Creatine

Encyclopedia : C : CR : CRE : Creatine

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Chemical name
Synonyms	(α-methylguanido)acetic acid Creatin Kreatin methylguanidinoacetic acid N-amidinosarcosine
Chemical formula	C4H9N3O2
Molecular mass
CAS number
EINECS number	200-306-6
Melting point
SMILES
[Chemical infoboxDisclaimer and references]

Creatine is a nitrogenous organic acid that naturally occurs in vertebrates and helps to supply energy to muscle 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 is said to function as part of the cell's energy shuttle. The high energy phosphate group of ATP is transferred to creatine to form phosphocreatine in the following reaction: Cr + ATP <-> PCr + ADP. This reaction is reversibly catalysed by creatine kinase. At sites of high energy usage, e.g. at the site of muscle contraction or in the tail of a sperm cell, creatine kinase transfers the high energy phosphate back from phosphocreatine to ADP to reform ATP. This allows the cellular ATP/ADP ratio to remain stable within the cell, even if it is undergoing high energy fluctuations. Creatine kinase is typically located in cells that undergo high energy fluctuations, e.g. muscle cells, cardiac muscle cells, neurons, the photoreceptor cells of the eye and spermatozoa. The presence of this energy shuttle keeps the ATP/ADP ratio high, which ensures that the free energy of ATP remains high and prevents the loss of adenosine nucleotides, which would cause the death of the cell.

Synthesis

In the human body creatine is synthesized mainly in the liver by the use of parts from three different amino acids - arginine, glycine, and methionine. 95% of it is later stored in the skeletal muscles, with the rest in the brain, heart, testes.

The enzyme GATM (Guanidinoacetate N-methyltransferase, also known as L-arginine:glycine amidinotransferase (AGAT), EC 2.1.4.1), is a mitchondrial enzyme responsible for catalyzing the first rate-limiting step of creatine biosynthesis, and is primarily expressed in the kidneys.

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

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

Sources

In humans typically half of stored creatine originates from food (mainly from meat and fish). As vegetables do not contain creatine, and vegetarians do not suffer from creatine deficiency, endogenous synthesis of creatine in the liver is sufficient for normal activities. However, addition of creatine to the vegetarian diet has been shown to improve athletic performance [link] . Vegetarian creatine can be obtained via chemical synthesis using plant-derived amino acids.

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, neurological and neuromuscular diseases (arthritis, congestive heart failure, disuse atrophy, gyrate atrophy, McArdle's disease, Huntington's disease, miscellaneous neuromuscular diseases, mitochondrial diseases, muscular dystrophy, neuroprotection, etc.).

Two scientific studies have indicated that creatine may be beneficial for neuromuscular disorders. First, a study (Klivenyi et al. 1999) by MDA-funded researcher M. Flint Beal of Cornell University Medical Center demonstrated that creatine was 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). Beal suspects that the neuroprotective effects of creatine in the mouse model of ALS are 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, a study by Canadian researchers Mark Tarnopolsky and Joan Martin of McMaster University Medical Center in Hamilton, Ontario found that creatine can cause modest increases in strength in people with a variety of neuromuscular disorders. The latter paper was published in the March 1999 issue of Neurology.

History of use as a nutritional supplement

In 1912, researchers found that ingesting creatine can dramatically boost the creatine content of the muscle. In the late 1920s, after finding that the intramuscular stores of creatine can be increased by ingesting creatine in larger than normal amounts, scientists discovered creatine phosphate, and determined that creatine is a key player in the metabolism of skeletal muscle.

While creatine's influence on physical performance has been well documented since the early twentieth century, it only recently came into public view following the 1992 Olympics in Barcelona. An August 7, 1992 article in The Times reported that Linford Christie, the gold medal winner at 100 meters, had utilized creatine prior to the Olympics, and an article in Bodybuilding Monthly named Sally Gunnell, gold medalist in the 400-meter hurdles, as another creatine user. Several medal-winning British rowers also used creatine during their preparations for the Barcelona games.

At the time, low-potency creatine supplements were available in Britain, but creatine supplements designed for strength enhancement were not commercially available until 1993 when a company called Experimental and Applied Sciences (EAS) introduced the compound to the sports nutrition market under the name Phosphagen. In 1998, the launch of the first creatine-carbohydrate-alpha lipoic acid supplement, Cell-Tech, by another company called MuscleTech Research and Development, took place. Alpha lipoic acid enhances muscle phosphocreatine levels and total muscle creatine concentrations. This approach to creatine supplementation was validated in a [study] performed in 2003 by Burke et al., of the Department of Human Kinetics at St. Francis Xavier University. Another important event in creatine supplementation occurred in 2004 when the first creatine ethyl ester supplements were launched.

