.