TRPV1 mediates tetrathiomolybdate-induced muscle hypertrophy via peroxynitrite-dependent redox signaling

Reactive oxygen species (ROS), notably superoxide (O₂^•-), serve as essential signaling molecules for muscle remodeling. While tetrathiomolybdate (TM)-O₂^•- axis can induce myofiber hypertrophy, the precise redox signaling mechanisms remain incompletely understood. In this study, transient receptor potential cation channel subfamily V member 1 (TRPV1) is identified as a critical mediator of TM-O₂^•--induced hypertrophy through transcriptome analysis and functional validation. Genetic and pharmacological manipulation demonstrates TRPV1's essential role downstream of O₂^•-, where TRPV1 knockout abolishes while its activation mimics TM-induced hypertrophy effects. O₂^•- stimulates nitric oxide synthase (NOS) activity and nitric oxide (NO) production, leading to formation of peroxynitrite (ONOO^-) which directly activates TRPV1. The ONOO^--TRPV1 axis is specifically required for hypertrophy, as ONOO^- scavengers block TRPV1 activation and hypertrophy despite normal O₂^•- and NO levels. In conclusion, these findings reveal TRPV1 as a redox-sensitive mediator that orchestrates superoxide-triggered muscle remodeling via the ONOO^--TRPV1 axis.