Creatine Ethyl Ester (CEE) is becoming a widely used form of creatine, with many companies now carrying both creatine monohydrate-based supplements and Creatine Ethyl Ester supplements, or combinations of both. CEE is touted to have absorption rates tens of times higher than regular creatine monohydrate, by several supplement companies. Once ingested, however, creatine is highly bioavailable (easily measured by its plasma appearance kinetics and urinary excretion), whether it is ingested as the crystalline monohydrate form, the free form in solution, or even in meat. Creatine salts will of course become the free form when dissolved in aqueous solution. With studies repeatedly reporting an upper maximal range for muscular creatine concentration it is unlikely that the form of creatine ingested results in increased or altered final gains. Creatine monohydrate ($400 million in annual sales in the United States alone) remains the most used form of creatine.

Creatine Ethyl Ester (CEE) is not allowed to be sold in Germany and France.

Creatine and Athletic Performance

Creatine is often taken by humans as a supplement for those wishing to gain muscle mass (bodybuilding). There are a number of forms but the most common are creatine monohydrate - creatine bonded with a molecule of water, and creatine ethyl ester (CEE) – which is creatine monohydrate with an ester attached. A number of methods for ingestion exist - as a powder mixed into a drink, or as a pill.

There is scientific evidence that taking creatine supplements can marginally increase athletic performance in high-intensity anaerobic repetitive cycling sprints, but studies in swimmers and runners have been less than promising, possibly due to the weight gain. Ingesting creatine can increase the level of phosphocreatine in the muscles up to 20%. It must be noted creatine has no significant effect on aerobic exercise (Engelhardt et al, 1998).

Some studies have shown that creatine supplementation increases both total and fat-free body mass, though it is difficult to say how much of this is due to the training effect. Since body mass gains of about 1 kg (about 2.2 pounds) can occur in a week's time, several studies suggest that the gain is simply due to greater water retention inside the muscle cells. However, studies into the long-term effect of creatine supplementation suggest that body mass gains cannot be explained by increases in intracellular water alone. In the longer term, the increase in total body water is reported to be proportional to the weight gains, which means that the percentage of total body water is not significantly changed. The magnitude of the weight gains during training over a period of several weeks argue against the water-retention theory.

It is possible that the initial increase in intracellular water increases osmotic pressure, which in turn stimulates protein synthesis. A few studies have reported changes in the nitrogen balance during creatine supplementation, suggesting that creatine increases protein synthesis and/or decreases protein breakdown. Again, while hypothesized, this remains unproven.

Also, research has shown that creatine increases the activity of myogenic cells. These cells, sometimes called satellite cells, are myogenic stem cells that make hypertrophy (increase in size of cells) of adult skeletal muscle possible. These stem cells are simply generic or non-specific cells that have the ability to form new muscle cells following damage to the muscle tissue, or to fuse with the existing muscle fibres in the case of exercise to permit growth of the muscle fibre. Following proliferation (reproduction) and subsequent differentiation (to become a specific type of cell), these satellite cells will fuse with one another or with the adjacent damaged muscle fiber, thereby increasing myonuclei numbers necessary for fiber growth and repair. The study, published in the International Journal of Sports Medicine was able to show that creatine supplementation increased the number of myonuclei donated from satellite cells. This increases the potential for growth of those fibers. This increase in myonuclei probably stems from creatine's ability to increase levels of the myogenic transcription factor MRF4 (Hespel, 2001).

Current studies indicate that short-term creatine supplementation in healthy individuals is safe (Robinson et al., 2000). Longer term studies have occasionally been done, but have been small. One such study that is often cited involved a minimum length of 3 months, but only had 10 creatine subjects (Mayhew et al 2002). However, there is still controversy over the use of creatine, and many experts believe that creatine should not be used by individuals under the age of 18. ^{[[Citing sources citation needed]]}

There has been controversy over the incidence of muscle cramping with the use of creatine. A study done at the University of Memphis showed no reports of muscle cramping in subjects taking creatine-containing supplements during various exercise training conditions in trained and untrained endurance athletes (Kreider R. et al, 1998).

Creatine use is not considered doping and is not banned by sport-governing bodies. In some countries however, creatine is banned.

See also

• Acetyl-L-carnitine
• Adenosine triphosphate (ATP)
• Citric acid cycle (Krebs cycle)
• Coenzyme Q10
• Idebenone
• Lipoic acid
• Pyritinol
• Vitamin B5
• Nitric oxide

References

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External links

• [Biochemical flowchart of creatine synthesis]
• [NCBI Online Mendelian Inheritance In MAN (OMIM) GATM human mutation record]
• [Quackwatch on creatine]
• BBC News - [Creatine 'boosts brain power']
• [Creatine F.A.Q.]

• For a full list of external links to MSDSs, spectroscopic data, commercial chemicals suppliers etc. for this compound, see [Chemical sources].

 

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