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

Abstract

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.