Elsevier

Neuroscience

Volume 112, Issue 2, 18 June 2002, Pages 243-260
Neuroscience

Commentary
Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?

https://doi.org/10.1016/S0306-4522(02)00088-XGet rights and content

Abstract

Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine:glycine amidinotransferase (AGAT), S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT), and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity.

Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency. In addition, creatine supplementation displayed neuroprotective effects in several animal models of neurological disease, such as Huntington’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis. All these findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphorylcreatine/creatine system and proper brain function. They also offer a starting-point for novel means of delaying neurodegenerative disease, and/or for strengthening memory function and intellectual capabilities.

Finally, creatine biosynthesis has been postulated as a major effector of homocysteine concentration in the plasma, which has been identified as an independent graded risk factor for atherosclerotic disease. By decreasing homocysteine production, oral creatine supplementation may, thus, also lower the risk for developing, e.g., coronary heart disease or cerebrovascular disease.

Although compelling, these results require further confirmation in clinical studies in humans, together with a thorough evaluation of the safety of oral creatine supplementation.

Section snippets

The first 150 years of creatine research

Creatine (from the Greek kreas, flesh) was first isolated from meat extract by Chevreul (1835) (Table 1). It took almost another hundred years until Fiske and Subbarow (1927) and Eggleton and Eggleton (1927) discovered PCr which, because of its labile nature, was also called ‘phosphagen’. Lundsgaard (1930) showed that muscle contraction is accompanied by PCr breakdown rather than lactate production, and therefore proposed that PCr plays a central role in energy supply for muscle contraction.

Insights from CK knockout mice: the problem of redundancy

Stimulated by the findings on sea urchin spermatozoa (see above), many researchers in the field expected CK knockout mice to confirm the critical importance of the CK/PCr/Cr system for high-energy phosphate metabolism and transport. Surprisingly, however, most CK knockout mice displayed rather mild phenotypes (for a review, see Wyss and Kaddurah-Daouk, 2000).

In higher vertebrates, four CK isoenzymes are present. The muscle cytosolic isoform of CK (M-CK) and sarcomeric Mi-CK (Mib-CK) are found

Inborn errors of creatine metabolism

In order to more fully comprehend the clinical manifestations associated with Cr biosynthesis disorders, it seems important to provide a short introduction into the basics of Cr metabolism in humans (for a review see Wyss and Kaddurah-Daouk, 2000). Cr is either taken up from the food by intestinal absorption, and/or is synthesized endogenously, primarily in kidney, pancreas, and liver. Arginine:glycine amidinotransferase (AGAT) catalyzes the reversible transamidination of the guanidino group

Health—beneficial effects of creatine and its analogues: oral creatine supplementation as a multi-purpose prevention strategy?

A considerable list of health benefits have been reported or proposed for oral supplementation with Cr and/or its analogues (Table 2; for a review, see Wyss and Kaddurah-Daouk, 2000). Based on this list, one might be inclined to consider Cr and its analogues promising pharmaceutical drugs. The following thoughts and arguments, however, are intended to help put the current knowledge on the potential benefits and limitations of oral Cr supplementation into context.

  • 1.

    Since disruption of the

Neuroprotective effects of creatine

Despite the fact that neurological disorders are caused by many different primary defects, they often converge to display similar impairments in cellular energy metabolism in the brain. In these instances, intracellular concentration of ATP is decreased, resulting in cytosolic accumulation of Ca2+ and stimulation of formation of reactive oxygen species (ROS). Ca2+ and ROS, in turn, trigger apoptotic or necrotic cell death (see Fig. 1). For many of these disorders, impairments of brain Cr

Potential of creatine supplementation in lowering plasma homocysteine concentration

Homocysteine has been suggested to be an independent, graded risk factor for atherosclerotic disease affecting coronary, cerebral and/or peripheral vessels (for reviews, see Boers, 1998, Welch and Loscalzo, 1998, Selhub, 1999, Hankey and Eikelboom, 1999). For instance, a 5-μM increment in total homocysteine plasma level was found to be associated with an increased risk for developing coronary heart disease of 60% for men and 80% for women. Additional studies have demonstrated associations

