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Received: December 23, 2022; Published: January 10, 2023
*Corresponding author: Marco Machado, Universidade Iguaçu – Campus Itaperuna, Brazil
Creatine supplementation was initially used as a therapeutic resource that was forgotten for decades until it was “rediscovered” by coaches and athletes. However, its therapeutic applications have been increasingly highlighted, such as in diseases of the nervous system. Some gaps remain about the mechanisms linked to the possible therapeutic effects of creatine on the central nervous system. One of the ways to understand the mechanisms will certainly pass through the expansion of knowledge about creatine transporters. So far, we have broad but still limited knowledge of the interference that these transporters may have on the action of dietary creatine (supplemented or not) on neurons, astrocytes and the blood-brain barrier.
Abbrevations: ADP: Adenosine Diphosphate; AGAT: Arginine: Glycine Amidinotransferase; Akt: Protein kinase B (also called PKB) is a serine/threonine kinase; AMPK: Adenosine monophosphate-activated protein kinase; Arg: Arginine; ATP: Adenosine triphosphate; BB-CK: CK brain-specific isoform; CK: Creatine kinase; CNS: Central Nervous System; Cr: Creatine; CrP: Phosphocreatine; CrT: Creatine Transporter; GAA: Guinidinoacetate; GAMT: S-Adenosylmethionine: Guanidinoacetate Methyltransferase; Gly: Glycine; IOC: International Olimpic Committee; ISSN: International Society of Sports Nutrition; mTBI: Mild Traumatic Brain Injury; PKB: Protein kinase B (also called Akt) a Serine/Threonine Kinase; ROS: Reactive Oxigen Species
The maintenance of the cell’s energy charge is a priority for maintaining its operation. The numerous tasks that each cell has to maintain for itself and to fulfil the tissue and organ functions to which they belong demand high rates of energy consumption, obtained through food. Some metabolic pathways (a set of reactions that occur in a chain) are responsible for the production of energy, with emphasis on the reactions that occur within an organelle called mitochondria. However, when energy demand exceeds certain values in a specific system for short periods, the creatine phosphate (CrP) system becomes prominent in maintaining high rates of available energy.
As initially summarized, cellular energy is primarily maintained by (a) glycolysis, (b) mitochondrial oxidative phosphorylation, and (c) ATP regeneration by CrP via the Lohmann reaction (ADP + CrP + H+ → ATP + Cr) [1,2]. We can highlight that in skeletal muscles, Cr/CrP also works as an energy carrier between the mitochondria where ATP is produced and the cytosol, where ATP is used, but rapidly regenerated by Cr/CrP [1,2]. This elaborate scheme of Cr/CrP-mediated ATP regeneration and energy transport confers several advantages to muscle cells . (Figure 1) can help better understand this process. CrP regenerates ATP at a rate 10 times faster than glycolysis and 40 times faster than mitochondrial oxidative phosphorylation, allowing muscle cells to handle sudden energy demands. On the other hand, 1 proton (H+) is released each time 1 ATP is hydrolyzed to ADP, which could cause acidosis (decreased cellular pH), but a proton will be immediately captured by the Lohmann reaction to regenerate ATP . Due to the smaller size of Cr (the molecular weight of creatine is ~130 daltons), skeletal muscle cells can store up to 10 times more Cr than ATP (the molecular weight of ATP is ~507 daltons, almost 4 times higher) as an energy reserve [1,2]. Last but not least, Cr stimulates oxidative phosphorylation when it reenters the mitochondria through voltage-gated anion channels, thus matching mitochondrial respiration with cellular demand for ATP [5,6]. (Figure 2) This function is also called an energy space buffer .
Under physiological conditions, Cr is obtained from food sources (beef, swine, poultry, fish, etc.) or endogenous synthesis. Endogenous synthesis is a two-step reaction catalyzed by the enzymes L-arginine: glycine amidinotransferase (AGAT) and S-adenosyl-L-methionine: N-guanidinoacetate methyltransferase (GAMT). AGAT converts glycine and arginine into guanidinoacetate (GAA) and ornithine. GAMT transfers a methyl group from S-adenosylmethionine (SAM) to GAA, generating Cr and S-adenosyl homocysteine [1,4]. This seemingly simple pathway is complicated by the fact that most cells do not produce these two enzymes in equivalent amounts. In this way, the intermediate product (GAA) needs to leave the producing tissues and be transported to the tissues that produce large amounts of the GAMT enzyme . For example, the mammalian kidney contains amounts of AGAT (which catalyzes large amounts of GAA) that must be transported via the bloodstream to the liver (which produces large amounts of the enzyme GAMT). Thus, in the liver finally, SAM can methylate GAA producing Cr. In contrast, the central nervous system (CNS) houses its Cr-synthesizing machinery (more on this later) . After endogenous synthesis or nutritional supply, Cr is ready to fulfil its functions in other cells. Cr is a polar hydrophilic molecule incapable of crossing cell membranes (primarily nonpolar formed by phospholipids) so it requires a transporter, a protein capable of facilitating/permeabilizing the membrane for the passage of creatine.
