Shikimic acid ameliorates immobilization-induced muscle atrophy through regulation of inflammation and muscle protein homeostasis.

Immobilization induces skeletal muscle atrophy by disrupting muscle protein homeostasis, leading to progressive loss of muscle mass and function. Shikimic acid (SA), a plant-derived organic acid with anti-inflammatory and antioxidant properties, has not been previously evaluated in immobilization-associated muscle atrophy. This study aimed to determine whether SA attenuates skeletal muscle atrophy by regulating inflammation and muscle protein turnover using cellular and animal models. In tumor necrosis factor α (TNFα)-induced L6 myotubes, SA significantly suppressed inflammatory cytokine expression through inhibition of nuclear factor-κB) (NF-κB) signaling and attenuated forkhead box O3a (FoxO3a)-dependent protein degradation, while restoring protein kinase B (Akt)/mechanistic target of rapamycin (mTOR)-dependent anabolic signaling to promote myogenic differentiation and protein synthesis. In an immobilization-induced muscle atrophy model in mice, SA administration prevented declines in grip strength and exercise capacity and preserved skeletal muscle mass and myofiber cross-sectional area. At the molecular level, SA alleviated inflammatory responses and restored the balance between protein synthesis and degradation in the tibialis anterior muscle. Furthermore, molecular docking analysis revealed that SA interacts with the activation pocket of phosphoinositide 3-kinase (PI3K), providing structural insight into the mechanism of anabolic signaling reactivation. Collectively, these findings demonstrate that SA mitigates immobilization-induced skeletal muscle atrophy by suppressing NF-κB-mediated inflammatory signaling and restoring muscle protein turnover through reactivation of the PI3K/Akt/mTOR signaling pathway, highlighting its potential as a functional compound for preventing disuse-induced muscle loss.