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.