Arginase II plays a central role in the sexual dimorphism of arginine metabolism in C57BL/6 mice

Authors: MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC); DIDELIJA, INKA - Children'S Nutrition Research Center (CNRC); MARINI, JUAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/22/2020
Publication Date: 11/13/2020
Citation: Mohammad, M.A., Didelija, I.C., Marini, J.C. 2020. Arginase II plays a central role in the sexual dimorphism of arginine metabolism in C57BL/6 mice. Journal of Nutrition. 150(12):3133-3140. https://doi.org/10.1093/jn/nxaa318.
DOI: https://doi.org/10.1093/jn/nxaa318

Interpretive Summary: Differences between male and female mice in the metabolism of the amino acid arginine have been reported. These differences may (partially) explain the gender differences in humans in some traits such as reduced blood pressure and better outcomes during critical illness seen in women. Arginine is utilized for the synthesis of many products but its utilization by arginase (a reaction that consumes arginine in a 'wasteful' manner) is one of the most predominant. Two different arginases exist, I and II; here we used a transgenic mouse model that lacks arginase II to determine its effect on arginine metabolism. Female mice have a greater arginine production which resulted in greater arginine availability than in male mice. The lack of arginase II increases arginine availability in male mice to a level similar to the female animals. These findings highlight the potential of novel arginase inhibitors to increase arginase availability in certain pathological situations.

Technical Abstract: Sex differences in plasma concentration of arginine and arginase activity of different tissues have been reported in mice. In addition, male but not female C57BL/6 mice have a dietary arginine requirement for growth. The goal of this research was to test the hypothesis that arginase II is a key factor in the sexual dimorphism of arginine metabolism. Young adult male and female wild type, heterozygous and arginase II KO mice on a C57BL/6 background mice were infused with labeled citrulline, arginine, ornithine, phenylalanine and tyrosine to determine the rates of appearance and interconversion of these amino acids. Tissue arginase activity was measured in liver, heart, jejunum, kidney, pancreas and spleen with an arginine radioisotope. The effect of genotype, sex and their interaction was tested. Female mice produced ~36% more citrulline than their male littermates which translated into a greater arginine endogenous synthesis, flux and plasma concentration (42, 6, 27% respectively; P<0.001). Female mice also had a greater phenylalanine flux (10%) indicating a greater rate of whole protein breakdown; however, they had a lower protein synthesis rate than males (18%; P<0.001). The ablation of arginase II reduced the production of citrulline and the de novo synthesis of arginine in females and increased the rate of appearance of arginine and plasma arginine concentration in male mice (16 and 22%, respectively; P<0.001). No effect of arginase II deletion, however, was observed for whole body protein kinetics. Arginase II activity was present in pancreas, kidney, jejunum and spleen; wild type females had a ~2-fold greater renal arginase activity than their wild type counterparts. A clear sexual dimorphism exist in the endogenous synthesis of arginine and its disposal. Female mice have a greater arginine availability than their male littermates. The ablation of arginase II increases arginine availability in male mice.