Icariin ameliorates sarcopenia via activation of the estrogen receptor α/fatty acid transport protein 1 pathway

BACKGROUND: Sarcopenia is a prevalent disorder among postmenopausal women, representing a debilitating condition with limited treatment options. Icariin (ICA), a prenylated flavonol glycoside, is commonly used in conditions associated with estrogen deficiency; however, its efficacy and mechanism in postmenopausal sarcopenia remain undefined. PURPOSE: This study aimed to evaluate the therapeutic effect of ICA on postmenopausal sarcopenia and to elucidate its underlying mechanism, with a focus on the estrogen receptor α/fatty acid transport protein 1 (ERα/FATP1) pathway. STUDY DESIGN: An integrated approach was employed, combining in vivo pharmacological evaluation, multi-omics analyses, and in vitro mechanistic validation. METHODS: The in vivo therapeutic effect of oral ICA was assessed by evaluating muscle function, histology, and senescence markers. Human muscle transcriptome datasets and mouse single-cell RNA sequencing data were analyzed. In vitro validation was performed in D-galactose-induced senescent C2C12 myoblasts. Target engagement was confirmed by molecular docking, cellular thermal shift assay, and surface plasmon resonance, and mechanistic validation was performed via FATP1 knockdown. RESULTS: Oral administration of ICA significantly improved muscle mass, function, and fiber cross-sectional area, while attenuating lipid deposition and cellular senescence. Single-cell RNA sequencing revealed a diminished myoblast pool with downregulated ERα in aged muscle. This finding aligns with human transcriptome data, linking reduced ERα/FATP1 signaling and dysregulated fatty acid metabolism to sarcopenia. Metabolomic analysis identified FATP1 as a critical transporter of eicosapentaenoic acid and docosapentaenoic acid, which activated the protein kinase B/ mammalian target of rapamycin pathway to promote myogenesis. Importantly, ICA functioned as a dual-target agonist, directly binding to and upregulating both ERα and FATP1, thereby elevating eicosapentaenoic/ docosapentaenoic acid levels and reactivating the protein kinase B/ mammalian target of rapamycin/ myogenic differentiation 1 axis. The specificity of this pathway was confirmed, as FATP1 knockdown completely abrogated the protective effects of ICA. CONCLUSION: This study identifies the ERα/FATP1 axis as a pivotal therapeutic target for sarcopenia. ICA, acting as a first-in-class dual agonist of this pathway, represents a promising candidate for sarcopenia treatment by synchronously modulating estrogen signaling and fatty acid metabolism.