Metabolism and Role of Creatine: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Maurizio Balestrino.

Creatine is a key player in  energy metabolism of excitable cells. This is an essential outline of its role and procurement by the organism, adapted by the author (Balestrino M, University of Genoa, Italy) from his Open Access paper  Role of Creatine in the Heart: Health and Disease, that was published in Nutrients, 2021; 13(4):1215. https://doi.org/10.3390/nu13041215.

  • phosphocreatine
  • creatine transporter
  • supplementation
  • creatine

1. Functions of Creatine

Creatine plays a key role in cellular energy metabolism. The creatine kinase enzyme reversibly phosphorylates it to phosphocreatine. Then, when phosphocreatine is reverted to creatine, its phosphate bond breaks, and such a break provides enough energy to allow phosphorylating a molecule of adenosine diphosphate (ADP) to adenosine triphosphate (ATP). Thus, phosphocreatine acts as an energy reserve to synthesize ATP rapidly, with no need for oxygen. The reaction is the following one:

Creatine + ATP ⇆ Phosphocreatine + ADP + H

+

This reaction plays a crucial role in heart contraction [1]. Its roles have been reviewed elsewhere [2] and are, in summary:

(1) Transfer of ATP from its production site (mitochondria) to its place of exploitation (neuronal membrane or cytoplasm). This function is often called “the ATP shuttle”. To carry out this transport (“shuttle”) of ATP energy, creatine first receives the phosphate from ATP near the mitochondria, becoming phosphocreatine. It then diffuses through its concentration gradient to the periphery of the cell. Near cytoplasmic ATPase, it donates its phosphate to ADP, effectively forming ATP far away from the mitochondria and delivering it precisely where and when it is required. In doing so, it reverts to creatine and diffuses back, again along its concentration gradient, to the mitochondrion to start the cycle again. The reason why the cell needs this complex mechanism to transport energy between mitochondria and cytoplasmic ATPase is that ATP is a very large molecule, therefore its diffusion through the organelle-filled cytoplasm is slow and cumbersome. By contrast, phosphocreatine is a much smaller molecule, thus it diffuses more quickly through the cytoplasm.

(2) Restoration by phosphocreatine of ATP concentration in conditions of increased energy demand and in diseases involving a reduced supply of blood or oxygen. In the first scenario, the consumption of ATP is excessive compared to the ability of the cell to synthesize it. For instance, a muscle exposed to a particularly intense effort quickly uses more ATP than it can produce, thus exhausting its reserve. In the second scenario, an organ cannot produce enough ATP because of a blood deficiency (ischemia) or an oxygen deficiency (anoxia). For example, in case of a myocardial infarction, phosphocreatine intervenes by transferring its phosphoric group to ADP, to provide ATP at a time when the heart cannot synthesize it due to ischemia.

Among all the biochemical reactions that our cells use to synthesize ATP, the one that starts from the creatine/phosphocreatine system is the quickest in buffering ATP levels at times of increased energy expenditure [3]. This explains the researchers’ interest in this molecule, whose administration has been proposed in various conditions, both physiological and pathological [4,5].

Among all the biochemical reactions that our cells use to synthesize ATP, the one that starts from the creatine/phosphocreatine system is the quickest in buffering ATP levels at times of increased energy expenditure [3]. This explains the researchers’ interest in this molecule, whose administration has been proposed in various conditions, both physiological and pathological [4][5].

2. Procurement of Creatine by the Organism, with Specific Reference to the Heart

Creatine is normally degraded to creatinine [6], leading to a steady depletion of the body creatine store. The creatine store is replenished partly from endogenous synthesis and partly by ingesting creatine with food [7].

