The sparing effects of creatine and its precursor guanidinoacetic acid on protein synthesis in a neonatal TPN piglet model

Arginine and methionine are indispensable amino acids for the neonate. Significant quantities of both are required for de novo creatine synthesis to satisfy whole body accretion requirements, even when creatine is provided in milk. Neonates that require intravenous feeding (parenteral nutrition, PN) are at risk of arginine deficiency because arginine is synthesized in the small intestine from dietary precursors; arginine deficiency may limit creatine synthesis. Larginine: glycine amidinotransferase (AGAT) is the first enzyme involved in creatine biosynthesis and catalyzes the conversion of arginine and glycine to guanidinoacetic acid (GAA) in the kidney. GAA is then methylated by methionine in the liver to produce creatine via guanidinoacetate N-methyltransferase. Our objective was to determine whether a parenteral diet supplemented with GAA or creatine could spare arginine and methionine for growth and protein synthesis. Piglets (6-10 d old, N = 31) were parenterally-fed for 5 days, with one of five diets: 1) low arginine and low methionine (base), 2) base plus GAA, 3) base plus creatine, 4) high arginine and high methionine (Arg&Met), or 5) high methionine and low arginine plus GAA (Met&GAA). On day 6 of the experiment, piglets underwent a 6 hour constant infusion using stable isotopes of arginine, GAA and creatine to measure fractional arginine conversion to GAA and creatine. In addition, isotopes of phenylalanine and tyrosine were infused to measure whole body protein dynamics. In piglets fed the GAA and creatine diets, there was significantly lower kidney AGAT activity compared to the Arg&Met diet (P < 0.05), which indicates GAA and creatine downregulate kidney AGAT and suggests that less arginine was used for GAA synthesis. Whole body nitrogen retention was higher in the group fed GAA with excess methionine (Met&GAA) , compared to GAA alone (P < 0.05) suggesting that methionine was directed towards GAA methylation rather protein synthesis even when limited amounts were provided in the diet. This is consistent the higher weight gain in the Met&GAA group compared to all groups (P < 0.05) except the Arg&Met. A greater amount of arginine was utilized for GAA synthesis in the Arg&Met group compared to all other groups except for the base group (P < 0.05), which suggests that providing creatine or GAA in the diet spared arginine. However, greater protein accretion rate occurred in the group provided arginine and methionine in excess (Arg&Met) compared to supplementing just creatine.