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Can creatine supplementation prolong lifespan and quality of life in subjects with Amyotrophic Lateral Sclerosis (ALS) through decreasing the degenerative process of motor control, decreasing muscle atrophy, and decreasing muscle weakness?

A magazine article for patients with ALS and their family members

Holly Hanzel

Fall 2005

An article for an information packet for ALS patients

(Packet is printed for offices of ALS neurologists)


**Parentheses[] will be definition boxes in magazine article**

When my father-in-law was diagnosed with a neurodegenerative disease, he was not ready or willing to through in the towel on life. Even though he has a non-curable disease, he has taken every possible step to educate himself and our family regarding the medical aspects and the available research concerning his disease. This has enabled him to effectively communicate with the doctors, and enabled him to critically analyze all possible data and information on the disease. He has tried a plethora of drugs and supplementations. Five years ago he was told he had five years to live and would be in a wheelchair in three. Today he is not in a wheelchair; furthermore, his motor performance degeneration has only progressed to the estimated point of one year after his diagnosis. Having a family member with a terminal illness, of which symptoms have been reduced by supplements, is my motive for writing this review article.

My purpose is to analyze the available literature on the treatment of ALS symptoms with creatine monohydrate, which will provide you, patients with ALS and their family members, with insight into the impact of creatine in the treatment of ALS. This easily obtainable over-the-counter supplement could provide an affordable treatment for you, by possibly prolonging your quality of life.


Introduction to Analysis

Following is my analysis about the muscular and neurological symptoms of ALS. I need to assess both because motor neurons control the movement of voluntary muscles, and evidence shows creatine has neuroprotective effects in addition to helping muscular symptoms. Therefore, my analysis is based on one review article assessing the long-term efficacy of creatine supplementation in health and disease, and seven research studies that used creatine supplementation to determine its efficacy in treating the degenerative muscular symptoms of ALS. My review is also based on one research study that analyzed the efficacy of creatine supplementation on the muscular symptoms of ALS and Huntington’s disease, which has similar neurodegenerative symptoms. In addition, my review is based on six studies that discuss the neuroprotective properties of creatine in relation to the neurological symptoms of ALS. These studies will not be analyzed in detail like the muscular studies because my primary concern is your muscular symptoms. I am using them to strengthen my claim that creatine can help you. These sources date from 1994 through 2003, and were obtained by computerized searches of PubMed, Science Direct, Sport Discus and Web of Science databases, using key search terms such as ‘amyotrophic lateral sclerosis’, ‘creatine’ and ‘neurological disease’.


Definition of ALS

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, usually effects males and has an incidence rate between 1 and 5 out of every 100,000 people, which typically strikes during mid to late life (Cluskey and Ramsden, 2001). ALS is a progressive neuromuscular disease that causes degeneration of some of the largest of all nerve cells, called motor neurons (Rowland and Shneider, 2001). Motor neurons control the movement of voluntary muscles. Motor neurons extend from the brain to the spinal cord [the upper motor neurons] and from the spinal cord to the muscles throughout the body [the lower motor neurons]. The disease causes the motor neurons to degenerate and eventually die. As the motor neurons die, the muscle cells are paralyzed and eventually deteriorate. The ongoing loss of motor neurons leads to progressive weakness and atrophy of skeletal muscles [loss of muscle fiber volume characterized by a visible decrease in muscle size] along with impaired control of those muscles (Cluskey and Ramsden, 2001). In the beginning of the disease, the person starts out with fatigue and becomes progressively weaker, eventually becoming paralyzed. In most cases, ALS results in fatality within two to five years from the first appearance of the symptoms.