Safety of oral creatine supplementation

Little in the area of Cr metabolism has been discussed so controversially over the last several months and years as the safety of oral Cr supplementation. Rather than to further polarize the discussion, this section tries to provide a comprehensive overview of the perceived and potential risks of oral Cr supplementation. As such, this section may serve as a rational basis for educated decisions on when and how broadly to allow and/or advocate oral Cr supplementation for ergogenic or preventive

Conclusions

Although Cr was discovered 170 years ago, and despite its astounding success as an ergogenic aid since the 1990s, much is still unknown about its biological functions. This is particularly true for its potential in disease prevention. Recent progress in different areas of research has consistently shown that there may be a tight correlation between the capacity of the CK system and brain function. Inborn errors of Cr metabolism in humans and knockout mice lacking CK activity in the brain are

Note added in Proof

In the context of the present article, three notable articles have recently been published. Watanabe et al. (2002) present evidence that Cr supplementation reduces mental fatigue when subjects repeatedly perform simple mathematical calculations. According to Jacobs et al. (2002), creatine supplementation enhances upper extremity work capacity in subjects with complete cervical-level spinal cord injury. And finally, Lawler et al. (2002) demonstrate direct antioxidant effects of creatine.

Acknowledgments

The participants of the 6th International Conference on Guanidíno Compounds in Biology and Medicine (Cincinnati, OH, USA, 31 August–3 September 2001) and, in particular, Joseph F. Clark, are gratefully acknowledged for stimulating discussions.

References (147)

  • J.W. Edmunds et al.

    Creatine supplementation increases renal disease progression in Han:SPRD-cy rats

    Am. J. Kidney Dis.

    (2001)
  • V. Ganesan et al.

    Guanidinoacetate methyltransferase deficiency: new clinical features

    Pediatr. Neurol.

    (1997)
  • A.S. Graham et al.

    Creatine: a review of efficacy and safety

    J. Am. Pharmacol. Assoc.

    (1999)
  • G.J. Hankey et al.

    Homocysteine and vascular disease

    Lancet

    (1999)
  • D. Holtzman et al.

    Brain creatine phosphate and creatine kinase in mice fed an analogue of creatine

    Brain Res.

    (1989)
  • C.B. Item et al.

    Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans

    Am. J. Hum. Genet.

    (2001)
  • P.L. Jacobs et al.

    Oral creatine supplementation enhances upper extremity work capacity in persons with cervical-level spinal cord injury

    Arch. Phys. Med. Rehabil.

    (2002)
  • M.S. Juhn et al.

    Oral creatine supplementation in male collegiate athletes: a survey of dosing habits and side effects

    J. Am. Diet. Assoc.

    (1999)
  • W.F. Kaemmerer et al.

    Creatine-supplemented diet extends Purkinje cell survival in spinocerebellar ataxia type 1 transgenic mice but does not prevent the ataxic phenotype

    Neuroscience

    (2001)
  • L. Kay et al.

    Direct evidence for the control of mitochondrial respiration by mitochondrial creatine kinase in oxidative muscle cells in situ

    J. Biol. Chem.

    (2000)
  • J.M. Lawler et al.

    Direct antioxidant properties of creatine

    Biochem. Biophys. Res. Commun.

    (2002)
  • S. Lussier-Cacan et al.

    Plasma total homocysteine in healthy subjects: sex-specific relation with biological traits

    Am. J. Clin. Nutr.

    (1996)
  • C. Malcon et al.

    Neuroprotective effects of creatine administration against NMDA and malonate toxicity

    Brain Res.

    (2000)
  • L. Massieu et al.

    Neurotoxicity of glutamate uptake inhibition in vivo: correlation with succinate dehydrogenase activity and prevention by energy substrates

    Neuroscience

    (2001)
  • R.T. Matthews et al.

    Creatine and cyclocreatine attenuate MPTP neurotoxicity

    Exp. Neurol.

