Creatine Supplementation Reduces Guanidinoacetate via Downregulation of <scp>AGAT</scp> in a Mouse Model of <scp>GAMT</scp> Deficiency

The cornerstone of treatment in creatine synthesis defects is the supplementation of creatine (CT). The treatment leads to partial replenishment of creatine; it also leads to the reduction of guanidinoacetate (GAA). Considering the neurotoxic accumulation of GAA in patients with guanidinoacetate methyltransferase (GAMT) deficiency, understanding the process by which CT reduces GAA is crucial. Ten-week-old GAMT mice were fed with different diets, either CT-free or containing 2% and 4% CT for 10 weeks. Subsequent investigations included the analysis of CT and GAA in urine, blood, and mouse organs, and the analysis of AGAT expression in mouse organs by qPCR, western blotting, and enzymatic activity. CT supplementation in GAMT mutant mice led to a significant reduction of GAA in body fluids and organs, with the exception of the liver. The GAA-lowering effect of CT was mediated through downregulation of AGAT expression. The CT supplementation was sufficient to correct CT deficiency in all organs. Even in wild type mice, CT supplementation demonstrated a consistent reduction of GAA and increased the CT concentration in kidney and liver. CT supplementation in wild type mice did not change the CT concentration in brain, heart, and skeletal muscle. The liver exhibited a peculiar situation characterized by resistance to the GAA-lowering effects of CT. Our mouse study provides new insights in the effects of CT supplementation in wild type and GAMT deficient mice and the mechanism by which CT reduces the GAA accumulation in GAMT deficiency via downregulation of AGAT. This mechanism should be further explored for the treatment of GAMT deficiency.