2.1. Endogenous Synthesis of Creatine

In the body as a whole, creatine is synthesized in the kidney and in the liver [6]. Specifically, the kidney accomplishes the first step of the synthesis, forming guanidinoacetic acid from arginine and glycine. Guanidinoacetic acid is then transported to the liver, where it is converted into creatine with the intervention of the methyl donor S-adenosyl-methionine [6]. Specific organs can additionally synthesize creatine for their own consumption, such as the brain [8] and the testis [9,10]. Concerning the heart, it is generally believed that cardiomyocytes cannot synthesize creatine [11,12]. However, there is evidence that such synthesis may actually occur, i.e., cardiomyocytes may indeed synthesize creatine just as other organs do. In fact, the heart expresses the first enzyme of creatine synthesis, arginine-glycine amidino transferase (AGAT). Its expression in the heart is comparable to that of other tissues under basal conditions and increases several fold in pathological states [13]. Moreover, experiments showed that the addition of arginine (a precursor of creatine) to the incubation medium of toad hearts mitigated the decrease in creatine upon in vitro incubation, as if arginine was metabolized to creatine [14]. Furthermore, the addition of arginine to isolated rabbit hearts caused an increase in their content of creatinine (the product of creatine cyclization) [15]. Both these latter experiments strongly suggested that in the isolated heart arginine is indeed converted into creatine, as it is in other organs [16,17]. However, the possible creatine synthesis by the heart has received so far very little attention, and additional research is definitely warranted [18].

In the body as a whole, creatine is synthesized in the kidney and in the liver [6]. Specifically, the kidney accomplishes the first step of the synthesis, forming guanidinoacetic acid from arginine and glycine. Guanidinoacetic acid is then transported to the liver, where it is converted into creatine with the intervention of the methyl donor S-adenosyl-methionine [6]. Specific organs can additionally synthesize creatine for their own consumption, such as the brain [8] and the testis [9][10]. Concerning the heart, it is generally believed that cardiomyocytes cannot synthesize creatine [11][12]. However, there is evidence that such synthesis may actually occur, i.e., cardiomyocytes may indeed synthesize creatine just as other organs do. In fact, the heart expresses the first enzyme of creatine synthesis, arginine-glycine amidino transferase (AGAT). Its expression in the heart is comparable to that of other tissues under basal conditions and increases several fold in pathological states [13]. Moreover, experiments showed that the addition of arginine (a precursor of creatine) to the incubation medium of toad hearts mitigated the decrease in creatine upon in vitro incubation, as if arginine was metabolized to creatine [14]. Furthermore, the addition of arginine to isolated rabbit hearts caused an increase in their content of creatinine (the product of creatine cyclization) [15]. Both these latter experiments strongly suggested that in the isolated heart arginine is indeed converted into creatine, as it is in other organs [16][17]. However, the possible creatine synthesis by the heart has received so far very little attention, and additional research is definitely warranted [18].

2.2. Uptake of Creatine from Dietary or Supplement Sources

About half of the creatine that the organism needs is normally ingested and taken up from dietary sources [19]. Creatine is not present in vegetables, but it is only present in foods of animal origin [4]. Thus, subjects who do not regularly consume meat or fish tend to have some degree of creatine deficiency, and should supplement their diet with it [4].

Moreover, exogenous supplementation of creatine permits administering high amounts of this compound, and increasing its content above normal levels [20,21,22]. Throughout the paper, only supplementation with creatine monohydrate will be reviewed, as this is by far the most used and best-known way of supplementing creatine. When administered in this way at adequate doses, creatine is stored in the tissues, where it increases the intracellular pool of both creatine and phosphocreatine. Such an increase is especially relevant for the muscular tissue. Creatine supplementation allows the muscles to contract more powerfully and to a longer extent [23], an effect that is exploited by athletes to improve their performance [24,25].

Moreover, exogenous supplementation of creatine permits administering high amounts of this compound, and increasing its content above normal levels [20][21][22]. Throughout the paper, only supplementation with creatine monohydrate will be reviewed, as this is by far the most used and best-known way of supplementing creatine. When administered in this way at adequate doses, creatine is stored in the tissues, where it increases the intracellular pool of both creatine and phosphocreatine. Such an increase is especially relevant for the muscular tissue. Creatine supplementation allows the muscles to contract more powerfully and to a longer extent [23], an effect that is exploited by athletes to improve their performance [24][25].

