Prophylactic polydatin protects against sepsis-induced muscle atrophy by suppressing endoplasmic reticulum stress via SIRT3 upregulation in a mouse CLP model.

Abstract

Sepsis-induced muscle atrophy is closely related to the poor prognosis of patients and poses a clinical challenge due to the lack of effective therapies. Polydatin (PD) is a natural phenolic compound possessing great anti-inflammatory property, but its potential effect on sepsis-induced muscle atrophy has not been clarified. In this study, a mouse sepsis model established by cecal ligation and puncture (CLP) using male C57BL/6J mice (8 weeks old) and an in vitro model of LPS-stimulated C2C12 myotubes were employed to investigate the effect of PD against sepsis-induced muscle atrophy. The underlying molecular mechanisms were further explored by integrating transcriptomic analysis, network pharmacology, and experimental validation. The results demonstrated that PD intervention markedly reduced protein degradation mediated by the ubiquitin-proteasome system and attenuated sepsis-induced muscle atrophy. Mechanistically, transcriptomic analysis suggested that its effect was associated with the modulation of endoplasmic reticulum (ER) stress, while network pharmacology identified sirtuin 3 (SIRT3) as the potential molecular target. Further experiments indicated that PD upregulated SIRT3 expression and suppressed the activation of ER stress in vivo and in vitro. Notably, the protective effects of PD were counteracted by inhibition of SIRT3 via specific inhibitor and siRNA, suggesting its important role in mitigating ER stress and muscle atrophy. Collectively, PD effectively alleviates sepsis-induced muscle atrophy, which might be achieved by suppressing ER stress via the upregulation of SIRT3, highlighting its potential as a protective strategy against this clinical condition.