Creatine metabolism: regulation and neonatal accretion

Edison, Erica (2014) Creatine metabolism: regulation and neonatal accretion. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

A fraction of the body’s creatine and creatine-phosphate spontaneously degrades to creatinine, which is excreted by the kidneys. In humans, this amounts to about 1-2 g per day and demands a comparable rate of de novo creatine synthesis. This is a two-step process in which L-arginine:glycine amidinotransferase (AGAT) catalyzes the conversion of glycine and arginine to ornithine and guanidinoacetate (GAA); guanidinoacetate methyltransferase (GAMT) then catalyzes the SAM-dependent methylation of GAA to creatine. AGAT is found in the kidney and GAMT in the liver, which implies an inter-organ movement of GAA from the kidney to the liver. We have studied the renal production of this metabolite in both rats and humans. In control rats, [GAA] was 5.9 μM in arterial plasma and 10.9 μM in renal venous plasma for a renal A-V difference of –5.0 μM. In the rat, infusion of arginine or citrulline markedly increased renal GAA production but infusion of glycine did not. Rats fed 0.4% creatine in their diet had decreased renal AGAT activity and mRNA, and arterial plasma [GAA] of 1.5 μM and a decreased renal A-V difference for GAA of –0.9 μM. In humans, [GAA] was 2.4 μM in arterial plasma, with a renal A-V difference of -1.1 μM. These studies show, for the first time, that GAA is produced by both rat and human kidneys in vivo. Creatine is essential for normal neural development; children with inborn errors of creatine synthesis or transport exhibit neurological symptoms such as mental retardation, speech delay, and epilepsy. Creatine accretion may occur through dietary intake or de novo creatine synthesis. The objective of this study is to determine how much creatine an infant must synthesize de novo. We have calculated how much creatine an infant needs to account for urinary creatinine excretion (creatine’s breakdown product) and new muscle lay-down. To measure an infant’s dietary creatine intake, we measured creatine in mother’s milk and in various commercially available infant formulas. Knowing the amount of milk/formula ingested, we calculated the amount of creatine ingested. We have found that a breast-fed infant receives about 9% of the creatine needed in the diet and that infants fed cow’s milk-based formula receive up to 36% of the creatine needed. However, infants fed a soy-based infant formula receive negligible dietary creatine and must rely solely on de novo creatine synthesis. This is the first time that it has been shown that neonatal creatine accretion is largely due to de novo synthesis and not through dietary intake of creatine. This has important implications both for infants suffering from creatine deficiency syndromes and for neonatal amino acid metabolism. Approximately 1.7% of the body’s creatine pool is spontaneously converted to creatinine each day and excreted in the urine. This loss must be replaced by a combination of diet and synthesis. During lactation there may be an additional requirement due to the provision of creatine to the milk. Our objectives were (i) to quantify milk creatine in lactating rats, (ii) to determine the origin of milk creatine, (iii) to determine the activities of the enzymes of creatine synthesis in lactating rats and suckling pups and (iv) to quantify the origin of the creatine that accumulates in suckling rat pups. The origin of milk creatine was determined by administering 14C-creatine to lactating rats, followed by determination of its isotopic enrichment in milk and plasma. These experiments indicate that the mammary gland extracts creatine from the circulation, rather than synthesising it. This was confirmed by our failure to find significant activities of the enzymes of creatine synthesis in mammary glands. The provision of milk creatine requires an additional 35-55% of creatine above the daily requirement by lactating mothers. However, there was no increased creatine synthesis by these dams, so that the additional creatine was largely provided by hyperphagia, as creatine is present in rat chow. There was substantial accumulation of creatine in the growing pups but only approximately 12 % was obtained from milk. The great bulk of creatine accretion was via de novo synthesis by the pups, which imposed a substantial metabolic burden on them.

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