Whey protein hydrolysate rich in branched-chain amino acid-containing oligopeptide as a novel nutritional strategy to attenuate age-related muscle weakness.

Abstract

Although whey protein is widely used to support muscle health, its effectiveness against age-related muscle decline may be limited by aging-associated anabolic resistance. Whey protein hydrolysate (WPCH) enriched in branched-chain amino acid (BCAA)-containing oligopeptides may offer additional benefits through improved peptide availability and metabolic regulation. Here, a BCAA-rich WPCH was characterized and its effects on age-related muscle functional decline were evaluated using peptidomics, network pharmacology, animal experiments, and muscle metabolomics. BCAA-containing oligopeptides accounted for over 75% of identified peptides, including 35 peptides with predicted favorable absorption-related and muscle-regulatory properties. Compared with intact whey protein, 6 weeks of WPCH administration in 48-week-old mice significantly improved running endurance and grip strength, increased muscle fiber cross-sectional area and packing density, and reduced muscular oxidative stress and inflammation. Integrated metabolomics and protein expression analyses further indicate that WPCH promoted mitochondrial energy metabolism and fatty acid utilization while attenuating inflammation- and oxidative stress-related lipid signaling. These benefits were associated with enhanced mTOR signaling, improved mitochondrial function, and membrane lipid homeostasis, indicating that WPCH rich in BCAA-containing oligopeptides may provide greater protection against age-related muscle functional decline than intact whey protein.