Creatine

For the use of creatine to enhance athletic performance, please see Creatine supplements.

Creatine is nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to muscle and nerve cells. Creatine was identified in 1832 when Michel Eugène Chevreul discovered it as a component of skeletal muscle, which he later named creatine after the Greek word for flesh, Kreas.

Function

Creatine by way of conversion to and from phosphocreatine is present and functions in all vertebrates, as well as some invertebrates, in conjunction with the enzyme creatine kinase. A similar system based on arginine/phosphoarginine operates in many invertebrates via the action of Arginine Kinase. The presence of this energy buffer system keeps the ATP/ADP ratio high at subcellular places where ATP is needed, which ensures that the free energy of ATP remains high and minimizes the loss of adenosine nucleotides, which would cause cellular dysfunction. Such high-energy phosphate buffers in the form of phosphocreatine or phosphoarginine are known as phosphagens. In addition, due to the presence of subcompartmentalized Creatine Kinase Isoforms at specific sites of the cell, the phosphocreatine/creatine kinase system also acts as an intracellular energy transport system from those places where ATP is generated (mitochondria and glycolysis) to those places where energy is needed and used, e.g., at the myofibrils for muscle contraction, at the sarcoplasmic reticulum (SR) for calcium pumping, and at the sites of many more biological processes that depend on ATP.[9,10]

Biosynthesis

In the human body, approximately half of the daily creatine is biosynthesized mainly in the vertebrates by the use of parts from three different amino acids - arginine, glycine, and methionine. The rest is taken in by alimentary sources mainly from fresh fish and meat. Ninety-five percent of creatine is later stored in the skeletal muscles, with the rest in the brain, heart, testes, inner ear, hair cells, and other organs and cells.

File:CreatineSynthesis-GAMT.png

The pathway for the synthesis of creatine
Arg - Arginine; GAMT - Guanidinoacetate N-methyltransferase; GAMT - Glycine amidinotransferase; Gly - Glycine; Met - Methionine; SAH - S-adenosyl homocysteine; SAM - S-adenosyl methionine.

The color scheme is as follows:enzymes, coenzymes and the Met part, substrate names, the Gly part, the Arg part

The enzyme GAMT (guanidinoacetate N-methyltransferase, also known as L-arginine:glycine amidinotransferase (AGAT), EC 2.1.4.1) is a mitochondrial enzyme responsible for catalyzing the first rate-limiting step of creatine biosynthesis, and is primarily expressed in the kidneys and pancreas[1].

The second enzyme in the pathway (GAMT, guanidinoacetate N-methyltransferase, EC:2.1.1.2) is primarily expressed in the liver and pancreas[2].

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects[3].

Controversy

While creatine's effectiveness in the treatment of many muscular, neuromuscular, and neuro-degenerative diseases is documented, its utility as a performance-enhancing food supplement in sports has been questioned (see Creatine supplements for more information). Despite this, and perhaps because of its popularity, some have proposed that its use as a performance enhancer should be banned.

Side Effects

Continuous intake of excessively high dosages of creatine may lead to any of several possible side effects. It has been hypothesized that consistently high doses could lead to hypertension due to increased water retention . It can also cause dehydration by another mechanism. There is some discussion of kidney problems resulting from supplementation, as excess creatine is not broken down into nitrogenous wastes but instead released in a more benign form .

Creatine supplementation utilizing proper cycling and dosages, however, has not been linked with any adverse side effects beyond occasional dehydration due to increased muscular water uptake from the rest of the body.

