Effects of Delivering Guanidinoacetic Acid or Its Prodrug to the Neural Tissue: Possible Relevance for Creatine Transporter Deficiency

The creatine precursor guanidinoacetate (GAA) was used as a dietary supplement in humans with no adverse events. Nevertheless, it has been suggested that GAA is epileptogenic or toxic to the nervous system. However, increased GAA content in rodents affected by guanidinoacetate methyltransferase (GAMT) deficiency might be responsible for their spared muscle function. Given these conflicting data, and lacking experimental evidence, we investigated whether GAA affected synaptic transmission in brain hippocampal slices. Incubation with 11.5 μM GAA (the highest concentration in the cerebrospinal fluid of GAMT-deficient patients) did not change the postsynaptic compound action potential. Even 1 or 2 mM had no effect, while 4 mM caused a reversible decrease in the potential. Guanidinoacetate increased creatine and phosphocreatine, but not after blocking the creatine transporter (also used by GAA). In an attempt to allow the brain delivery of GAA when there was a creatine transporter deficiency, we synthesized diacetyl guanidinoacetic acid ethyl ester (diacetyl-GAAE), a lipophilic derivative. In brain slices, 0.1 mM did not cause electrophysiological changes and improved tissue viability after blockage of the creatine transporter. However, diacetyl-GAAE did not increase creatine nor phosphocreatine in brain slices after blockage of the creatine transporter. We conclude that: (1) upon acute administration, GAA is neither epileptogenic nor neurotoxic; (2) Diacetyl-GAAE improves tissue viability after blockage of the creatine transporter but not through an increase in creatine or phosphocreatine. Diacetyl-GAAE might give rise to a GAA–phosphoGAA system that vicariates the missing creatine–phosphocreatine system. Our in vitro data show that GAA supplementation may be safe in the short term, and that a lipophilic GAA prodrug may be useful in creatine transporter deficiency.

Performance, carcass traits, and relative organ weight of broiler supplemented by guanidinoacetic acid: A meta-analysis

Guanidinoacetic acid (GAA) is formed by the arginine and glycine that are catalysed by arginine:glycine amidinotransferase in the kidney. In the liver, GAA is methylated by s-adenosyl methionine and converted to creatine, then deposited into muscle as energy supply. This meta-analysis was done by integrating 20 articles from various journals. Supplementation doses ranged from 0 to 8000 ppm/kg feed. The mixed model methodology was employed with GAA level and broiler strain as fixed effects and studies as random effects. The results showed that increasing GAA level improved average daily gain day 0-21 and reduced feed conversion ratio day 0-35 (P<0.05). A higher GAA also accompanied by decreasing relative liver weight (P<0.05). GAA supplementation did not affect average daily feed intake and percentage of carcass traits (carcass, legs, breast, wings, drum, thigh) and other parameters such as abdominal fat, gizzard, heart, bursa, thymus and spleen (P>0.05). It was concluded that supplementation of GAA improved the performance of broilers.

Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?

Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effectively increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompeting traditional bioenergetics agents in maintaining ATP status during stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as SLC6A6 and SLC6A13), previously dismissed as un-targetable carriers by other therapeutics, including creatine. The promising effects of dietary GAA might be countered by side-effects and possible toxicity. Animal studies reported neurotoxic and pro-oxidant effects of GAA accumulation, with exogenous GAA also appearing to increase methylation demand and circulating homocysteine, implying a possible metabolic burden of GAA intervention. This mini-review summarizes GAA toxicity evidence in human nutrition and outlines functional GAA safety through benefit-risk assessment and multi-criteria decision analysis.

Regulative Mechanism of Guanidinoacetic Acid on Skeletal Muscle Development and Its Application Prospects in Animal Husbandry: A Review

Guanidinoacetic acid is the direct precursor of creatine and its phosphorylated derivative phosphocreatine in the body. It is a safe nutritional supplement that can be used to promote muscle growth and development. Improving the growth performance of livestock and poultry and meat quality is the eternal goal of the animal husbandry, and it is also the common demand of today's society and consumers. A large number of experimental studies have shown that guanidinoacetic acid could improve the growth performance of animals, promote muscle development and improve the health of animals. However, the mechanism of how it affects muscle development needs to be further elucidated. This article discusses the physical and chemical properties of guanidinoacetic acid and its synthesis pathway, explores its mechanism of how it promotes muscle development and growth, and also classifies and summarizes the impact of its application in animal husbandry, providing a scientific basis for this application. In addition, this article also proposes future directions for the development of this substance.