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

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.

L-Citrulline Supplementation Reduces Blood Pressure and Myocardial Infarct Size under Chronic Intermittent Hypoxia, a Major Feature of Sleep Apnea Syndrome

“…However, women’s sensitivity and OSA-related diseases seem to differ depending on the hypoxic burden, reoxygenation, and hypoxia duration [ 70 ]. Likewise, females produced 36% more endogenous citrulline than males, which caused greater arginine production [ 71 ]. Then, citrulline supplementation increased plasmatic arginine more in men than women, which resulted in a decrease in DBP and in an increase in blood flow and vascular conductance in men while no change in women [ 72 ].…”

Metabolic effects of L‐citrulline in type 2 diabetes

“…Furthermore, rates of Cit conversion to Arg [85][86][87]90 and Arg conversion to Cit [85][86][87] are also higher in rodents. Differences have also been reported between rats and mice; male rats have higher serum Cit (64.6 ± 7.8 109 and 70.0 ± 8.0 110 vs 40 ± 5 85 μM) and plasma Cit flux (197 ± 11 80 vs 95.4 ± 29.1 85 and 81.1 ± 4.7 80 μmol/kg/h) than male mice. Furthermore, a higher rate of NO production was reported in mice (7.68 ± 1.47 μmol/kg/h) than in rats (0.55 ± 0.05 μmol/kg/h).…”

“…104 However, some pharmacokinetic parameters of Cit metabolism have not been reported in women, an issue that warrants further investigation, as highlighted previously. 105 Female mice have higher serum Cit concentration than males 85,106 ; this is due to higher endogenous Arg synthesis (by ~42%) 85 and flux (by ~6%) 85 as well as higher serum (147 ± 17 vs 106 ± 14 μM), 107 kidney (440 ± 79 vs 263 ± 88 μmol/kg), 107 and skeletal muscle (728 ± 220 vs 367 ± 37 μmol/kg) 107 Arg concentrations in females. In addition, compared to males, Cit plasma flux, 80,85 Cit renal clearance, 85 rate of Cit conversion to Arg, 85 and rate of Arg conversion to Cit 85 as well as arginase activity in the pancreas (0.43 ± 0.04 vs 0.34 ± 0.1 μmol/mg/min) 85 and kidney (0.49 ± 0.04 vs 1.1 ± 0.08 μmol/mg/min) 85 are higher in female mice.…”

“…85,108 Considering species differences in Cit metabolism (Table 1), the main source of Cit production is glutamine in humans 79,80 but proline in rodents. [81][82][83] In addition, compared to humans, values of endogenous production, 83,84 plasma concentration, 85,88,89 plasma flux, 80,[84][85][86][87] renal clearance, 85,91 and half-life of Cit 92,93 are higher in rodents. Furthermore, rates of Cit conversion to Arg [85][86][87]90 and Arg conversion to Cit [85][86][87] are also higher in rodents.…”

“…[81][82][83] In addition, compared to humans, values of endogenous production, 83,84 plasma concentration, 85,88,89 plasma flux, 80,[84][85][86][87] renal clearance, 85,91 and half-life of Cit 92,93 are higher in rodents. Furthermore, rates of Cit conversion to Arg [85][86][87]90 and Arg conversion to Cit [85][86][87] are also higher in rodents. Differences have also been reported between rats and mice; male rats have higher serum Cit (64.6 ± 7.8 109 and 70.0 ± 8.0 110 vs 40 ± 5 85 μM) and plasma Cit flux (197 ± 11 80 vs 95.4 ± 29.1 85 and 81.1 ± 4.7 80 μmol/kg/h) than male mice.…”