Definition of Creatine Monohydrate

α-Methylguanidino-acetic acid, known as creatine monohydrate, is consumed in a typical western diet of about 1 g per day from protein foods (Persky and Brazeau, 2001). Creatine is also synthesized by the body primarily in the liver, kidneys and pancreas (Persky and Brazeau, 2001). Most creatine is not stored in the tissue in which it is synthesized. Actually, 95% is found in skeletal muscle, with the remainder found in the brain, liver and kidneys (Persky and Brazeau, 2001). Creatine is actively transported (uses energy) from the synthesized tissue into the target tissue by a transporter protein called CreaT (Persky and Brazeau, 2001). Once inside the cell, creatine becomes phosphocreatine (PCr), which constitutes 60-70% of stored creatine in muscle cells. Once creatine has been used by the muscle tissue, it is eliminated by the kidneys (Persky and Brazeau, 2001).

The best known function of creatine is its role in the support of energy production inside the cell. The biological form of energy is called ATP. Creatine provides nearly half the energy for the first 10 seconds of muscle contraction. (Bogdanis, Nevill and Boobis, 1996) This increase in energy is why some athletes believe creatine supplementation enhances high-intensity performance. In fact, some studies have shown that ingestion of 20g of creatine per day for 2-5 days, increases creatine in the muscle by about 20% (Bogdanis, Nevill and Boobis, 1996).

Creatine also has neuroprotective properties. These properties include direct antioxidant activity, stabilization of mitochondrial [produce energy for the cell through cellular respiration] membranes, stimulation of glutamate [produced by the body, plays an essential role in initiating and transmitting nerve impulses, and in human metabolism] uptake into synaptic vesicles and increased delivery of ATP to sarcoplasmic reticulum [membrane structures in muscle involved in the control of calcium concentration and hence muscle contraction] (Persky and Brazeau, 2001).



Introduction to Scientific Studies

The eight studies, which are based on muscular symptoms, I have investigated aimed to answer the question of whether creatine supplementation can prolong quality of life in ALS patients by decreasing the progression of the degenerative symptoms, such as decreased motor control, increased muscle atrophy, and decreased muscle weakness. Two of these studies also aimed to investigate whether creatine can increase the lifespan of mice (Andreassen et al., 2001 and Klivenyi et al., 1999). Of the eight studies, four used animals and four used humans for their subject populations (Table 1and 2). The population sizes of the animal studies do not vary much, ranging from 10 to 12 mice per investigation. On the other hand, the population sizes of the clinical trials vary greatly, ranging from 14 to 175 ALS patients. Creatine concentrations range from 1% to 3% (equivalent to 5g and 20g in humans) of daily food intake for three of the animal studies, with one study using 50 mg/kg (mg per kg of body weight) daily. The clinical trials use a variety of creatine dosage, ranging from 5g/day to 20g/day. The study durations for the humans range from 5 and 7 days with a six month follow-up to 16 months. These eight studies assessed an assortment of findings, such as maximum voluntary isometric contraction [example is pushing down on a table with your hand and forearm as hard as you can], muscle atrophy and muscle weight for the animals, motor performance, muscle weakness by measuring fatigability, grip strength, and vital capacity. The results indicate major differences in the findings with creatine supplementation, in helping with the symptoms of ALS, in three animal studies and one clinical trial. In contrast, three clinical trials and one animal study found no major difference in the findings.


Scientific Evidence of Creatine in the Treatment of ALS

Table 1: Supporting evidence to date on the efficacy of creatine supplementation for treatment of ALS.


Study

Population (N)

Duration


Creatine Monohydrate

Results

Andreassen et al. (2001)

12 ALS mice

150 days

1, 2 and 3% daily food intake

1. Lifespan increased by 14.6% with 2% creatine

2. Delayed onset motor performance decline increased by 15 days

3. Weight loss significantly delayed with 2% creatine from 110-150 days

4. Concentrations of glutamate significantly decreased with 2% creatine at 80 days from 0.62 to 0.27 % glutamate

Klivenyi et al. (1999)

10 ALS mice


Up to 200 days

1% or 2% daily food intake

1. Rotorod performance significantly better from 116 to 136 days


2. No significant difference in motor performance

3. Lifespan increased 13 days with 1% and 26 days with 2%

4. No difference with 1%, significant reduction in neuron loss with 2%

5. No significant difference in body weight


Mazzini et al. (2001)

