Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review

Diego A Bonilla, Richard B Kreider, Jeffrey R Stout, Diego A Forero, Chad M Kerksick, Michael D Roberts, Eric S Rawson, Diego A Bonilla, Richard B Kreider, Jeffrey R Stout, Diego A Forero, Chad M Kerksick, Michael D Roberts, Eric S Rawson

Abstract

Creatine (Cr) is a ubiquitous molecule that is synthesized mainly in the liver, kidneys, and pancreas. Most of the Cr pool is found in tissues with high-energy demands. Cr enters target cells through a specific symporter called Na+/Cl--dependent Cr transporter (CRT). Once within cells, creatine kinase (CK) catalyzes the reversible transphosphorylation reaction between [Mg2+:ATP4-]2- and Cr to produce phosphocreatine (PCr) and [Mg2+:ADP3-]-. We aimed to perform a comprehensive and bioinformatics-assisted review of the most recent research findings regarding Cr metabolism. Specifically, several public databases, repositories, and bioinformatics tools were utilized for this endeavor. Topics of biological complexity ranging from structural biology to cellular dynamics were addressed herein. In this sense, we sought to address certain pre-specified questions including: (i) What happens when creatine is transported into cells? (ii) How is the CK/PCr system involved in cellular bioenergetics? (iii) How is the CK/PCr system compartmentalized throughout the cell? (iv) What is the role of creatine amongst different tissues? and (v) What is the basis of creatine transport? Under the cellular allostasis paradigm, the CK/PCr system is physiologically essential for life (cell survival, growth, proliferation, differentiation, and migration/motility) by providing an evolutionary advantage for rapid, local, and temporal support of energy- and mechanical-dependent processes. Thus, we suggest the CK/PCr system acts as a dynamic biosensor based on chemo-mechanical energy transduction, which might explain why dysregulation in Cr metabolism contributes to a wide range of diseases besides the mitigating effect that Cr supplementation may have in some of these disease states.

Keywords: bioinformatics; cell survival; cellular allostasis; creatine kinase; dynamic biosensor; energy metabolism; systems biology.

Conflict of interest statement

D.A.B. serves as science product manager for MTX Corporation®, a company that produces, distributes, sells and does research on dietary supplements (including creatine) in Europe, has acted as scientific consultant for MET-Rx and Healthy Sports in Colombia, and has received honoraria for speaking about creatine at international conferences. R.B.K. has conducted industry sponsored research on creatine, received financial support for presenting on creatine at industry sponsored scientific conferences, and has served as an expert witness on cases related to creatine. Additionally, he serves as Chair of the “Creatine in Health” Scientific Advisory Board for AlzChem Tostberg GmbH who sponsored this special issue. J.R.S. has conducted industry-sponsored research on creatine and other nutraceuticals over the past 25 years. Further, J.R.S has also received financial support for presenting on the science of various nutraceuticals, except creatine, at industry-sponsored scientific conferences. D.A.F. has been previously supported by grants from MinCiencias but not related to creatine. C.M.K. have consulted with and received external funding from companies who sell certain dietary ingredients, and have received remuneration from companies for delivering scientific presentations at conferences. M.D.R. has received academic and industry funding related to dietary supplements, served as a non-paid consultant for industry and received honoraria for speaking at various conferences. E.S.R. has conducted industry-sponsored research on creatine and received financial support for presenting on creatine at industry-sponsored scientific conferences. R.B.K. acts as chair of the “Creatine in Health” scientific advisory board for AlzChem Tostberg GmbH while all other authors serve as members (except D.A.F.).

