Formononetin Mitigates Age-Related Sarcopenia by Blocking Mitochondrial Ferroptosis via SIRT1/PGC-1α Signaling.

Abstract

Age-related muscle atrophy is closely associated with mitochondrial dysfunction and ferroptosis. This study established a D-gal-induced sarcopenia model in aged mice and a C2C12/GM17940 cell myotube senescence model, with young/control, old/D-gal, and formononetin (FMN) intervention groups. After shSIRT1 transfection and mitochondrial-targeted antioxidant Mito-C intervention, the effects and mechanism of FMN were detected by measuring mouse phenotypic indicators (lean mass, hindlimb muscle mass, grip strength) and cell indicators (viability, mitochondrial membrane potential, ROS, ATP, ferroptosis-related proteins). Results showed that FMN improved lean mass, grip strength, mitochondrial membrane potential, and ATP production, while reducing ROS and ferroptosis by regulating ACSL4, GPX4, and SLC7A11. Mechanistically, FMN exerted protective effects via the SIRT1/PGC-1α pathway, which was partially attenuated by SIRT1 knockdown or Mito-C. Collectively, FMN alleviates age-related sarcopenia by targeting mitochondrial function and ferroptosis, providing potential targets for sarcopenia treatment.