 

Specific mechanisms of the benefit provided by creatine supplementation include:

Specific mechanisms of the benefit provided by creatine supplementation include:

  • Restoration of normal creatine content when it is lower than normal due to lifestyle (e.g., vegetarian or vegan subjects [26]) or to disease (e.g., heart failure, see below).

  • Increase in energy availability (obtained by increasing phosphocreatine concentration in the tissue) in cases where the balance between energy availability and requirement is limited by decreased energy production (as is the case in hypoxia or ischemia), or by increased demand (e.g., the muscle of athletes during athletic performance).

  • Restoration of normal creatine content when it is lower than normal due to lifestyle (e.g., vegetarian or vegan subjects [26]) or to disease (e.g., heart failure, see below).
  • Increase in energy availability (obtained by increasing phosphocreatine concentration in the tissue) in cases where the balance between energy availability and requirement is limited by decreased energy production (as is the case in hypoxia or ischemia), or by increased demand (e.g., the muscle of athletes during athletic performance).

Finally, we should note that creatine by itself does not enter cells, instead it needs a specific transporter to cross plasma membranes [16]. The same happens in the heart, where the creatine transporter is present on the plasma membrane of the myocytes and is necessary for creatine to enter myocardial cells [27,28].

References

  1. Ventura-Clapier, R.; Vassort, G. The Hypodynamic State of the Frog Heart. Further Evidence for a Phosphocreatine-Creatine Pathway. J Physiol (Paris) 1980, 76, 583–589.
  2. Wallimann, T.; Tokarska-Schlattner, M.; Schlattner, U. The Creatine Kinase System and Pleiotropic Effects of Creatine. Amino acids 2011, 40, 1271–1296, doi:10.1007/s00726-011-0877-3.
  3. Sahlin, K.; Harris, R.C. The Creatine Kinase Reaction: A Simple Reaction with Functional Complexity. Amino Acids 2011, 40, 1363–1367, doi:10.1007/s00726-011-0856-8.
  4. Balestrino, M.; Adriano, E. Beyond Sports: Efficacy and Safety of Creatine Supplementation in Pathological or Paraphysiological Conditions of Brain and Muscle. Med Res Rev 2019, doi:10.1002/med.21590.
  5. Balestrino, M.; Sarocchi, M.; Adriano, E.; Spallarossa, P. Potential of Creatine or Phosphocreatine Supplementation in Cerebrovascular Disease and in Ischemic Heart Disease. Amino Acids 2016, 48, 1955–1967, doi:10.1007/s00726-016-2173-8.
  6. Wyss, M.; Kaddurah-Daouk, R. Creatine and Creatinine Metabolism. Physiological Reviews 2000, 80, 1107–1213, doi:10.1152/physrev.2000.80.3.1107.
  7. Casey, A.; Greenhaff, P.L. Does Dietary Creatine Supplementation Play a Role in Skeletal Muscle Metabolism and Performance? American Journal of Clinical Nutrition 2000, 72, 607S-617S.
  8. Hanna-El-Daher, L.; Braissant, O. Creatine Synthesis and Exchanges between Brain Cells: What Can Be Learned from Human Creatine Deficiencies and Various Experimental Models? Amino Acids 2016, 48, 1877–1895, doi:10.1007/s00726-016-2189-0.
  9. Koszalka, T.R. Creatine Synthesis in the Testis. Proceedings of the Society for Experimental Biology and Medicine 1968, 128, 1130–1137, doi:10.3181/00379727-128-33212.
  10. Lee, H.; Kim, J.H.; Chae, Y.J.; Ogawa, H.; Lee, M.H.; Gerton, G.L. Creatine Synthesis and Transport Systems in the Male Rat Reproductive Tract. Biol Reprod 1998, 58, 1437–1444, doi:10.1095/biolreprod58.6.1437.
  11. Lygate, C.A.; Bohl, S.; ten Hove, M.; Faller, K.M.E.; Ostrowski, P.J.; Zervou, S.; Medway, D.J.; Aksentijevic, D.; Sebag-Montefiore, L.; Wallis, J.; et al. Moderate Elevation of Intracellular Creatine by Targeting the Creatine Transporter Protects Mice from Acute Myocardial Infarction. Cardiovasc Res 2012, 96, 466–475, doi:10.1093/cvr/cvs272.
