Arginase II Plays a Central Role in the Sexual Dimorphism of Arginine Metabolism in C57BL/6 Mice

Abstract

ABSTRACT Background 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. Objective The goal of this research was to test the hypothesis that arginase II is a key factor in the sexual dimorphism of arginine metabolism. Methods Young adult male and female wild type (WT), and heterozygous and arginase II knockout 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 the liver, heart, jejunum, kidney, pancreas, and spleen with an arginine radioisotope. The effect of genotype, sex, and their interaction was tested. Results Female mice produced ∼36% more citrulline than their male littermates, which translated into a greater arginine endogenous synthesis, flux, and plasma concentration (42, 6, and 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 the pancreas, kidney, jejunum, and spleen; WT females had a ∼2-fold greater renal arginase activity than their WT counterparts. Conclusions A clear sexual dimorphism exists 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.