l‐Citrulline Supplementation‐Increased Skeletal Muscle PGC‐1α Expression Is Associated with Exercise Performance and Increased Skeletal Muscle Weight

SCOPE: l‐citrulline has recently been reported as a more effective supplement for promoting intracellular nitric oxide (NO) production compared to l‐arginine. Here, the effect of l‐citrulline on skeletal muscle and its influence on exercise performance were investigated. The underlying mechanism of its effect, specifically on the expression of skeletal muscle peroxisome proliferator‐activated receptor‐gamma coactivator‐1α (PGC‐1α), was also elucidated. METHODS AND RESULTS: Six‐week‐old ICR mice were orally supplemented with l‐citrulline (250 mg kg(−1)) daily, and their performance in weight‐loaded swimming exercise every other day for 15 days, was evaluated. In addition, mice muscles were weighed and evaluated for the expression of PGC‐1α and PGC‐1α‐regulated genes. Mice orally supplemented with l‐citrulline had significantly higher gastrocnemius and biceps femoris muscle mass. Although not statistically significant, l‐citrulline prolonged the swimming time to exhaustion. PGC‐1α upregulation was associated with vascular endothelial growth factor α (VEGFα) and insulin‐like growth factor 1 (IGF‐1) upregulation. VEGFα and IGF‐1 are important for angiogenesis and muscle growth, respectively, and are regulated by PGC‐1α. Treatment with NG‐nitro‐l‐arginine methyl ester hydrochloride (l‐NAME), a nitric oxide synthesis inhibitor, suppressed the l‐citrulline‐induced PGC‐1α upregulation in vitro. CONCLUSION: Supplementation with l‐citrulline upregulates skeletal muscle PGC‐1α levels resulting in higher skeletal muscle weight that improves time to exhaustion during exercise.