Synergistic effects of fucoidan from Undaria pinnatifida and grouper peptides on glucocorticoid-induced muscle atrophy via protein turnover modulation

Muscle atrophy, whether associated with aging, chronic disease, or glucocorticoid treatment, remains a significant clinical challenge with few effective therapeutic options. This study investigated the protective effects of fucoidan from Undaria pinnatifida and peptides derived from the hybrid grouper (Epinephelus fuscoguttatus × Epinephelus lanceolatus) against dexamethasone (DEX)-induced muscle atrophy in vitro and in vivo. In C2C12 myotubes, DEX suppressed anabolic signaling (mTOR, p-Akt, PI3K, p-S6K1, TRPV4) and upregulated catabolic mediators (FOXO3, MuRF1, Atrogin-1, Cathepsin L, REDD2). Fucoidan mainly suppressed catabolic signaling, peptides enhanced anabolic pathways, and their combination synergistically restored protein turnover. In a DEX-induced mouse model, the combined treatment significantly preserved muscle weight, improved strength and endurance, and protected myofiber morphology, exceeding the effects of either treatment alone or leucine. Compositional profiling confirmed that fucoidan was enriched in fucose and sulfate, whereas grouper peptides were abundant in branched-chain amino acids and bioactive dipeptides, supporting their complementary mechanisms. These findings demonstrate that fucoidan and grouper-derived peptides exert distinct yet synergistic effects on muscle protein homeostasis, highlighting their translational potential as safe, mechanism-based interventions for preventing and treating muscle-wasting conditions such as sarcopenia, cachexia, and glucocorticoid-induced atrophy.