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.

Function

In the muscles, a fraction of the total creatine binds to phosphate - forming creatine phosphate. The reaction is catalysed by creatine kinases, and the result is phosphocreatine (PCr). Phosphocreatine binds with ADP to convert it back to ATP, an important cellular energy source.

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 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 of adult skeletal muscle possible. These stem cells are simply generic or non-specific cells that have the ability to transform themselves into new muscle cells when they are instructed to. 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 occassionally been done, but have been small. One such study that is often cited involved a minimum length of 3 months (0.25 years), 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 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, like France, creatine is banned.

Sources

In humans typically half of creatine intake comes from food (mainly from meat and fish). The liver can synthesise creatine in small amounts but most of the creatine we digest is stored in the muscles and bones for future use. .

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.

The majority of scientific studies have been conducted using creatine monohydrate in powdered form and similar effects may not be obtained from other formulas.

Loading and consumption

Several manufacturers suggest that creatine should be loaded into the body - for the first few days a high dose is taken followed by a lower maintenance dose. Various supplementation strategies have been used in attempts to increase total creatine concentration, particularly phosphocreatine. The most commonly used protocol is to ingest a daily total of 20 to 30 g of creatine, usually creatine monohydrate, in four equal doses of 5 to 7 g dissolved in fluids over the course of a day, for 5 to 7 days. Greenhaff (et al. 2003) suggests this increases the concentration in the muscles.

However, some suggest that the same effects can be gained using a consistent dosage. In testing this, Dr. Hultman and coworkers employed several strategies, including a rapid protocol involving 6 days of creatine supplementation at a rate of 20 g/day, and a slower protocol with supplementation for 28 days at a rate of 3 g/day. Following the rapid protocol, they also studied a maintenance dose of 2 g/day for 28 days. Both the rapid and slow loading protocols produced similar findings, about a 20% increase in muscle total creatine concentration. The elevated muscle total creatine concentration was maintained when supplementation was continued at a rate of 2 g/day.

In the early 90's, researchers found that the intake of carbohydrates (such as dextrose) with creatine promoted creatine storage beyond isolated creatine supplementation. (Stout et al. 1993) In fact, these studies suggest that the consumption of creatine with these high-glycemic sugars improves creatine storage by up to 60% on average.

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.