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Title: Arginine depletion by arginine deiminase does not affect whole protein metabolism or muscle fractional protein synthesis rate in mice

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

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/20/2015
Publication Date: 3/16/2015
Citation: Marini, J.C., Didelija, I. 2015. Arginine depletion by arginine deiminase does not affect whole protein metabolism or muscle fractional protein synthesis rate in mice. PLoS One. 10(3):e0119801. doi:10.1371/journal.pone.0119801.

Interpretive Summary: All cell types need the amino acid arginine in order to make protein and maintain other functions. Most cells can also utilize the amino acid citrulline to make arginine; however, some cancer cells are unable to make their own arginine, and for this reason depend on arginine from the circulation. ADI-PEG is a drug that converts all the circulating arginine back to citrulline and is being used in the treatment of certain cancers. Here we investigated if the citrulline generated by ADI-PEG could be used by many tissues and organs to produce arginine which was incorporated into tissue protein. Our findings show that most tissues can utilize citrulline to make arginine and in this way maintain protein synthesis and a normal function. This study helps to answer some fundamental questions regarding protein synthesis that will be used in future research.

Technical Abstract: Due to the absolute need for arginine that certain cancer cells have, arginine depletion is a therapy in clinical trials to treat several types of cancers. Arginine is an amino acids utilized not only as a precursor for other important molecules, but also for protein synthesis. Because arginine depletion can potentially exacerbate the progressive loss of body weight, and especially lean body mass, in cancer patients we determined the effect of arginine depletion by pegylated arginine deiminase (ADI-PEG 20) on whole body protein synthesis and fractional protein synthesis rate in multiple tissues of mice. ADI-PEG 20 successfully depleted circulating arginine (<1 micomol/L), and increased citrulline concentration more than tenfold. Body weight and body composition, however, were not affected by ADI-PEG 20. Despite the depletion of arginine, whole body protein synthesis and breakdown were maintained in the ADI-PEG 20 treated mice. The fractional protein synthesis rate of muscle was also not affected by arginine depletion. Most tissues (liver, kidney, spleen, heart, lungs, stomach, small and large intestine, pancreas) were able to maintain their fractional protein synthesis rate; however, the fractional protein synthesis rate of brain, thymus and testicles was reduced due to the ADI-PEG 20 treatment. Furthermore, these results were confirmed by the incorporation of ureido [(14)C]citrulline, which indicate the local conversion into arginine, into protein. In conclusion, the intracellular recycling pathway of citrulline is able to provide enough arginine to maintain protein synthesis rate and prevent the loss of lean body mass and body weight.