The Enhanced Whey Protein Oral Bioavailability and Muscle Anabolism Ability by a Simple and Effective Piperine‐Whey Protein Synergistic Codelivery System

ABSTRACT The strength of skeletal muscle is critical for daily function and exercise capacity. Whey protein (WP) is widely utilized to support muscle strength, but WP alone is insufficient to achieve desired muscle synthesis. Here, a simple and effective piperine (Pip)‐WP synergistic supplementation system was developed. A nanoemulsion with high interfacial‐volume WP layer, designated as WP(Pip), was prepared with 10 wt.% WP and Pip loaded in the oil phase. Compared with the single dose of WP and Pip, the co‐delivered system of WP(Pip) combined with major WP can increase in vivo WP and Pip absorption, with increase of 6.10% and 890%, respectively. The mechanism of Pip for WP hydrolysate absorption is investigated in a Caco‐2 monolayer model. Pip enhances WPH bioavailability by reversibly modulating epithelial tight junctions. Increased circulating free amino acids, together with Pip, synergistically activate mTOR signaling pathway in skeletal muscle through direct and indirect regulation. This promotes efficient utilization of absorbed WP for muscle protein synthesis and improves exercise performance. Meanwhile, the WP(Pip) co‐supplementary system mitigates muscle fatigue and damage in healthy mice and in a dexamethasone‐induced sarcopenia model, respectively. These findings suggest a strategy to enhance protein absorption and translate dietary protein intake into muscle‐building outcomes, with potential nutritional and clinical relevance.