Figures

Figure 1
Figure 1
Creatine synthesis/excretion and the creatine kinase reaction. Enzymes are represented by ovals. Once synthesized from L-arginine, glycine, and S-adenosyl-L-methionine, creatine (Cr) is converted to phosphocreatine (PCr) by means of the creatine kinase (CK), which catalyzes the reversible transference of a phosphoryl group (PO32−), not a phosphate (PO43−), from ATP. The kinetic rate of the non-enzymatic conversion of Cr (or PCr) to creatinine (Crn) depends on the H+ concentration of the media. It is important to note that neither Crn nor PCr are substrates of the sodium- and chloride-dependent creatine transporter (not shown). Oval size represents the expression level of AGAT (black), GAMT (white), and CK (orange) in some tissues. For more details related to expression in different tissues or conditions (i.e., pathologies) use the following BioGPS ID numbers: AGAT–2628; GAMT–2593. AGAT: L-Arginine-Glycine amidinotransferase; GAMT: Guanidinoacetate N-Methyltransferase; H+: hydrogen ion; Pi: inorganic phosphate. Modified with permission from Bonilla and Moreno [7] using the Freeware ACD/ChemSketch 2021 (Advanced Chemistry Development, Inc., Toronto, ON, Canada).
Figure 2
Figure 2
Clustering of CK-interacting proteins using the Markov Cluster Algorithm. Network nodes represent proteins while edges represent protein–protein associations. The red cluster includes a subgroup of enzymes participating in the tricarboxylic acid cycle that are represented in the graph with blue nodes. To visualize our interactive network access to this permanent link: https://version-11-0b.string-db.org/cgi/network?networkId=bu20zAE45PpB (accessed on 14 February 2021).
Figure 3
Figure 3
General overview of the CK/PCr system. The diagram represents the super-connected subcellular energy production and cellular mechanics of Cr metabolism. This chemo-mechanical energy transduction network involves structural and functional coupling of the mitochondrial reticulum (mitochondrial interactosome and oxidative metabolism), phosphagen and glycolytic system (extramitochondrial ATP production), the linker of nucleoskeleton and cytoskeleton complex (nesprins interaction with microtubules, actin polymerization, β-tubulins), motor proteins (e.g., myofibrillar ATPase machinery, vesicles transport), and ion pumps (e.g., SERCA, Na+/K+-ATPase). The cardiolipin-rich domain is represented by parallel black lines. Green sparkled circles represent the subcellular processes where the CK/PCr system is important for functionality (see the previous sections for rationale and citations). Several proteins of the endoplasmic reticulum–mitochondria organizing network (ERMIONE), the SERCA complex, the TIM/TOM complex, the MICOS complex, the linker of nucleoskeleton and cytoskeleton complex, and the architecture of sarcomere and cytoskeleton are not depicted for readability. ANT: adenine nucleotide translocase; CK: creatine kinase; Cr: creatine; Crn: creatinine; CRT: Na+/Cl−-dependent creatine transporter; ERMES: endoplasmic reticulum-mitochondria encounter structure; ETC: electron transport chain; GLUT-4: glucose transporter type 4; HK: hexokinase; mdm10: mitochondrial distribution and morphology protein 10; MICOS: mitochondrial contact site and cristae organizing system; NDPK: nucleoside-diphosphate kinase; NPC: nuclear pore complex; PCr: phosphocreatine; SAM: sorting and assembly machinery; SERCA: Sarco/Endoplasmic Reticulum Ca2+ ATPase; TIM: translocase of the inner membrane complex; TOM: translocase of the outer membrane complex; UCP: uncoupling protein; VDAC: voltage-dependent anion channel. Source: designed by the authors (D.A.B.) using figure templates developed by Servier Medical Art (Les Laboratoires Servier, Suresnes, France), licensed under a Creative Common Attribution 3.0 Generic License. http://smart.servier.com/ (accessed on 14 January 2021).
Figure 4
Figure 4
Importance of Cr metabolism in whole-body physiology. The CK/PCr system is essential for the chemo-mechanical energy transduction of cells/tissues with high, fluctuant, and constant energy demands. Source: designed by the authors (D.A.B.) using an anatomy template developed by 3dMediSphere (https://www.turbosquid.com/), licensed 3D standard Vray 3.60. accessed on 14 February 2020.

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Source: PubMed

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