Work

Huangjing Yangji Decoction ameliorates skeletal muscle aging and mitochondrial dysfunction via SIRT1/ATF5-mediated mitochondrial unfolded protein response

Year: 2025

Type: article

Abstract: BackgroundSarcopenia is a progressive age-associated disorder characterized by the loss of skeletal muscle mass, strength, and function. Mitochondrial dysfunction and impaired proteostasis are central to its pathogenesis, yet effective pharmacological interventions remain lacking. Huangjing Yangji Decoction (HJYJD), a traditional Chinese medicinal formula, has demonstrated promising clinical benefits in managing age-related muscle atrophy, but its mechanisms remain unclear. PurposeThis study aimed to investigate the therapeutic effects and underlying mechanisms of HJYJD in alleviating age-related sarcopenia. MethodsThe chemical constituents of HJYJD were identified using UPLC-Q-TOF/MS. Aged SAMP8 mice and D-galactose-induced C2C12 myoblasts were used to evaluate the therapeutic effects of HJYJD. Behavioral assays, histological analysis, transmission electron microscopy (TEM), immunofluorescence, biochemical assays, western blotting, qRT-PCR, and mitochondrial function probes were employed to assess muscle function, myotube differentiation, cellular senescence, oxidative stress, and mitochondrial function. Untargeted metabolomics and transcriptomic sequencing were performed to explore regulatory pathways. Key molecular markers were validated by qRT-PCR, western blotting, and immunofluorescence. The role of the SIRT1/ATF5-mitochondrial unfolded protein response (UPRmt) signaling axis was further explored using siRNA-mediated knockdown and pharmacological inhibition. ResultsHJYJD significantly improved muscle mass, strength, coordination, and endurance in sarcopenic mice, and attenuated cellular senescence and muscle atrophy in myotubes. Treatment with HJYJD ameliorated oxidative stress, improved mitochondrial morphology, membrane potential, and ATP production. Multi-omics data revealed that HJYJD modulated key metabolic and protein folding pathways related to mitochondrial function. Mechanistically, HJYJD activated the UPRmt, evidenced by upregulation of ClpP, LONP1, HSP60, and HSP10. These effects were abolished by UPRmt inhibition. Furthermore, HJYJD promoted the expression of SIRT1 and ATF5, and silencing of SIRT1/ATF5 suppressed UPRmt activation and mitochondrial restoration, indicating that SIRT1/ATF5 mediates HJYJD-induced UPRmt activation. ConclusionsHJYJD alleviates skeletal muscle aging and mitochondrial dysfunction by activating the SIRT1/ATF5-mediated UPRmt pathway. These findings offer novel mechanistic understanding of the therapeutic potential of HJYJD and support its further development as a promising intervention for sarcopenia.

Source: Phytomedicine

DOI: 10.1016/j.phymed.2025.157432