According to the opinion statement of the European Food Safety Authorities (EFSA) published in 2004 it was concluded that "The safety and bioavailability of the requested source of creatine, creatine monohydrate in foods for particular nutritional uses, is not a matter of concern provided that there is adequate control of the purity of this source of creatine (minimum 99.95%) with respect to dicyandiamide and dihydro-1,3,5-triazine derivatives, as well as heavy metal contamination. The EFSA Panel endorses the previous opinion of the SCF that high loading doses (20 gram / day) of creatine should be avoided. Provided high purity creatine monohydrate is used in foods for particular nutritional uses, the Panel considers that the consumption of doses of up to 3g/day of supplemental creatine, similar to the daily turnover rate of creatine, is unlikely to pose any risk". Publication date of the EFSA Statement is 26/04/2006. EFSA statement

This opinion is corroborated by the fact that creatine is a natural component in mothers milk and that creatine is absolutely necessary for brain development in the human embryo and the baby, as well as for optimal physiological functioning of the adult human body, especially the brain, nervous system, the muscles and other organs and cells of high energy expenditure, where the creatine kinase (CK) system is highly expressed and creatine levels are high. For a scientific update on CK and creatine function see the recently published book Function of CK and Creatine in Health and Disease.

Sources

In humans, approximately half of stored creatine originates from food (mainly from fresh meat and fish). Since vegetables do not contain creatine, vegetarians clearly show lower levels of muscle creatine which, upon creatine supplementation, rise to a level higher than in meat-eaters.

Creatine and the treatment of muscular diseases

Creatine supplementation has been, and continues to be, investigated as a possible therapeutic approach for the treatment of muscular, neuromuscular, neurological and neurodegenerative diseases (arthritis, congestive heart failure, Parkinson's disease, disuse atrophy, gyrate atrophy, McArdle's disease, Huntington's disease, miscellaneous neuromuscular diseases, mitochondrial diseases, muscular dystrophy, neuroprotection, etc.).

Two studies have indicated that creatine may be beneficial for neuromuscular disorders. First, a study demonstrated that creatine is twice as effective as the prescription drug riluzole in extending the lives of mice with the degenerative neural disease amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). The neuroprotective effects of creatine in the mouse model of ALS may be due either to an increased availability of energy to injured nerve cells or to a blocking of the chemical pathway that leads to cell death.

Second, creatine has been demonstrated to cause modest increases in strength in people with a variety of neuromuscular disorders.

Third, creatine has been shown to be beneficial as an adjuvant treatment for several neuro-muscular and neuro-degenerative diseases (11,12) and its potential is just beginning to be explored in several multi-center clinical studies in the USA and elsewhere.

See also

• Adenosine triphosphate (ATP)
• Beta-alanine
• Creatine kinase
• Citric acid cycle (Krebs cycle)
• Creatine Ethyl Ester
• Coenzyme Q10
• Idebenone
• Lipoic acid
• Pyritinol
• Vitamin B5
• Nitric oxide

References

10. Schlattner U, Tokarska-Schlattner M, Wallimann T. (2006) Mitochondrial creatine kinase in human health and disease. Biochim Biophys Acta. 2006 Feb;1762(2):164-80. Review

11. Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis. Biochem J. 1992 Jan 1;281 ( Pt 1):21-40. Review.

12. Creatine and Creatine Kinase in Health and Disease (2007) Series: Subcellular Biochemistry , Vol. 46 Salomons, Gajja S.; Wyss, Markus (Eds.) 2007, XVIII, 352 p., Hardcover ISBN: 978-1-4020-6485-2

12. Wallimann T, Tokarska-Schlattner M, Neumann D, Epand RM, Epand RF, Andres RH, Widmer HR, Hornemann T, Saks VA, Agarkova I, Schlattner U. (2007) The phospho-creatine circuit: molecular and cellular physiology of creatine kinases, sensitivity to free radicals and enhancement by creatine supplementation. In: Molecular Systems Bioenergetics: Energy for Life, Basic Principles, Organization and Dynamics of Cellular Energetics (Saks, V.A., Editor), Wiley-VCH, Weinheim, Germany, pp. 195-264 (2007)

External links

• NCBI Online Mendelian Inheritance In MAN (OMIM) GATM human mutation record
• Quackwatch on creatine
• BBC News - Creatine 'boosts brain power'
• Review article on creatine's function in the neurological context (from the Science Creative Quarterly)
• Creatine Supplementation for Health and Diseases on Creatine and Creatine Kinase Function
• Creatine during Pregnancy and Protection of Babies against Anoxia A mouse study