Dose-dependent beneficial effects of citrulline supplementation in short bowel syndrome in rats

International audienceObjectives: Supplementing diet with citrulline has proved an efficient means of preserving nitrogen balance and improving nutritional status after massive intestinal resection. The aim of this study was to model the action of citrulline in gut-resected rats using a dose-ranging study focused on skeletal muscle nitrogen homeostasis.Methods: Forty-six rats were randomly assigned to one of the following groups: citrulline 0.5 g.kg.d(-1) (n = 9), citrulline 1 g.kg.d(-1) (n = 7), citrulline 2.5 g.kg.d(-1) (n = 8), citrulline 5 g.kg.d(-1) (n = 8), control (n = 6), and sham (n = 8). The sham group underwent transection and the other groups underwent resection of 80% of the small intestine. All rats were then fed enteral nutrition (EN; all diets were isocaloric and isonitrogenous). After 10 d, the rats were sacrificed to measure and analyze animal weight; duodenum, jejunum, and ileum weight; and muscle trophicity. Protein fractional synthesis rate (FSR) and mammalian target of rapamycin complex (mTORC)1 activation were measured in the tibialis muscle.Results: There was a significant dose-dependent association between rat weight and citrulline dose up to 2.5 g.kg.d(-1) (P = 0.004). There was a significant improvement in tibialis weight correlated to plasma citrulline. Net protein FSR in the tibialis tended to be greater after resection and tended to return to baseline after citrulline supplementation. Citrulline supplementation significantly decreased the activated phosphorylated forms of S6 K1 (P = 0.003) and S6 RP (P = 0.003), with a significant positive association between myofibrillar FSR and activation of S6 K1 (r = 0.614; P = 0.02) and S6 RP (r = 0.601; P = 0.023). Jejunum weight was significantly positively correlated with plasma citrulline (r = 0.319; P = 0.0345).Conclusion: Citrulline promotes body weight gain, preserves muscle trophicity, and enhances intestinal adaptation in a dose-dependent manner in a model of resected rats

Citrulline directly modulates muscle protein synthesis via the PI3K/MAPK/4E-BP1 pathway in a malnourished state: evidence from in vivo, ex vivo, and in vitro studies

Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has consistently shown CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both interorgan and intraorgan trafficking and metabolism, we combined three approaches: in vivo, ex vivo, and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle. Interestingly, the increase in S6K1 phosphorylation was positively correlated (P < 0.05) with plasma CIT concentration. In a model of isolated incubated skeletal muscle from malnourished rats, CIT enhanced MPS (from 30 to 80% CIT vs. Ctrl, P < 0.05), and the CIT effect was abolished in the presence of wortmannin, rapamycin, and PD-98059. In vitro, on myotubes in culture, CIT led to a 2.5-fold increase in S6K1 phosphorylation and a 1.5-fold increase in 4E-BP1 phosphorylation. Both rapamycin and PD-98059 inhibited the CIT effect on S6K1, whereas only LY-294002 inhibited the CIT effect on both S6K1 and 4E-BP1. These findings show that CIT is a signaling agent for muscle homeostasis, suggesting a new role of the intestine in muscle mass contro

Association citrulline-statine : un traitement innovant pour l’obésité et le diabète de type 2

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Citrulline Supplementation Induces Changes in Body Composition and Limits Age-Related Metabolic Changes in Healthy Male Rats

International audienceBACKGROUND: Aging is associated with profound metabolic disturbances, and citrulline may be of use to limit them. OBJECTIVE: The aim of this work was to evaluate the long-term effect of citrulline supplementation on metabolism in healthy aged rats. METHODS: Twenty-month-old male rats were randomly assigned to be fed (ad libitum) for 12 wk with either a citrulline-enriched diet (1 g kg(-1) d(-1)) or a standard diet [rendered isonitrogenous by addition of nonessential amino acids (NEAAs)]. Motor activity and muscle strength were measured, body composition was assessed, and muscle metabolism (protein structure, mitochondrial exploration, and transductional factors) and lipid metabolism (lipoprotein composition and sensitivity to oxidative stress) were explored. RESULTS: Compared with the NEAA-treated group, citrulline supplementation was associated with lower mortality (0% vs. 20%; P = 0.05), 9% higher lean body mass (P \textless 0.05), and 13% lower fat mass (P \textless 0.05). Compared with the NEAA-treated group, citrulline-treated rats had greater muscle mass (+14-48% depending on type of muscle; P \textless 0.05 for tibialis, gastrocnemius, and plantaris). Susceptibility to oxidation of lipoproteins, as measured by the maximal concentration of 7-ketocholesterol after copper-induced VLDL and LDL oxidation, was lower in citrulline-treated rats than in NEAA-treated rats (187 +/- 8 mumol/L vs. 243 +/- 7 mumol/L; P = 0.0005). CONCLUSIONS: Citrulline treatment in male aged rats favorably modulates body composition and protects against lipid oxidation and, thus, emerges as an interesting candidate to help prevent the aging process