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Purpose: Carnosine is a dipeptide composed of β-alanine and L-histidine and is present in skeletal muscle. Chronic oral β-alanine supplementation can induce muscle carnosine loading and is therefore seen as the rate-limiting factor for carnosine synthesis. However, the effect of L-histidine supplementation on carnosine levels in humans is never established. This study aims to investigate whether 1) L-histidine supplementation can induce muscle carnosine loading and 2) combined supplementation of both amino acids is more efficient than A-alanine supplementation alone. Methods: Fifteen male and 15 female participants were equally divided in three groups. Each group was supplemented with either pure β-alanine (BA) (6 g⋅d-1), L-histidine (HIS) (3.5 g⋅d-1), or both amino acids (BA + HIS). Before (D0), after 12 d (D12), and after 23 d (D23) of supplementation, carnosine content was evaluated in soleus and gastrocnemius medialis muscles by ¹H-MRS, and venous blood samples were collected. Muscle biopsies were taken at D0 and D23 from the vastus lateralis. Plasma and muscle metabolites (β-alanine, histidine, and carnosine) were measured by high-performance liquid chromatography. Results: Both BA and BA + HIS groups showed increased carnosine concentrations in all investigated muscles, with no difference between these groups. By contrast, carnosine levels in the HIS group remained unaltered. Histidine levels were significantly decreased in plasma (-30.6%) and muscle (-31.6%) of the BA group, and this was prevented when β-alanine and L-histidine were supplemented simultaneously. Conclusion: We confirm that β-alanine, and not L-histidine, is the rate-limiting precursor for carnosine synthesis in human skeletal muscle. Yet, although L-histidine is not rate limiting, its availability is not unlimited and gradually declines upon chronic β-alanine supplementation. The significance of this decline still needs to be determined, but may affect physiological processes such as protein synthesis. [ABSTRACT FROM AUTHOR]