  12. Zervou, S.; Whittington, H.J.; Russell, A.J.; Lygate, C.A. Augmentation of Creatine in the Heart. Mini Rev Med Chem 2016, 16, 19–28, doi:10.2174/1389557515666150722102151.
  13. Cullen, M.E.; Yuen, A.H.Y.; Felkin, L.E.; Smolenski, R.T.; Hall, J.L.; Grindle, S.; Miller, L.W.; Birks, E.J.; Yacoub, M.H.; Barton, P.J.R. Myocardial Expression of the Arginine:Glycine Amidinotransferase Gene Is Elevated in Heart Failure and Normalized after Recovery: Potential Implications for Local Creatine Synthesis. Circulation 2006, 114, I16-20, doi:10.1161/CIRCULATIONAHA.105.000448.
  14. Nekhorocheff, J. [Degradation and synthesis of creatine in isolated toad heart]. C R Hebd Seances Acad Sci 1955, 240, 1284–1285.
  15. Fisher, R.B.; Wilhelmi, A.E. The Metabolism of Creatine: The Conversion of Arginine into Creatine in the Isolated Rabbit Heart. Biochem J 1937, 31, 1136–1156, doi:10.1042/bj0311136.
  16. Snow, R.J.; Murphy, R.M. Creatine and the Creatine Transporter: A Review. Mol Cell Biochem 2001, 224, 169–181, doi:10.1023/a:1011908606819.
  17. Wyss, M.; Kaddurah-Daouk, R. Creatine and Creatinine Metabolism. Physiol. Rev. 2000, 80, 1107–1213, doi:10.1152/physrev.2000.80.3.1107.
  18. Ingwall, J.S. On the Hypothesis That the Failing Heart Is Energy Starved: Lessons Learned from the Metabolism of ATP and Creatine. Curr Hypertens Rep 2006, 8, 457–464, doi:10.1007/s11906-006-0023-x.
  19. Brosnan, M.E.; Brosnan, J.T. The Role of Dietary Creatine. Amino Acids 2016, 48, 1785–1791, doi:10.1007/s00726-016-2188-1.
  20. Harris, R.C.; Söderlund, K.; Hultman, E. Elevation of Creatine in Resting and Exercised Muscle of Normal Subjects by Creatine Supplementation. Clin Sci (Lond) 1992, 83, 367–374, doi:10.1042/cs0830367.
  21. Ipsiroglu, O.S.; Stromberger, C.; Ilas, J.; Höger, H.; Mühl, A.; Stöckler-Ipsiroglu, S. Changes of Tissue Creatine Concentrations upon Oral Supplementation of Creatine-Monohydrate in Various Animal Species. Life Sci 2001, 69, 1805–1815, doi:10.1016/s0024-3205(01)01268-1.
  22. Dechent, P.; Pouwels, P.J.W.; Wilken, B.; Hanefeld, F.; Frahm, J. Increase of Total Creatine in Human Brain after Oral Supplementation of Creatine-Monohydrate. American Journal of Physiology - Regulatory Integrative and Comparative Physiology 1999, 277, R698–R704.
  23. Sweeney, H.L. The Importance of the Creatine Kinase Reaction: The Concept of Metabolic Capacitance. Med Sci Sports Exerc 1994, 26, 30–36.
  24. Peeling, P.; Binnie, M.J.; Goods, P.S.R.; Sim, M.; Burke, L.M. Evidence-Based Supplements for the Enhancement of Athletic Performance. International Journal of Sport Nutrition and Exercise Metabolism 2018, 28, 178–187, doi:10.1123/ijsnem.2017-0343.
  25. Kreider, R.B.; Kalman, D.S.; Antonio, J.; Ziegenfuss, T.N.; Wildman, R.; Collins, R.; Candow, D.G.; Kleiner, S.M.; Almada, A.L.; Lopez, H.L. International Society of Sports Nutrition Position Stand: Safety and Efficacy of Creatine Supplementation in Exercise, Sport, and Medicine. Journal of the International Society of Sports Nutrition 2017, 14, doi:10.1186/s12970-017-0173-z.
  26. Blancquaert, L.; Baguet, A.; Bex, T.; Volkaert, A.; Everaert, I.; Delanghe, J.; Petrovic, M.; Vervaet, C.; De Henauw, S.; Constantin-Teodosiu, D.; et al. Changing to a Vegetarian Diet Reduces the Body Creatine Pool in Omnivorous Women, but Appears Not to Affect Carnitine and Carnosine Homeostasis: A Randomised Trial. Br. J. Nutr. 2018, 119, 759–770, doi:10.1017/S000711451800017X.
  27. Guimbal, C.; Kilimann, M.W. A Na(+)-Dependent Creatine Transporter in Rabbit Brain, Muscle, Heart, and Kidney. CDNA Cloning and Functional Expression. J Biol Chem 1993, 268, 8418–8421.
  28. Fischer, A.; Ten Hove, M.; Sebag-Montefiore, L.; Wagner, H.; Clarke, K.; Watkins, H.; Lygate, C.A.; Neubauer, S. Changes in Creatine Transporter Function during Cardiac Maturation in the Rat. BMC Dev Biol 2010, 10, 70, doi:10.1186/1471-213X-10-70.

