Lignan-rich Eucommia ulmoides extract, prioritized by large-scale literature mining, ameliorate sarcopenia by revitalizing the systemic GH/IGF-1 mediated anabolic signaling axis.

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This study aims to elucidate the bioactive foundation and therapeutic mechanisms of Eucommia ulmoides for sarcopenia. Large-scale literature mining prioritized lignans and iridoids as primary candidates for muscle health intervention. Bioinformatics validated the molecular isomorphism between age-related sarcopenia and a D-galactose/hydrocortisone-induced mouse model. In BALB/c mice, the lipophilic lignan-rich ethanolic extract (EEE), but not the iridoid-rich aqueous extract (EAE), effectively reversed the sarcopenic phenotype, restoring muscle mass and fiber cross-sectional area while correcting pathological fiber-type transitions toward fast-twitch fibers. Mechanistically, EEE elevated serum growth hormone (GH) and restored systemic/local insulin-like growth factor-1 (IGF-1) levels. This reactivated the IGF-1 receptor and its downstream Akt-mTOR/FOXO3a-4E-BP1/p70S6K signaling axis, thereby promoting protein synthesis and inhibiting degradation. Furthermore, EEE upregulated muscle-regenerative genes (Myog, Myod, Pax7) and mitochondrial biogenesis regulators (Pgc1α, Tfam), while downregulating muscle-wasting markers (Mstn) and preserving mitochondrial integrity via Bnip3 modulation. To establish causality, the selective IGF-1R inhibitor picropodophyllin (PPP) was co-administered. Despite sustained GH elevation, blocking IGF-1R abolished EEE’s therapeutic benefits across functional and molecular dimensions, demonstrating that the muscle-rescue effect is strictly IGF-1R-dependent. In conclusion, Eucommia ulmoides alleviates age-related sarcopenia by restarting hormone-mediated anabolic signaling, with lipophilic lignans, rather than the frequently investigated iridoids, serving as the primary bioactive foundation.

Institutions

• Xihua University

  Sichuan, Chengdu

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