28 ALS

7 days and six

20 g/day for 7 days, 3 g/day for 6 months

1. Increase MVIC after 7 days, 70% increase knee extensors in 20, 53% increase elbow flexors in 15

2. Significant decrease fatigue elbow flexors 39% in 11, decrease in knee flexors but not significant

Ikeda et al. (2000)

10 ALS mice

Four weeks

50 mg/kg daily

1. Grip strength significantly increased (p<0.01)

2. Biceps muscle weight significantly increased (p<0.01)

3. Number motor neurons significantly increased (p<0.01)


Table 2: Non-supporting evidence to date on the efficacy of creatine supplementation for treatment of ALS.


Study

Population (N)

Duration

Creatine Monohydrate


Results

Shefner et al. (2003)

104 ALS patients

5 days and six months

20 g/day for 5 days, 5 g/day for 6 months

1. No significant difference in MIVC

2. No significant difference in grip strength

Groeneveld et al. (2003),

175 ALS patients

16 months

10 g/day

1. No significant difference in MVIC

2. No significant difference in vital capacity (found difference but not significant p=0.12)

3. No significant difference in quality of life

Drory and Gross (2002),

14 ALS patients

1 mo.(10 subjects), 2 mo. (8), 3 mo. (5) and 4 mo. (5)

5g/ day

No significant difference in all 4 outcomes: forced vital capacity, forced expiratory volume, peak expiratory flow rate and maximum voluntary ventilation

Derave et al. (2003)

10 ALS mice

120 days



2 % daily food intake


1. No difference in MVIC, fatigue or rotorod performance

2. Significant increase in soleus muscle weight from 0.31 mg/ g to 4.2 mg/g (P<0.05)

Animal Studies

By looking at the data in Table 1, you can see the majority of studies examining creatine supplementation in ALS mice support creatine’s efficacy. In one study, oral administration of 1% creatine resulted in a significant 13-day increase in lifespan. An even greater increase in lifespan by 26 days was shown with 2 % creatine. Creatine was also associated with improvements in motor performance and protection against loss of motor neurons (Klivenyi et al., 1999). In addition, a study performed by Ikeda, Iwasaki, and Kinoshita, (2000) found a daily dose of 50 mg/ kg for four weeks considerably improved all three findings of grip strength, bicep muscle weight and number of motor neurons.

You can see in Table 2 one study by Derave, Bosch, Lemmens, Eijnde, Robberecht and Hespel (2003), implementing 2% creatine in ALS mice failed to show major effects on grip strength, body weight or rotorod (exercise wheel for mice) performance; however, a separate study in Table 1 found that 2% creatine supplementation considerably improved motor performance, delayed onset of motor deficits by an average of 15 days, and deferred weight loss (Andreassen et al, 2001). Creatine was also shown to increase glutamate [produced by the body and plays an essential role in human metabolism and in initiating and transmitting nerve impulses] at 80, but not 110 days. In this study, all doses of creatine administered considerably improved survival.

Human Studies

You can also see in Table 1 and 2 the clinical trials of the efficacy of creatine supplementation in ALS that are available. Of these only one indicates a major potential benefit with creatine supplementation (Mazzini et al., 2001). In this study, 28 ALS patients received creatine 20 g/day for 7 days, then 3 g/day for 3-6 months. Maximal voluntary isometric muscle contraction (MVIC) was tested at the beginning, after 7 days, 3 months and 6 months. Major improvement was seen in MVIC for knee extensors and elbow flexors after 7 days. A trend for increased body max index (BMI) was also observed. All variables tested showed a linear progressive decline during the 6 months of follow-up. The researchers concluded that creatine supplementation increased high-intensity, isometric [muscle contraction without movement at the joint] power in ALS patients, which may indicate an effect to prolong your quality of life (Mazzini et al., 2001).

