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. 2018 May 24;62(14):e1701043.
doi: 10.1002/mnfr.201701043. Online ahead of print.

L-Citrulline Supplementation-Increased Skeletal Muscle PGC-1α Expression Is Associated With Exercise Performance and Increased Skeletal Muscle Weight

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Free PMC article

L-Citrulline Supplementation-Increased Skeletal Muscle PGC-1α Expression Is Associated With Exercise Performance and Increased Skeletal Muscle Weight

Myra O Villareal et al. Mol Nutr Food Res. .
Free PMC article

Abstract

Scope: L-citrulline has recently been reported as a more effective supplement for promoting intracellular 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 (IGF1) upregulation. VEGFα and IGF1 are important for angiogenesis and muscle growth, respectively, and are regulated by PGC-1α. Treatment with 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 to higher skeletal muscle weight that improves time to exhaustion during exercise. This article is protected by copyright. All rights reserved.

Keywords: Exercise performance; L-citrulline; PGC-1α; skeletal muscle weight; supplementation.

Figures

Figure 1
Figure 1
Study design. Mice were made to perform a swimming exercise every other day for 14 days. A swimming‐until‐exhaustion test was carried out on day 15. During the experimental period, mice were orally administrated with l‐citrulline (250 mg kg−1) or distilled water (D.W.) every day.
Figure 2
Figure 2
Effect of l‐citrulline supplementation on the blood lactate and glucose levels after weight‐loaded exercise performance. Mice orally administrated with l‐citrulline (250 mg kg−1) or distilled water (D.W.) were made to perform a weight‐loaded forced swimming test for 10 min on day 13. A) Blood lactate levels before and after exercise (0 and 60 min) and B) blood glucose levels after exercise (0 min) were evaluated. Values are expressed as the mean ± standard deviation. *p ≤ 0.05 and **p ≤ 0.01 indicate a significant difference compared to the control group.
Figure 3
Figure 3
Effect of l‐citrulline supplementation on swimming endurance. Mice were trained to perform swimming exercise every other day for 14 days, then a swimming‐until‐exhaustion test was carried out on day 15. A) Swimming time to exhaustion, B) blood lactate levels before and after exercise (0 and 60 min), and C) blood glucose levels after exercise (0 min) were evaluated. Values are expressed as the mean ± standard deviation. *p ≤ 0.05 and **p ≤ 0.01 indicate a significant difference compared to the control group. The individual raw data was plotted over the bar graph.
Figure 4
Figure 4
Effect of l‐citrulline supplementation on the expression of PGC‐1α and PGC‐1α‐related genes in the gastrocnemius and biceps femoris. Expression levels of PGC‐1α and PGC‐1α‐targeted genes in the A) gastrocnemius and B) biceps femoris were evaluated. Expression levels of mRNA were normalized to the β‐actin expression level. Values are expressed as the mean ± standard deviation and relative to the “no exercise” group. *p ≤ 0.05 and **p ≤ 0.01 indicate a significant difference compared to the control group.
Figure 5
Figure 5
Effect of l‐citrulline supplementation on the protein expression of PGC‐1α in the gastrocnemius and biceps femoris. Protein expression levels of PGC‐1α in the A) gastrocnemius and B) biceps femoris were evaluated. All gels were run under the same experimental conditions and the representative blots were shown. The protein expression levels were normalized to GAPDH expression. Values are expressed as the mean ± standard deviation and relative to the unexercised group. *p ≤ 0.05 and **p ≤ 0.01 indicate a significant difference from the control group.
Figure 6
Figure 6
Effect of l‐citrulline on the gene expression of PGC‐1α in C2C12 myotubes. Differentiated C2C12 myotubes were treated with or without l‐citrulline for 24 h. A) After that, cell viability was evaluated and value expressed as percentage (%) of control. B) C2C12 myotubes were treated with or without l‐citrulline (10, 50, 100 μM) for 1 h. C) l‐citrulline (50 μM) treatment was performed with or without 100 μM NG‐nitro‐l‐arginine methyl ester hydrochloride (l‐NAME) for 1 h. Following treatment, PGC‐1α mRNA levels were quantified using real‐time PCR and the values normalized to the expression level of β‐actin. Values are expressed as the mean ± standard deviation of triplicate experiments. **p ≤ 0.01 indicates a significant difference from the control group. ## p ≤ 0.01 indicate a significant difference from the l‐NAME‐treated l‐citrulline group.

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