Creatine

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 (by way of conversion to and from creatine phosphate) functions as part of a system based on arginine/phosphoarginine that operates in many invertebrates. The presence of this energy shuttle keeps the ATP/ADP ratio high 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 are known as phosphagens.

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, and testes.



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.

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.

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.

Creatine as a diagnostic of kidney function
Hospitals and doctors routinely measure blood creatinine levels to determine kidney function. Creatine is broken down to creatinine, which is eliminated through the kidneys.

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. Another advance in creatine supplementation was Phosphagen HP. Research at the University of Memphis funded and designed by EAS showed that the consumption of high glycemic carbohydrates in conjunction with creatine vastly increases creatine muscle stores and performance. The combination of creatine and carbohydrates is the only formula that has been proven in published studies to improve muscular performance and weight gain over regular creatine. Many products from several different companies now contain this formula. In 1998, the launch of the first creatine-carbohydrate-alpha lipoic acid supplement, Cell-Tech, by MuscleTech Research and Development, took place. Alpha lipoic acid has been demonstrated to enhance 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 - however no peer-reviewed studies have emerged to conclusively prove these claims. 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 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 Ethyl Ester (CEE) is not allowed to be sold in Germany and France.

Creatine and Athletic Performance
Creatine is often taken by athletes 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 capsule or caplet.

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, many 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).

In another study researchers concluded that changes in substrate oxidation may influence the inhibition of fat mass loss associated with creatine after weight training when they discovered that fat mass did not change significantly with creatine but decreased after the placebo trial in a 12-week study on ten active men. The study also showed that 1-RM bench press and total body mass increased after creatine, but not after placebo.

Safety
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).

There has been controversy over the incidence of muscle cramping with the use of creatine. A study 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. However, the NCAA recently ruled that colleges could not provide creatine supplements to their players, though the players are still allowed to obtain and use creatine independently. In some countries, such as France, creatine is nevertheless banned.

Creatine and Mental Performance
Creatine administration was shown to significantly improve performance in cognitive and memory tests in double-blind, placebo-controlled cross-over trials.