Creatine
Disease Mechanism III: Abnormalities in Energy Metabolism

An Energy Buffer

Drug Summary: Creatine (Cr) is a natural molecule of the human body, produced at a rate of about one gram per day in our liver, pancreas, and kidney. We also consume about one gram per day, mostly from eating meat. Creatine is distributed throughout the body, with about 95% of Cr found in our skeletal muscles. Once Cr reaches our muscles, it exerts several effects that are believed to be responsible for the improvement of muscle function and energy metabolism. Creatine supplementation, as discussed below, has several potential therapeutic benefits. Increasing the amounts of Cr can prevent energy depletion, stabilize biological membranes, and initiate other mechanisms that protect cells from damage.

Creatine as an energy buffer

In muscle, Cr undergoes a chemical reaction that converts it to phosphocreatine (PCr). Increasing the amount of Cr ingested increases the amount of PCr inside our cells. This can be helpful, according to current thinking, because PCr acts as a reservoir for the energy rich molecule ATP in the muscle. When there is not enough ATP in cells, PCr undergoes a reaction in which it loses the phosphate group and is transformed back to simple Cr. The phosphate group from PCr binds to a molecule called ADP and converts it to ATP. The reaction is shown below:

During periods of low energy:

PCr + ADP -> Cr + ATP

The above reaction effectively increases the amount of ATP molecules available in the cell.

The above reaction, however, is reversible. During periods when the cell has sufficient ATP, Cr is converted back to PCr. At the same time, ATP is converted back to ADP. PCr and ADP are then retained in the muscle and serve as forms of energy storage. The reaction is reversed once again and Cr and ATP is produced during times of low energy. Below is the reaction between Cr and ATP:

During periods of high energy:

Cr + ATP -> PCr + ADP

Cr and PCr also act as shuttles that connect sites of energy production and sites of energy consumption. They transport ATP from the mitochondria to the cytosol, the part of the cell where most energy consuming activities occur.

Knowing the mechanism by which Cr increases the cell’s energy supply, one might ask why it’s not possible simply to take PCr, since PCr is the form needed in order to generate ATP. In theory, one would think that PCr supplementation ought to offer the same beneficial effects as Cr. However, research to date has not confirmed this prediction.

Creatine’s role in stabilizing membranes

Creatine can potentially prevent tissue damage by stabilizing biological membranes, particularly the membranes that form the outer boundary of nerve cells. Inside such cells, the protein mtCK (mitochondrial creatine kinase) exists in two different forms. When activated, it exists in a form that binds to certain molecules in the cell membrane, making the membrane more stable. But mtCk is inactivated by various toxic substances called free radicals. (For more information of free radicals, click here.) Once mtCk is inactivated, it transforms into a less stable form that does not bind to membrane molecules, leaving the membrane less stable. Decreased stability of the membrane allows essential molecules to pass through, leaving the cell susceptible to the loss of important substances. Furthermore, the unstable membrane can allow the entrance of foreign substances that are toxic to the cell. Cr and PCr have been found to delay the inactivation of mtCk, thus stabilizing the membranes of cells.

Other neuroprotective effects

Researchers speculate that glutamate, an excitatory neurotransmitter, exerts toxic effects on nerve cells due to increased sensitivity of the nerve cells to glutamate. (Click here for background on the neurobiology of HD.) Experiments have shown that PCr has the ability to stimulate the removal of glutamate from the site of neurotransmitter release, thereby reducing the amount of glutamate in cells.

Side Effects

Because Cr is naturally produced by the body and often consumed in diet, few side effects have been reported. There have been two case reports of renal dysfunction due to creatine supplementation. However, most studies show that short-term Cr supplementation has no adverse side effects. There has been concern about the effects of long-term supplementation. Some researchers are concerned that long-term supplementation could lead to reduction in the production of Cr by the body or decrease in its transporters. A reduction in Cr transporters was reported in rats fed 4% Cr for 3 to 6 months. 4% Cr is equivalent to 24 g/day if given to a 70 kg male. (Conversion Factor: approximately 0.1 g/kg/day) However, a study in young male athletes supplemented with 10g/day of Cr for 2 months did not result in lower transporters. The difference in results has been attributed to the much larger dose of Cr given to the rats.

In conclusion, current studies indicate that short-term creatine supplementation may be safe, but the effects of long-term supplementation are still unknown.

Research on Creatine

Ferrante, et al. (2000) inserted expanded C-A-G repeats to the genes of a group of mice so that they exhibit symptoms similar to human HD. (For more on CAG repeats & HD, click here.) The researchers then placed the mice on either non-supplemented diets or diets supplemented with 1, 2, or 3% Cr. If one assumes that the average 70-kg male eats a mixed diet providing 2,700 kcal/day, a supplementation of 1% would amount to about 6 g/day. The researchers found that survival rates increased as supplementation increased from 1% to 2%. However, administration of 3% Cr improved survival only minutely and was not as effective as either 1 or 2% creatine supplementation. Mice supplemented with 1% and 2% Cr also showed improved motor performance, maintained brain weight, and reduced huntingtin aggregates and delayed death of neurons. The explanation for why increased concentration of Cr at 3% did not bring about increased improvement is unclear, but the researchers believe that Cr may be toxic at very high concentrations.

Matthews, et al. (1998) used a toxic compound known as 3 – NP (3- nitroproprionic acid) to mimic the changes in energy metabolism seen in people with HD. 3-NP interacts with one of the protein complexes involved in the respiratory chain and produces lesions in the cells caused by energy depletion. The researchers discovered that administration of 1% Cr after 2 weeks showed a decrease in nerve cell lesions. The supplemented animals also showed an increased number of molecules that are essential in energy metabolism, indicating improved energy production compared to non-supplemented mice. Scientists then wondered whether creatine analogs—that is, drugs related to creatine but whose chemical and biological properties may be different—will exert similar neuroprotective effects. Additional experiments showed that animals treated with cyclocreatine, a creatine analog, showed no improvements. Results even indicate that cyclocreatine may be toxic to animals.

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For further reading:

1. Ferrante, et al. “Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington’s Disease.” The Journal of Neuroscience. 2000, Jun 15; 20(12): 4389-4397.
   This article reports that Creatine supplementation was able to increase survival rates in a mouse model of HD.
2. Matthews, et al. “Neuroprotective Effects of Creatine and Cyclocreatine in Animal Models of Huntington’s Disease." The Journal of Neuroscience. 1998, 18: 156-163.
   This article reports the Creatine supplementation results in decreased nerve cell lesions often found in cells with energy depletion.
3. Persky, et al. “Clinical Pharmacology of the Dietary Supplement Creatine Monohydrate.” Pharmacological Reviews. 2001, Jun; 53(2): 161-176.
   Contains a lot of technical information about creatine, its mechanisms of action, its reactive properties, and various studies of its beneficial effects.

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Last Modified: 7-5-03

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