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Title: Dietary arginine requirements for growth are dependent on the rate of citrulline production in mice

item MARINI, JUAN - Children'S Nutrition Research Center (CNRC)
item AGARWAL, UMANG - Children'S Nutrition Research Center (CNRC)
item DIDELIJA, INKA CAJO - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/16/2015
Publication Date: 4/8/2015
Citation: Marini, J.C., Agarwal, U., Didelija, I. 2015. Dietary arginine requirements for growth are dependent on the rate of citrulline production in mice. Journal of Nutrition. 145(6):1227-1231.

Interpretive Summary: Arginine is an amino acid used to make protein and other compounds and it needs to be provided in the diet when there is a high demand such as during rapid growth. Differences among species exist, with some species having an absolute requirement for arginine throughout their lives. In this study we identified differences between two mouse lines. Whereas a mouse strain required arginine for optimal growth; the other one did not. This was the result of differences in the gene expression of the molecular machinery to make the amino acid arginine between the different mice. This helps researchers obtain some fundamental answer in growth requirements that will aid future research.

Technical Abstract: In many species, including humans, arginine is considered a semiessential amino acid because under certain conditions endogenous synthesis cannot meet its demand. The requirements of arginine for growth in mice are ill defined and seem to vary depending on the genetic background of the mice. The objective of this study was to determine the metabolic and molecular basis for the requirement of arginine in 2 mouse strains. Institute of Cancer Research (ICR) and C57BL/6 (BL6) male mice were fed arginine-free or arginine-sufficient diets (Experiment 1) or 1 of 7 diets with increasing arginine concentration (from 0- to 8-g/kg diet, Experiment 2) between day 24 and 42 of life to determine the arginine requirements for growth. Citrulline production and "de novo" arginine synthesis were measured with use of stable isotopes, and arginine requirements were determined by breakpoint analysis and enzyme expression by reverse transcriptase-polymerase chain reaction. The results in Experiment 1, ICR mice grew at the same rate regardless of the arginine concentration of the diet (mean +/- SE: 0.66 +/- 0.04 g/d, "P" = 0.80), but BL6 mice had a reduced growth rate when fed the arginine-free diet (0.25 +/- 0.02 g/d, "P" < 0.001) compared to the 8-g arginine/kg diet (0.46 +/- 0.03 g/d). ICR mice showed at least a 2-fold greater expression ("P" < 0.001) of ornithine transcarbamylase ("OTC") than BL6 mice, which translated into a greater rate of citrulline (25%) and arginine synthesis (49%, "P" < 0.002). In Experiment 2, breakpoint analysis showed that the requirement for growth of BL6 mice was met with 2.32 +/- 0.39 g arginine/kg diet; for ICR mice, however, no breakpoint was found. In conclusion our data indicate that a reduced expression of "OTC" in BL6 mice translates into a reduced production of citrulline and arginine compared with ICR mice, which results in a dietary arginine requirement for growth in BL6 mice, but not in ICR mice.