Tectorigenin protects against muscle atrophy from in vitro nutrient deprivation and in vivo denervation by activating the AMPK/SIRT1/PGC-1α pathway.

Background

AND

Purpose

The molecular mechanisms underlying denervation-induced muscle atrophy remain incompletely understood, and effective therapeutic interventions are currently lacking. Tectorigenin (TG), a natural isoflavonoid, has demonstrated antioxidant and metabolic regulatory activities. This study investigated whether TG also alleviates denervation-induced muscle atrophy via activation of the AMPK/SIRT1/PGC-1α signalling pathway. EXPERIMENTAL APPROACH A sciatic nerve transection model was established in ICR mice to evaluate the therapeutic effects of TG. Histomorphology, oxidative stress markers, mitochondrial function and pathway activity were assessed. A nutrient deprivation-induced C2C12 myotube atrophy model was used for in vitro validation. Pathway-specific inhibitors (Compound C, EX-527 and SR18292) were applied both in vivo and in vitro to confirm mechanistic involvement. KEY

Results

TG treatment significantly improved muscle wet weight ratio, myofibre cross-sectional area and myosin heavy chain expression in denervated mice. It reduced levels of atrophy-related ubiquitin ligases, attenuated oxidative stress and improved mitochondrial integrity. TG reversed the denervation-induced suppression of AMPK/SIRT1/PGC-1α signalling and downstream effectors. In C2C12 myotubes, TG dose-dependently ameliorated atrophy and up-regulated SIRT1/PGC-1α. Pharmacological inhibition of AMPK, SIRT1 or PGC-1α abolished TG's protective effects, both in vitro and in vivo.

Conclusions

AND IMPLICATIONS TG mitigates denervation-induced muscle atrophy through a multi-mechanistic approach involving activation of the AMPK/SIRT1/PGC-1α axis, enhancement of mitochondrial dynamics and restoration of redox homeostasis. This study identifies TG as a promising candidate for clinical translation in the treatment of neurogenic muscle atrophy.