Guizhi Wuling Decoction alleviates myocardial fibrosis by restoring mitochondrial homeostasis: Evidence from network pharmacology, molecular docking, and multi-omics integration.
Guizhi Wuling Decoction may alleviate myocardial fibrosis in mice by restoring mitochondrial homeostasis via AMPK/PGC-1α signaling, but human relevance is unproven.
Where it sits
this study against the rest of the mots-c corpusSummary and findings
The study evaluated the effects of Guizhi Wuling Decoction (GWD) on myocardial fibrosis in C57BL/6J mice induced by isoproterenol. GWD improved cardiac function and mitochondrial homeostasis, potentially through the AMPK/PGC-1α signaling pathway. Pharmacological inhibition of AMPK attenuated these effects.
Abstract
<h4>Ethnopharmacological relevance</h4>Guizhi Wuling Decoction (GWD), a combined prescription consisting of the classical formulas Wuling San and Guizhi Fuling Wan without modification, has been clinically applied for cardiovascular diseases. Previous studies have reported its cardioprotective and anti-fibrotic effects; however, the underlying molecular mechanisms remain incompletely understood.<h4>Aim of the study</h4>To investigate whether restoration of mitochondrial homeostasis contributes to the anti-fibrotic effects of GWD and to explore the involvement of AMPK/PGC-1α signaling.<h4>Materials and methods</h4>Myocardial fibrosis (MF) was induced in C57BL/6 J mice by isoproterenol (ISO) administration. Cardiac function, myocardial fibrosis, mitochondrial ultrastructure, mitochondrial membrane potential, ATP production, and NAD+/NADH ratio were evaluated. Absorbed constituents in GWD-containing serum were characterized using UHPLC-MS/MS. Integrated transcriptomic-proteomic analysis highlighted AMPK signaling as one of the important pathways associated with GWD treatment. Molecular docking and molecular dynamics simulations were conducted to evaluate the interactions between representative absorbed compounds and candidate targets. The involvement of AMPK signaling was further validated by pharmacological inhibition using Compound C.<h4>Results</h4>GWD significantly improved cardiac function, attenuated myocardial fibrosis, and restored mitochondrial homeostasis, as evidenced by improved mitochondrial ultrastructure, increased mitochondrial membrane potential, ATP production, and NAD+/NADH ratio. Integrated transcriptomic and proteomic analyses identified AMPK signaling as an important pathway associated with the protective effects of GWD. Mechanistically, GWD activated the AMPK/PGC-1α signaling pathway and upregulated mitochondrial biogenesis- and quality control-related proteins, including NRF1, TFAM, and MFN2. Pharmacological inhibition of AMPK by Compound C significantly attenuated GWD-associated improvement of mitochondrial homeostasis and anti-fibrotic effects.<h4>Conclusion</h4>GWD alleviates ISO-induced MF, at least in part, by restoring mitochondrial homeostasis. Integrated multi-omics analyses and pharmacological validation suggest that AMPK/PGC-1α signaling may contribute to the anti-fibrotic effects of GWD. These findings provide experimental evidence suggesting the involvement of mitochondrial homeostasis in MF and offer new insights into the anti-fibrotic effects of GWD.
Background
Myocardial fibrosis is a significant contributor to cardiovascular diseases, and there is interest in exploring traditional remedies like Guizhi Wuling Decoction (GWD) for their potential therapeutic effects. Previous studies have suggested cardioprotective and anti-fibrotic effects of GWD, but the molecular mechanisms remain unclear. This study aims to elucidate whether mitochondrial homeostasis plays a role in GWD's anti-fibrotic effects, focusing on the AMPK/PGC-1α signaling pathway.
Methods
The study used C57BL/6J mice with myocardial fibrosis induced by isoproterenol administration. GWD's effects on cardiac function, myocardial fibrosis, mitochondrial ultrastructure, membrane potential, ATP production, and NAD+/NADH ratio were assessed. UHPLC-MS/MS characterized absorbed constituents in GWD-containing serum. Transcriptomic-proteomic analysis and molecular docking evaluated AMPK signaling involvement, with pharmacological validation using Compound C.
Results
GWD treatment significantly improved cardiac function and reduced myocardial fibrosis in the mouse model. Mitochondrial homeostasis was restored, as indicated by improved ultrastructure, increased membrane potential, ATP production, and NAD+/NADH ratio. AMPK signaling was identified as a key pathway, with GWD activating the AMPK/PGC-1α pathway and upregulating mitochondrial biogenesis proteins. Inhibition of AMPK by Compound C reduced these beneficial effects.
Interpretation
The study suggests that GWD may exert its anti-fibrotic effects through the restoration of mitochondrial homeostasis, mediated by the AMPK/PGC-1α signaling pathway. While the findings are promising, they are limited to an animal model, and the clinical significance in humans remains uncertain. The lack of quantitative data in the abstract also limits the ability to assess the magnitude of the effects.
Key findings
- GWD significantly improved cardiac function in ISO-induced myocardial fibrosis.
- GWD restored mitochondrial ultrastructure and increased mitochondrial membrane potential.
- ATP production and NAD+/NADH ratio were increased with GWD treatment.
- AMPK signaling was identified as an important pathway in GWD's effects.
- Pharmacological inhibition of AMPK reduced GWD's benefits on mitochondrial homeostasis.
Limitations
- animal model only, no human data
- lack of quantitative effect sizes in abstract
- mechanistic focus, not clinical outcomes