O Chandani Dinesh - March 18
Arginine metabolism and creatine biosynthesis in neonatal piglets
Severe creatine deficiency, secondary to inborn errors in creatine synthesis or transport, results in profound neurological defects, demonstrating its importance in neonatal brain development. Neonates ingest creatine via mother's milk but also are capable of endogenous synthesis to maintain the body pool. In addition to the requirement for maintenance, rapidly growing neonates must accrue creatine in the expanding lean tissue mass. , Factorial assessment suggests that the creatine requirement in neonates is greater than that supplied by mammary milk; as such, the neonate must rely on de novo creatine synthesis. The global goal of my PhD program is to understand and quantify the demand for the precursor amino acid arginine to support creatine biosynthesis in neonates. During intravenous feeding (TPN), the entire creatine requirement must be met by de novo synthesis, as creatine is not added to paediatric TPN. My first study focused on the capacity for creatine biosynthesis and accretion in TPN-fed neonatal piglets when creatine was not provided in TPN. Neonatal piglets fed creatine-free TPN had lower tissue concentrations compared to those fed a creatine-supplemented TPN. We did not know if lower creatine accretion was due to limited enzyme capacity, or limited substrate availability. Arginine is an essential amino acid in neonates, and has several important metabolic roles other than creatine synthesis. When arginine availability is limited, an important question is how whole body arginine is quantitatively partitioned into creatine synthesis, which was addressed in my second study. Tissue GAA and creatine concentrations and in vitro enzyme activities involved in the creatine synthesis pathway were measured to describe the inter-organ system of creatine synthesis in piglets. However, the quantitative contribution of the pancreas and kidney to whole body GAA supply is not known. In my third study, we measured the net flux (organ balance) of creatine and its precursors (arginine, glycine, methionine, GAA) across the kidney and pancreas, to describe in vivo the inter-organ synthetic pathway of creatine and to quantify the capacity of the organs in sow-reared piglets.