Dietary manipulation of arginine supply and demand in mice
Authors: Raguin Rachel , Mohammad Mahmoud A. , Didelija Inka C. , Manjarin Rodrigo , Burrin Douglas G. , Marini Juan 
Published: June 2021

Male C57BL/6J mice have a dietary arginine requirement for maximal growth during the post‐weaning period. This is due to a limited production of its precursor, citrulline, which results in a reduced endogenous arginine synthesis. Typically, arginine supplementation has been used to increase arginine availability and maximize growth. Alternatively, citrulline supplementation may increase endogenous arginine synthesis, and therefore arginine supply. A third option is to supplement with some downstream metabolites (e.g., creatine) of arginine thus reducing its demand and sparing arginine that can be used to support growth. Male C57BL/6J were weaned at 21 d of age, and after a 4 d acclimation period were fed the treatment diets until they reached 42 d of age. Diets with different arginine content (0, 2.5 and 8 g/kg; A0, A2.5 and A8, respectively), or arginine‐free diets supplemented with citrulline (2.5 g/kg; Cit2.5) or creatine (2.5 g/kg; Cre2.5) were fed for 17 d, during the linear growth phase. On d 42 after a 3 h fast, mice were infused with tracers to determine the kinetics of citrulline, arginine, phenylalanine and tyrosine. As expected, mice fed the A0 diet grew slower (0.23 g/d; P < 0.001) and achieved a smaller final weight (18.7 g) than mice fed the A2.5 and A8 diets. The growth rate and final weight of the mice fed the Cit2.5 was not different than that from those fed the arginine supplemented diets (0.47 g/d and 22.6 g, respectively); however, mice fed the Cre2.5 diet grew at similar rate and achieved a similar final weight than mice fed the A0 diet (0.19 g/d and 18 g, respectively). Arginine flux was not different among the different treatments; however, citrulline flux was greater for mice fed the A0 and Cre2.5 diets than for mice fed the A2.5, A8 or Cit2.5 diet (125 vs 108 μmol*kg−1*h−1; P <0.001). This resulted in a greater de novo arginine synthesis for mice fed the A0 and Cre2.5 diets than for mice on the A2.5, A8 or Cit2.5 treatments (82.7 vs 72 μmol*kg−1*h−1; P < 0.001). Dietary treatments had no effect (P > 0.21) on whole body protein metabolism as determined by phenylalanine‐tyrosine kinetics. Increasing arginine supply by supplementing with arginine or citrulline successfully increased growth rate and final body weight in mice. However, reducing arginine demand by supplementing with creatine did not improve growth rate. During fasting citrulline flux and de novo arginine synthesis increased in mice fed A0 and Cre2.5, suggesting a response to arginine deprivation. In conclusion, increasing the supply of arginine is effective way to restore growth, but reducing the demand was ineffectual.Support or Funding InformationThis work was supported by federal funds from the USDA/Agricultural Research Service under Cooperative Agreement no. 58‐6250‐6‐001 (to JCM), and the NIH (R01 GM108940 to JCM).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.