You can see in Table 2 that three clinical trials failed to find major differences with creatine supplementation. The most recent clinical trial enrolled 104 ALS patients from 14 different sites in the US (Shefner, Cudkowiez, and Colombo, 2003). Patients were randomly assigned to receive either creatine or placebo (sugar pill) at a heavy dose of 20g for 5 days, followed by a maintenance dose of 5g for 6 months. This study failed to show a major difference between treatment and control groups for MVIC and grip strength. A study of ALS patients in the Netherlands failed to show benefits of creatine supplementation (Groeneveld et al., 2003). In a double-blind [a study in which neither the subject(s) nor the investigator(s) know which treatment a subject is receiving], placebo-controlled [an inactive substance or mock therapy (sugar pill) is given to one group while the treatment being tested is given to another] trial, 175 ALS patients ingested either creatine 10 g/day or placebo for 16 months. The primary endpoint, survival, did not considerably differ between the creatine and placebo groups. However, the study was terminated early due to an unexplained rate of death in the two groups. Creatine supplementation also had no major effect on secondary variables of functional decline and forced vital capacity [the amount of air in a full breath]. Another study that investigated forced vital capacity as the primary finding also found no effect of creatine supplementation on respiratory function (Drory and Gross, 2002). After 4 months of follow-up, ALS patients supplemented with creatine 5 g/day showed no major differences in forced vital capacity and other incidences of respiratory decline compared to controls.


Long Term Safety of Creatine

Finally, the review by Derave, Eijnde and Hespel, 2003, aimed to evaluate the long-term safety and efficacy of creatine in health and disease. They investigated several studies and found ingestion of creatine to be safe and well tolerated, with weight gain of up to 20% being the only confirmed side effect. Since ALS is characterized by weight loss and muscle atrophy, this side effect may indeed be beneficial for you.

Now that you have a clear understanding of the varying findings of creatine, you should appreciate that there is definitely an unresolved issue regarding its effect on ALS. Therefore, you can appreciate why I conclude that creatine does help ALS.

Assessment of the Study Designs for Muscular Symptoms

An assessment of the study designs is needed to clarify these confusing and different findings. This can be a challenging and puzzling process, but you are in luck because I have assessed several of these findings in great detail: the population type, the population numbers, the duration of the studies and the doses of creatine. These features of the different studies are considered limitations, which are aspects of a study that may influence the results or the extent to which the findings are generalizable. Therefore, you need to evaluate these limitations of the studies in order to read between the lines of their findings.


1. Population Type (Animal or Human)

The first limitation you need to evaluate is the population type. This leads to the question of why do most of the animal studies demonstrate that creatine helps ALS, and the majority of clinical trials exhibit that creatine does not help ALS? One reason why so many scientific studies are performed on animals is because the researchers can control for more of the variables than in clinical trials. For instance, diet, exercise, environmental factors, timing and assurance/ compliance of doses and population size can be controlled with animals. However, with clinical trials, humans drop out of studies for various reasons, do not obey one hundred percent with the timing and compliance of doses, and have varying diets and exercise routines. Another reason is that researchers can perform experiments on animals that would be unethical on humans. For instance, researchers take actual measurements of muscle size by taking the muscle tissue out of the animal body. Hence, you can understand that there is less room for differences in the findings of animal studies, making their findings more straightforward. This is a very important factor to consider when analyzing the limitations of the study designs.


2. Population Number

Another important factor to examine is population size. By looking at Table 1 and 2, you can see that the population size of the animal studies ranges from 10-12 mice per investigation. This factor allows for a clear cut comparison of the animal population sizes. However, you can see the population sizes for the clinical trials range from 14-175 ALS patients. This poses a problem for comparing the findings of the clinical trials because larger populations indicate more powerful studies, which means the findings are more convincing. For your understanding, the clinical trials with the larger populations indicate creatine not to have an effect on ALS (Drory and Gross, 2002, Groeneveld, Veldink, and Tweel, 2003 and Shefner, Cudkowiez, and Colombo, 2003). The clinical trail by Mazzini et al. (2001) illustrates a benefit to creatine supplementation, but at the end of the trial their population was only 28 patients due to a high number of dropouts. Due to the population numbers being different in the human studies, our analysis of these studies is difficult. Therefore, other important factors need to be examined, such as study duration and size of creatine doses.


