Superiority of Tetrapeptide Tyr–Gly–Leu–Phe over Amino Acid Mixture: Mechanisms Underlying Enhanced Systemic Amino Acid Delivery, Anti-Fatigue Efficacy, and Muscle Damage Repair

This study compared the anti-fatigue tetrapeptide YGLF with an equimolar amino acid (AA) mixture across three stages: postingestion absorption, postexercise fatigue, and muscle damage repair. Despite rapid in vitro degradation (<1% intact), YGLF elevated plasma AAs more effectively than the AA mixture 15 min postingestion (51.97 vs 46.34 mg/100 mL). Postexercise, YGLF outperformed the AA mixture by further increasing muscle AAs and blood glucose, reducing metabolic byproducts, and activating AMPK. Following muscle damage, transcriptomics revealed that the AA mixture primarily modulated energy metabolism, whereas YGLF uniquely upregulated muscle growth genes. Western blotting confirmed that YGLF promoted repair via the Sestrin2/mTOR and Pax7/MYOD pathways. These findings demonstrate the distinct bioactivity of YGLF over that of free AAs, establishing a rationale for utilizing specific peptides in sports nutrition and muscle recovery.