Creatine

Creatine
IUPAC name	2-(Carbamimidoyl-methyl- amino)acetic acid
Other names	• (α-Methylguanido)acetic acid • Creatin • Kreatin • Methylguanidinoacetic acid • N-Amidinosarcosine
Identifiers
CAS number	57-00-1
EINECS number	200-306-6
SMILES	[NH2+]=C(N)N(C)CC([O-])=O
ChemSpider ID	566
Properties
Molecular formula	C4H9N3O2
Molar mass	131.13 g/mol
Melting point	303 °C (decomp.)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references

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, functions in all vertebrates and 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.^{[1][2][3][4][5]}

Biosynthesis

In humans, approximately half of stored creatine originates from food (mainly from fresh meat). Since vegetables do not contain creatine, vegetarians show lower levels of muscle creatine which, upon creatine supplementation, rise to a level higher than in meat-eaters.^[6]

In humans, about half of the daily creatine is biosynthesized from three different amino acids - arginine, glycine, and methionine. The rest is taken in by alimentary sources. Ninety-five percent of creatine is later stored in the skeletal muscles.

The pathway for the synthesis of creatine
Arg - Arginine; GATM - Glycine amidinotransferase; GAMT - Guanidinoacetate N-methyltransferase; 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 GATM (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[2].

The second enzyme in the pathway (GAMT, guanidinoacetate N-methyltransferase, EC:2.1.1.2) is primarily expressed in the liver and pancreas[3].

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects.^[7]

Side effects

The use of creatine in healthy individuals is generally considered safe (see Creatine supplements#Safety). Studies have not yet been able to demonstrate either long-term or short term creatine supplementation result in adverse health effects.^[8] Creatine supplementation utilizing proper cycling and dosages has not been linked with any adverse side effects beyond occasional dehydration due to increased muscular water uptake from the rest of the body.^[9] In fact, an increase in body mass because of increased muscle hydration is the most widely accepted side effect of creatine supplementation^[10][11].

According to Dr.Clay and Dr.Zapata, 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^[12]. 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".^[13]

Side effects that produce lower leg pain may be associated with the use of creatine. Creatine may be the cause of an increase in the anterior pressures of the lower leg. This is usually found in post-creatine use when at rest and after exercise. Normal at-rest pressures have been found to be highly elevated by subjects who used creatine within the prior 35 days when compared to no supplementation. This can produce an extreme amount of pain in the lower leg due to the rigidity of the anterior compartment of the lower leg and lack of fluid drainage out of the compartment. It may also be exacerbated by the increase of water content in the muscle fibers, putting more pressure on the anterior compartment. If this condition persist, check with your doctor and inform them of your creatine use and dosage. Although this condition may and usually does subside, if left untreated complications may occur that require emergency medical attention. If the levels remain high for a long period of time, irreversible damage to tissue may occur, particularly to the peroneal nerve. These conditions can further be found under Chronic Compartment Syndrome.^[14]

A single case report in 2008 attributed a young patient's acute cholestatic liver injury to the use of creatine and whey supplements.^[15]

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)^[16]. 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^[17].

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. .

Cognitive ability

A placebo-controlled experiment found that vegetarians that took 5 grams of creatine per day for six weeks showed a significant improvement on two separate tests of fluid intelligence, Raven's Progressive Matrices and the backward digit span test from the WAIS. The treatment group was able to repeat back longer sequences of numbers from memory and had higher overall IQ scores than the control group. The researchers concluded that "supplementation with creatine significantly increased intelligence compared with placebo."^[18] A subsequent study found that creatine supplements improved cognitive ability in the elderly.^[19]

Controversy

Creatine's effectiveness in the treatment of many muscular, neuromuscular, and neuro-degenerative diseases is well-documented,^[20] yet institutions such as the NCAA and Agence française de sécurité sanitaire des aliments have proposed its banning as a performance enhancer.^[21][22][23] Despite this, creatine remains popular with consumers, holding approximately a 10% share of the sports supplement market.^[24]

See also

References

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