Diosgenin Alleviates Age‐Related Sarcopenia by Promoting Satellite Cell Proliferation and Myogenic Differentiation via Activation of the <scp>SIRT1</scp> / <scp>PGC</scp> ‐1α Signaling Pathway

Age-related sarcopenia is characterized by a progressive decline in skeletal muscle mass and function, with satellite cell dysfunction representing a central pathogenic mechanism. Diosgenin, a steroidal saponin derived from plants of the Dioscorea genus, has demonstrated potential anti-aging properties; however, its role in sarcopenia remains unclear. In this study, naturally aged C57BL/6J mice and a D-galactose (D-gal)-induced senescent C2C12 cell model were employed to systematically investigate the effects of diosgenin on muscle function, satellite cell dynamics, and the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling pathway. Diosgenin treatment significantly improved forelimb grip strength and exercise endurance, increased the gastrocnemius muscle index, and enlarged muscle fiber cross-sectional area in aged mice. Mechanistically, diosgenin upregulated the expression of myokines meteorin-like protein (METRNL) and insulin-like growth factor 1 (IGF-1) at both mRNA and protein levels, increased the number of proliferative satellite cells positive for paired box 7 (Pax7) and Ki67, and enhanced the expression of myogenic markers, including myogenic factor 5 (Myf5), Pax7, and myosin heavy chain II (MyHC II). These effects were mediated by direct activation of SIRT1, leading to deacetylation of PGC-1α. Notably, pharmacological inhibition of SIRT1 with EX527 markedly abrogated the diosgenin-induced effects. Molecular docking and cellular thermal shift assays further confirmed the direct interaction between diosgenin and SIRT1. Collectively, these findings demonstrate that diosgenin alleviates age-related sarcopenia by activating the SIRT1/PGC-1α signaling pathway to promote satellite cell proliferation and myogenic differentiation, highlighting its potential as a promising therapeutic candidate for sarcopenia.