Yeast Protein-Derived High Fischer Ratio Peptides Exert Superior Anti-Fatigue Efficacy to Amino Acid Mixtures by Regulating Muscle-Liver Axis Lactate Metabolism.

Yeast protein-derived high Fischer ratio peptides (HFYP) show great potential for alleviating exercise-induced fatigue, yet existing studies have focused only on skeletal muscle regulation, overlooking the muscle-liver axis in systemic lactate metabolism. We optimized HFYP preparation via response surface methodology, yielding peptides with a Fischer ratio of 40.01 and 23.95% BCAA content. Low-dose HFYP (0.128 g/kg) prolonged exhaustive swimming time from 9.53 to 29.88 min (3.1-fold), outperforming taurine (16.89 min) and BCAA-matched amino acid mixtures (22.25 and 18.78 min). Mechanistically, HFYP activated AMPK/PGC-1α and AKT/FOXO1 pathways in muscle to promote mitochondrial biogenesis and glucose utilization, while upregulating hepatic PCK1 to enhance Cori cycle activity. HFYP alleviates exercise-induced fatigue through the synergistic regulation of skeletal muscle lactate metabolism and hepatic lactate-to-glucose recycling via the muscle-liver axis, which provides a solid theoretical basis for the high-value utilization of yeast protein and the development of HFYP-based antifatigue functional foods.