The creatine transporter (CRT or Cr transporter) is Na+/Cl− dependent and specific for cellular uptake [9,10]. CRT is encoded by the SLC6A8 gene, which is located on the long arm of the X chromosome and has a coding sequence of 13 exons [9,10]. The protein consists of 635 amino acids with a molecular mass of about 70.5 kDa . This transporter is a member of a protein superfamily (called SLC6), which includes transporters for the uptake of some neurotransmitters (eg, dopamine, GABA, serotonin) and amino acids (eg, glycine) . The SLC6 family has a common threedimensional structure, with 12 transmembranes (TM) domains, an extracellular loop between TM3 and TM4 with N-glycosylation and N- and C-terminal sites facing the cytoplasmic side of the membrane [13,14]. CRT is strongly regulated by extracellular levels of Cr, with high Cr reducing uptake activity . Furthermore, cellular energy depletion inhibits CRT via the AMPK-mTOR pathway . CRT is widely expressed in different tissues [9,14,16], including the brain, where it has been predominantly detected in cortical and subcortical regions involved in motor and sensory processing, learning and memory, and in the control of affective behaviour [9,17,18]. At the cellular level, CRT is expressed in oligodendrocytes and neurons, with notably high levels in fast-peaking parvalbumin inhibitory neurons [19,20]. It is also present in capillary endothelial cells that make up the blood-brain barrier (BBB), whereas it was detected only in smaller amounts in astrocytes .
Thus, Cr can enter the brain across the BBB, but blood-brain transport of Cr appears relatively inefficient, at least at a mature age [22-24]. Creatine (Cr) and creatine phosphocreatine (CrP) have the highest concentration in tissues that require a constant or rapid supply of energy, including skeletal muscle, heart and brain [1,25]. Cr/CrP accumulates functions of ATP resynthesis and transport of energy produced in cellular respiration. It also has neuroprotective effects and positively interferes with cognition [26,27]. There is already enough empirical evidence to support that both in conditions of hypoxia and normoxia it is advantageous to use oral supplementation of Crem in healthy adults [4,8,28]. On the other hand, when Cr/CrP concentrations and CK activity are low, they are correlated with neurodegenerative diseases . Intellectual disability, autism or seizures in children also show changes in Cr concentrations [7,30]. Brain injuries seem to be more difficult to treat when Cr concentrations are low, mainly due to a slow bloodbrain transport of Cr that is mediated by CRT [7,31,32]. Although Cr/CrP may have functions similar to those of skeletal muscle in the brain, the effects of CRT deficiency on stress adaptation and energy homeostasis remain unclear. CrP regenerates ATP at a rate 10 times faster than glycolysis and 40 times faster than mitochondrial respiration. This speed of catalysis allows muscle fibres to respond very efficiently to sudden energy demands [33-35].
Furthermore, it is important to remember that ATP hydrolysis releases 1 proton (H+) in addition to ADP, potentiating acidosis (decrease in cell pH), but the Lohmann reaction to regenerate ATP consumes a proton with each transfer of phosphate from CrP to the ADP . As the molecular weight of creatine is low (about 130 daltons), skeletal muscle fibres can store up to 10 times more Cr than ATP (the molecular weight of ATP is ~507 daltons, almost 4 times higher) as a reserve of energy [1,2]. (Figure 3) Last but not least, free Cr after transfer of the phosphate group stimulates cellular respiration when ´w is transported into the mitochondria through voltage-gated anion channels, thus matching mitochondrial respiration with the cellular demand for ATP. [5,6]. This function is also called na energy space buffer .
As described, knowledge about the functions of creatine in energy metabolism themselves seems to be well described by science, especially in skeletal muscle. However, there are still limitations to the knowledge of creatine production and transport in the central nervous system. Understanding the mechanisms of creatine transport into the brain (crossing the blood-brain barrier) and the production of creatine by neurons, astrocytes and oligodendrocytes will be essential to develop strategies for the use of creatine in the prevention and treatment of various diseases and loss of cognition in older people.
This work would not have been possible without the contribution of the great scientists who made the discoveries described here. I also thank Dr Marcelo F Costa for his support and encouragement.
The author declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article.
The author(s) received no financial support for the research, authorship, and/or publication of this article.