Abstract

A dual-functional platform with conductivity and piezoelectricity mimics the muscle electromechanical niche. • The hydrogel generates endogenous electrical signals under motion while scavenging ROS and resisting bacteria. • Piezoelectric cues activate PI3K-AKT/FoxO1, downregulating MuRF1 and Atrogin-1 to reduce protein loss. • The therapy promotes myofiber regeneration, reduces fibrosis, and restores motor function in rat VML. Volumetric muscle loss (VML) regeneration is still a major clinical challenge that requires creative regenerative techniques. We addressed this by creating a silver‑molybdenum disulfide composite hydrogel (Ag-MoS 2 -PAC) that is highly bioactive and electrically conductive. This physical cross-linking-created hydrogel showed remarkable mechanical and piezoelectric qualities, high biocompatibility, and strong antibacterial activity. The myogenic differentiation of C2C12 cells was greatly enhanced in vitro by Ag-MoS 2 -PAC, as demonstrated by the increased expression of markers MyoG, MEF2A, MHC, and TNNI1. Concurrently, it mitigated oxidative stress and suppressed the expression of the key atrophy-related factors FoxO1, MuRF1, and Atrogin-1. Ag-MoS 2 -PAC implantation resulted in strong muscle fiber regeneration, decreased collagen deposition, and improved functional recovery at 4 and 8 weeks after injury in a rat VML model. Transcriptomic analysis revealed that the hydrogel's mechanism involves the synergistic activation of the PI3K-AKT and PPAR pathways, which upregulate antioxidant and antibacterial gene expression while inhibiting FoxO1 signaling. All of these results show that Ag-MoS 2 -PAC promotes VML repair by generating a conductive milieu that simultaneously reduces oxidative stress and inhibits the FoxO1-mediated atrophy pathway, providing a potential therapeutic platform for functional muscle regeneration.