 

Finally, we should note that creatine by itself does not enter cells, instead it needs a specific transporter to cross plasma membranes [16]. The same happens in the heart, where the creatine transporter is present on the plasma membrane of the myocytes and is necessary for creatine to enter myocardial cells [27][28].

References

  1. Ventura-Clapier, R.; Vassort, G. The hypodynamic state of the frog heart. Further evidence for a phosphocreatine—Creatine pathway. J. Physiol. 1980, 76, 583–589.
  2. Wallimann, T.; Tokarska-Schlattner, M.; Schlattner, U. The Creatine kinase system and pleiotropic Effects of creatine. Amino Acids 2011, 40, 1271–1296.
  3. Sahlin, K.; Harris, R.C. The Creatine Kinase Reaction: A Simple reaction with functional complexity. Amino Acids 2011, 40, 1363–1367.
  4. Balestrino, M.; Adriano, E. Beyond sports: Efficacy and Safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle. Med. Res. Rev. 2019, 39.
  5. Balestrino, M.; Sarocchi, M.; Adriano, E.; Spallarossa, P. Potential of Creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease. Amino Acids 2016, 48, 1955–1967.
  6. Wyss, M.; Kaddurah-Daouk, R. Creatine and creatinine metabolism. Physiol. Rev. 2000, 80, 1107–1213.
  7. Casey, A.; Greenhaff, P.L. Does Dietary Creatine Supplementation Play a Role in Skeletal Muscle Metabolism and Performance? Am. J. Clin. Nutr. 2000, 72, 607S–617S.
  8. Hanna-El-Daher, L.; Braissant, O. Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models? Amino Acids 2016, 48, 1877–1895.
  9. Koszalka, T.R. Creatine synthesis in the testis. Proc. Soc. Exp. Biol. Med. 1968, 128, 1130–1137.
  10. Lee, H.; Kim, J.H.; Chae, Y.J.; Ogawa, H.; Lee, M.H.; Gerton, G.L. Creatine synthesis and transport systems in the male rat reproductive tract. Biol. Reprod. 1998, 58, 1437–1444.
  11. Lygate, C.A.; Bohl, S.; ten Hove, M.; Faller, K.M.E.; Ostrowski, P.J.; Zervou, S.; Medway, D.J.; Aksentijevic, D.; Sebag-Montefiore, L.; Wallis, J.; et al. Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction. Cardiovasc. Res. 2012, 96, 466–475.
  12. Zervou, S.; Whittington, H.J.; Russell, A.J.; Lygate, C.A. Augmentation of creatine in the heart. Mini Rev. Med. Chem. 2016, 16, 19–28.
  13. Cullen, M.E.; Yuen, A.H.Y.; Felkin, L.E.; Smolenski, R.T.; Hall, J.L.; Grindle, S.; Miller, L.W.; Birks, E.J.; Yacoub, M.H.; Barton, P.J.R. Myocardial Expression of the arginine: Glycine Amidinotransferase gene is elevated in heart failure and normalized after recovery: Potential implications for local Creatine synthesis. Circulation 2006, 114 (Suppl. 1), I16–I20.
  14. Nekhorocheff, J. Degradation and synthesis of creatine in isolated toad heart. C. R. Hebd. Séance Acad. Sci. 1955, 240, 1284–1285.