    (1999)
  • L. Mazzini et al.

    Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results

    J. Neurol. Sci.

    (2001)
  • M.F. McCarty

    Supplemental creatine may decrease serum homocysteine and abolish the homocysteine ‘gender gap’ by suppressing endogenous creatine synthesis

    Med. Hypotheses

    (2001)
  • S.H. Mudd et al.

    Labile methyl group balances in the human: the role of sarcosine

    Metabolism

    (1980)
  • S.R. Ness et al.

    Does supplemental creatine prevent herpes recurrences?

    Med. Hypotheses

    (2001)
  • S. Neubauer et al.

    Manipulating creatine levels post-myocardial infarction – chronic effects on left ventricular remodeling

    Magn. Reson. Mater. Phys. Biol. Med.

    (1998)
  • A.C. Passaquin et al.

    Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice

    Neuromusc. Disord.

    (2002)
  • N.R. Pritchard et al.

    Renal dysfunction accompanying oral creatine supplements

    Lancet

    (1998)
  • D. Pucar et al.

    Cellular energetics in the preconditioned state: protective role for phosphotransfer reactions captured by 18O-assisted 31P NMR

    J. Biol. Chem.

    (2001)
  • D. Pucar et al.

    Compromised energetics in the adenylate kinase AK1 gene knockout heart under metabolic stress

    J. Biol. Chem.

    (2000)
  • AFSSA, 2001. Avis de l’Agence française de sécurité sanitaire des aliments relatif à l’évaluation des risques présentés...
  • O.A. Andreassen et al.

    Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation

    J. Neurochem.

    (2001)
  • N.B. Bajuk

    Therapeutic comparison of metformin and creatine in the glycemic control of patients with type 2 diabetes mellitus

    Diabetes

    (2001)
  • A. Baylis et al.

    Inadvertent doping through supplement use by athletes: assessment and management of the risk in Australia

    Int. J. Sport Nutr. Exerc. Metab.

    (2001)
  • G. Benzi et al.

    Creatine as nutritional supplementation and medicinal product

    J. Sports Med. Phys. Fitness

    (2001)
  • S. Bermon et al.

    Effects of creatine monohydrate ingestion in sedentary and weight-trained older adults

    Acta Physiol. Scand.

    (1998)
  • S.P. Bessman et al.

    Transport of energy in muscle: the phosphorylcreatine shuttle

    Science

    (1981)
  • M.C. Bianchi et al.

    Reversible brain creatine deficiency in two sisters with normal blood creatine level

    Ann. Neurol.

    (2000)
  • G. Boers

    Moderate hyperhomocysteinaemia and vascular disease: evidence, relevance and the effect of treatment

    Eur. J. Pediatr.

    (1998)
  • A. Borchert et al.

    Supplementation with creatine monohydrate in children with mitochondrial encephalomyopathies

    Muscle Nerve

    (1999)
  • G.J. Brewer et al.

    Protective effect of the energy precursor creatine against toxicity of glutamate and β-amyloid in rat hippocampal neurons

    J. Neurochem.

    (2000)
  • N. Brustovetsky et al.

    On the mechanisms of neuroprotection by creatine and phosphocreatine

    J. Neurochem.

    (2001)
  • A.J. Carrasco et al.

    Adenylate kinase phosphotransfer communicates cellular energetic signals to ATP-sensitive potassium channels

    Proc. Natl. Acad. Sci. USA

    (2001)
  • Cecil, K.M., Degrauw, T.J., 2001. The clinical syndrome of creatine transporter deficiency. Oral presentation, 6th...
  • K.M. Cecil et al.

    Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect?

    Ann. Neurol.

    (2001)
  • Chevreul

    Sur la composition chimique du bouillon de viandes

    J. Pharm. Sci. Accessoires

    (1835)
  • Cited by (170)

    • Creatine monohydrate for mitochondrial nutrition

      2023, Molecular Nutrition and Mitochondria: Metabolic Deficits, Whole-Diet Interventions, and Targeted Nutraceuticals
    View all citing articles on Scopus
    View full text