Multi-omics-guided discovery: yeast protein alleviates glucocorticoid-induced muscle atrophy through dual activation of IGF-1/PI3K/Akt/FOXO and CaMKK/AMPK signaling pathways.

Sarcopenia, an aging-related disorder characterized by progressive loss of skeletal muscle mass and function, lacks well-defined mechanisms and specific therapeutics. This study investigated the therapeutic effects of yeast protein (YP) on dexamethasone (DEX)-induced muscle atrophy in C57BL/6J mice using transcriptomic and metabolomic approaches. High-dose (2 g per kg bodyweight) YP (H-YP) significantly ameliorated muscle histopathology, increased serum CAT and SOD activity, enhanced grip strength and hanging endurance, elevated muscle ATP and IGF-1 levels, and reduced MSTN expression (P < 0.05). Multi-omics integration revealed that H-YP improved sarcopenia primarily by modulating protein anabolism, energy metabolism, oxidative stress, lipid metabolism, and inflammatory pathways. Key upregulated targets included the Prkag3 gene and metabolites (L-histidine, L-leucine, L-tyrosine, and guanidinoacetate). Mechanistically, H-YP synergistically activated both the IGF-1/PI3K/Akt/FOXO pathway and CaMKK/AMPK axis, collectively improving insulin sensitivity, mitochondrial function, and protein homeostasis. These findings provide a strategic foundation for sarcopenia intervention.