Creatine synthesis and arginine partitioning during total parenteral nutrition in Yucatan miniature piglets

Aljaroudi, Alaa (2018) Creatine synthesis and arginine partitioning during total parenteral nutrition in Yucatan miniature piglets. Masters thesis, Memorial University of Newfoundland.

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Abstract

Arginine is an indispensable amino acid for the neonate. Significant quantities of both arginine and methionine 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 for arginine deficiency because arginine is synthesized in the small intestine from dietary precursors; as such, arginine deficiency may limit creatine synthesis. L-arginine:glycine amidinotransferase (AGAT) is the first enzyme, and the rate limiting step, 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 protein synthesis and growth. Piglets (6-10 d old, N = 31) were parenterally fed for 5 days 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 of stable isotopes of arginine, GAA and creatine to measure fractional conversion of arginine to GAA and creatine. In addition, continuous infusions of phenylalanine and tyrosine isotopes were used to measure whole body protein kinetics. At the end of the experiment, the piglets were killed and AGAT activity and GAA and creatine concentrations were measured in tissues. P values < 0.05 were considered statistically significant. 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 that GAA and creatine downregulated kidney AGAT and suggests that less arginine was used for GAA synthesis. Pancreatic AGAT activity was also significantly lower in the creatine group compared to Arg&Met (P < 0.05). Whole body nitrogen balance did not differ significantly between groups, however, nitrogen retention was higher in the group fed GAA with excess methionine (Met&GAA), compared to GAA alone (P < 0.05) suggesting that methionine in the GAA group was directed towards GAA methylation rather than protein synthesis even when limited amounts of methionine were provided in the diet. This is consistent with the higher weight gain in the Met&GAA group compared to all other 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 the GAA, creatine, and Met&GAA groups (P < 0.05), which demonstrated that providing creatine or GAA in the diet spared arginine in those groups. Overall, supplemental GAA in parenterally fed piglets seemed to be effective at sparing arginine for growth, provided that methionine was supplemented in adequate amounts. GAA may be useful as a supplement to parenteral nutrition formulas to preserve arginine for growth by facilitating creatine synthesis.

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