  15. Fisher, R.B.; Wilhelmi, A.E. The Metabolism of creatine: The conversion of arginine into creatine in the isolated rabbit heart. Biochem. J. 1937, 31, 1136–1156.
  16. Snow, R.J.; Murphy, R.M. Creatine and the creatine transporter: A review. Mol. Cell Biochem. 2001, 224, 169–181.
  17. Marques, E.P.; Wyse, A.T.S. Creatine as a Neuroprotector: An Actor that Can Play Many Parts. Neurotox Res. 2019, 423, 411–423.
  18. Ingwall, J.S. On the hypothesis that the failing heart is energy starved: Lessons learned from the metabolism of ATP and creatine. Curr. Hypertens. Rep. 2006, 8, 457–464.
  19. Brosnan, M.E.; Brosnan, J.T. The role of dietary creatine. Amino Acids 2016, 48, 1785–1791.
  20. Harris, R.C.; Söderlund, K.; Hultman, E. Elevation of creatine in resting and exercised muscle of normal subjects by Creatine supplementation. Clin. Sci. 1992, 83, 367–374.
  21. Ipsiroglu, O.S.; Stromberger, C.; Ilas, J.; Höger, H.; Mühl, A.; Stöckler-Ipsiroglu, S. Changes of tissue creatine concentrations upon oral supplementation of Creatine-monohydrate in various animal species. Life Sci. 2001, 69, 1805–1815.
  22. Dechent, P.; Pouwels, P.J.W.; Wilken, B.; Hanefeld, F.; Frahm, J. Increase of total creatine in human brain after oral supplementation of Creatine-monohydrate. Am. J. Physiol. Regul. Integr. Comp. Physiol. 1999, 277, R698–R704.
  23. Sweeney, H.L. The Importance of the Creatine Kinase Reaction: The Concept of Metabolic Capacitance. Med. Sci. Sports Exerc. 1994, 26, 30–36.
  24. Peeling, P.; Binnie, M.J.; Goods, P.S.R.; Sim, M.; Burke, L.M. Evidence-based supplements for the enhancement of athletic performance. Int. J. Sport Nutr. Exerc. Metab. 2018, 28, 178–187.
  25. Kreider, R.B.; Kalman, D.S.; Antonio, J.; Ziegenfuss, T.N.; Wildman, R.; Collins, R.; Candow, D.G.; Kleiner, S.M.; Almada, A.L.; Lopez, H.L. International Society of Sports Nutrition Position Stand: Safety and efficacy of creatine supplementation in exercise, sport, and medicine. J. Int. Soc. Sports Nutr. 2017, 14.
  26. Blancquaert, L.; Baguet, A.; Bex, T.; Volkaert, A.; Everaert, I.; Delanghe, J.; Petrovic, M.; Vervaet, C.; De Henauw, S.; Constantin-Teodosiu, D.; et al. Changing to a vegetarian diet reduces the body creatine pool in omnivorous women, but appears not to affect carnitine and carnosine homeostasis: A randomised trial. Br. J. Nutr. 2018, 119, 759–770.
  27. Guimbal, C.; Kilimann, M.W. A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. CDNA cloning and functional expression. J. Biol. Chem. 1993, 268, 8418–8421.
  28. Fischer, A.; Ten Hove, M.; Sebag-Montefiore, L.; Wagner, H.; Clarke, K.; Watkins, H.; Lygate, C.A.; Neubauer, S. Changes in creatine transporter function during cardiac maturation in the rat. BMC Dev. Biol. 2010, 10, 70.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Feedback