Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?

Abstract

While it has long been thought that most of cerebral creatine is of peripheral origin, the last 20 years has provided evidence that the creatine synthetic pathway (AGAT and GAMT enzymes) is expressed in the brain together with the creatine transporter (SLC6A8). It has also been shown that SLC6A8 is expressed by microcapillary endothelial cells at the blood-brain barrier, but is absent from surrounding astrocytes, raising the concept that the blood-brain barrier has a limited permeability for peripheral creatine. The first creatine deficiency syndrome in humans was also discovered 20 years ago (GAMT deficiency), followed later by AGAT and SLC6A8 deficiencies, all three diseases being characterized by creatine deficiency in the CNS and essentially affecting the brain. By reviewing the numerous and latest experimental studies addressing creatine transport and synthesis in the CNS, as well as the clinical and biochemical characteristics of creatine-deficient patients, our aim was to delineate a clearer view of the roles of the blood-brain and blood-cerebrospinal fluid barriers in the transport of creatine and guanidinoacetate between periphery and CNS, and on the intracerebral synthesis and transport of creatine. This review also addresses the question of guanidinoacetate toxicity for brain cells, as probably found under GAMT deficiency.

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

“…Knock-out mice that lack the brain CK isoforms (BCK and/or ubiquitous MtCK, uMtCK;Streijger et al 2004;Wallimann and Hemmer 1994) show defects in spatial memory acquisition and behavior, development of the hippocampus, correct functioning of hair bundle cells in the auditory system (Jost et al 2002;Shin et al 2007), and energy distribution within photoreceptor cells (Linton et al 2010). This is confirmed by more recent transgenic models of Cr deficiency, including mice deficient for the Cr biosynthetic enzymes arginine glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) or for the plasma membrane Na + /Cl − -dependent Cr-transporter SLC6A8, as well as by patients suffering from mutations in these proteins (for review see Hanna-El-Daher and Braissant 2016 in this issue).…”

International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine

“…Some individuals have been found to have creatine synthesis deficiencies due to inborn errors in AGAT, GMAT and/or creatine transporter (CRTR) deficiencies and therefore must depend on dietary creatine intake in order to maintain normal muscle and brain concentrations of PCr and Cr [13–19]. Vegetarians have been reported to have lower intramuscular creatine stores (90–110 mmol/kg of dry muscle) and therefore may observe greater gains in muscle creatine content from creatine supplementation [11, 13, 20, 21].…”

“…Vegetarians have been reported to have lower intramuscular creatine stores (90–110 mmol/kg of dry muscle) and therefore may observe greater gains in muscle creatine content from creatine supplementation [11, 13, 20, 21]. Conversely, larger athletes engaged in intense training may need to consume 5–10 g/day of creatine to maintain optimal or capacity whole body creatine stores [22] and clinical populations may need to consume 10–30 g/day throughout their lifespan to offset creatine synthesis deficiencies and/or provide therapeutic benefit in various disease states [13, 19, 23]. …”

Creatine: a miserable life without it

“…In the case of the CrT knockout mouse, one would expect to see similar changes in terms of mitochondrial propensity, size and shape, as well as in the appearance of intra-mitochondrial inclusions (O'Gorman et al 1997). However, since CrT knockout mice still express in certain brain cells both creatine synthesis enzymes (AGAT and GAMT), as well as both brain-type CK isoenzymes, only those neurons will be affected, which are devoid of endogenous creatine synthesis and therefore depend on creatine import via an intact CrT (see Hanna-El-Daher and Braissant 2016). Thus, one would expect to see the above-mentioned mitochondrial changes only in a this subpopulation of neurons.…”

“…The isolation of such micro-compartments, however, becomes increasingly more difficult with the heterogeneity of other tissues, e.g. brain, where there is a multitude of highly different cell types that are not organized in a homogeneous, orderly fashion as with skeletal muscle (see Hanna-El-Daher and Braissant 2016).…”