Citrulline and nitrogen homeostasis: an overview

Breuillard, C.; Cynober, Luc; Moinard, Christophe

doi:10.1007/s00726-015-1932-2

Cited by 115 publications

(100 citation statements)

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“…Citrulline has emerged as an important regulator of nitrogen homeostasis (6,9). Over the last 10 yr, the ability of CIT to modulate protein metabolism has been shown in different situations (short bowel syndrome, fasting, aging, etc.)…”

Section: Discussionmentioning

confidence: 99%

“…Intestinal CIT production is controlled largely by dietary protein supply (37). CIT has also emerged as an important regulator of nitrogen homeostasis in both humans and animals, as reviewed recently (6). For example, in pioneering work, we used a model of aged malnourished rats to demonstrate that CIT-enriched diet stimulated muscle protein synthesis (MPS) (ϩ80%), and led to a net muscle protein gain (ϩ20%) (10,33).…”

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confidence: 99%

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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

Plénier

Goron

Sotiropoulos

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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(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 Ͻ 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 Ͻ 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 control. eukaryotic initiation factor 4E-binding protein 1; mitogen-activated protein kinase; phosphatidylinositol 3-kinase; muscle; myotube; amino acids; protein synthesis; mammalian target of rapamycin CITRULLINE (CIT) is a nonprotein amino acid. It takes its name from the watermelon (citrullus vulgaris). CIT is known mainly as an intermediary of ureagenesis in periportal hepatocytes (24) and at the whole body level is produced almost exclusively by enterocytes (4). Intestinal CIT production is controlled largely by dietary protein supply (37). CIT has also emerged as an important regulator of nitrogen homeostasis in both humans and animals, as reviewed recently (6). For example, in pioneering work, we used a model of aged malnourished rats to demonstrate that CIT-enriched diet stimulated muscle protein synthesis (MPS) (ϩ80%), and led to a net muscle protein gain (ϩ20%) (10, 33). Interestingly, this metabolic effect was accompanied by muscle histological change and an increase in maximum strength as well as increased traction in treated animals (11). Similar results were obtained in healthy aged rats, in which CIT increased muscle protein content (28). This was also found in other situations such as fasting or caloric restriction in adults rats (22,38). Finally, our experimental work showing the ability of CIT to modulate MPS was confirmed in humans; in a crossover trial, Jourdan et al. (20) showed that CIT administration to healthy volunteers fed a hypoprotein diet increased MPS compared with a nonessential amino acid mixture. Thus all these studies confirm the ability of CIT to modulate MPS in vivo, but no work has yet determined the underlying mechanisms of CIT action (an increase in nitrogen...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Plénier

Goron

Sotiropoulos

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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“…133,134 Quantitatively, glutamine is considered a major precursor of intestinal citrulline release. 47,52,135,136 The intestines consume glutamine at a rate that is dependent on glutamine supply. Because glutamine breakdown in the gut produces citrulline, there is a good relation between the amount of metabolically active gut tissue and the production of citrulline in this tissue.…”

Section: Impact Of Aging On Glutamine Synthesis In the Gutmentioning

confidence: 99%

Glutamine metabolism in advanced age

Meynial-Denis

2016

Nutr Rev

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Glutamine, reviewed extensively in the last century, is a key substrate for the splanchnic bed in the whole body and is a nutrient of particular interest in gastrointestinal research. A marked decrease in the plasma glutamine concentration has recently been observed in neonates and adults during acute illness and stress. Although some studies in newborns have shown parenteral and enteral supplementation with glutamine to be of benefit (by decreasing proteolysis and activating the immune system), clinical trials have not demonstrated prolonged advantages such as reductions in mortality or risk of infections in adults. In addition, glutamine is not able to combat the muscle wasting associated with disease or age-related sarcopenia. Oral glutamine supplementation initiated before advanced age in rats increases gut mass and improves the villus height of mucosa, thereby preventing the gut atrophy encountered in advanced age. Enterocytes from very old rats continuously metabolize glutamine into citrulline, which allowed, for the first time, the use of citrulline as a noninvasive marker of intestinal atrophy induced by advanced age.

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“…The authors suggest that increased urinary excretion of citrulline could potentially explain this discrepancy. De novo synthesized citrulline could also be converted back to arginine in the kidneys by argininosuccinate synthase and argininosuccinate lyase (12) in an attempt to stabilize circulating and tissue concentrations of arginine. Reductions in citrulline could also simply reflect reductions in citrulline's precursor (arginine), with equivalent reductions in NO biosynthesis.…”

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confidence: 99%

“…The impact of metformin on whole-body urea biosynthesis could be tested using stable isotope methodologies (22). For example, in vivo synthesis of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]urea following administration of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]acetate has been reported as a reliable method for measuring in vivo urea biosynthesis (22). Of interest, in the present "translational" study, metformin did not affect citrulline concentrations in the db/db diabetic mouse liver and metformin's effects on other urea cycle metabolites was not evaluated.…”

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confidence: 99%