3. Study Duration and Creatine Doses

The last limitations you need to compare are the duration and the doses of the studies. The animal studies by Andreassen et al., 2001, Derave et al., 2003, and Klivenyi et al., 1999, all used similar durations and doses ranging from 120 to 200 days and from 1% to 3% creatine (equivalent to 5g and 20g in humans) of daily food intake respectively. Ikeda et al., 2000, used four weeks for their duration with a dose of 50mg/kg. Andreassen et al., 2001, and Ikeda et al., 2000, of whom used varying duration and doses, found major differences in all findings with creatine. However, Klivenyi et al., 1999, found major differences in two findings of rotorod (exercise wheel for mice) performance and lifespan, but found no major difference in motor performance and muscle weight. In addition, Derave et al., 2003, who used 2% creatine, found no major difference in three findings of MVIC, fatigue and rotorod performance, but found a difference in muscle weight. The differences in findings between these highly controlled animal studies are hard to assess because they are confusing for a nonscientist. For your purpose, the designs are similar and three out of four of the animal studies give a good indication that creatine can help decrease your symptoms.

On the other hand, the duration and doses for the clinical trials vary. The durations range from 5 and 7 days, with a six month follow-up, to 16 months. These differences are important and need to be addressed. The two studies by Shefner, Cudkowiez, and Colombo, 2003, and Mazzini et al, 2001, are easy to compare because both used a duration of six months with a high dose of 20g for 5 or 7days respectively, followed by a maintenance dose of 5g for six months. These two studies used a couple of different variables, but both used MVIC. Shefner, Cudkowiez, and Colombo, 2003, found no difference in MVIC and Mazzini et al, 2001, found a major difference in MVIC. These different findings with the same duration and doses leads you back to the population sizes. Therefore, you need to look at the different population sizes to determine the more legitimate study. Shefner, Cudkowiez, and Colombo, 2003, used 104 ALS patients and Mazzini et al, 2001, used 28 ALS patients. Therefore, the more legitimate study by Shefner, Cudkowiez, and Colombo, 2003, indicates creatine to not have an effect on ALS.

As you can see, it is very important to look at as many factors as you can in order to effectively analyze the results of scientific studies. For your purpose, all but one of the clinical trials indicate creatine to be ineffective for treating symptoms of ALS, but it is not as legitimate due to the population size. Now, you are directed to my counterargument because the majority of the human studies found creatine to not be effective in treating ALS.


Counterargument

The strongest counterargument to my claim is that the majority of the clinical trials did not find creatine to be effective in treating symptoms of ALS (Table 2). Furthermore, the clinical trial showing efficacy of creatine only used 28 patients (Mazzini et al, 2001), which causes their findings to be weaker than the studies with higher populations. Just because animal studies show a major difference, does not mean the same will be seen in humans. There are many important findings in animal studies, but when they are applied to humans, the findings are not there. This means that animal data cannot be directly applied to humans. It can be extrapolated and considered, but cannot be taken as a direct indication. This is very important to this analysis and indicates the need for further investigation on this subject. This being noted, I still conclude that creatine can help you. This is because it also has neuroprotective properties that are directly linked to the neurodegenerative symptoms of your disease. The support to this claim will be discussed next when you look at how ALS begins: the origin of motor neuron loss in ALS.



Refutation to Counterargument Based on the Origin of Motor Neuron Loss in ALS

Table 3 Neuroprotective Properties of Creatine




Origin of motor neuron loss in ALS

Neuroprotective properties of creatine

Damage by reactive oxygen species


Direct antioxidant activity

Mitochondrial dysfunction

Energy buffering and stabilization of mitochondrial membranes

Imbalance of calcium homeostasis inside the cell

Increased delivery of ATP by creatine kinase/ phosphocreatine

Glutamate excitotoxicity

Stimulation of glutamate uptake into synaptic vesicles

Table 3: Recent data suggests that creatine also has neuroprotective effects. Even though recent studies indicate conflicting results on the efficacy of creatine, the properties of creatine indicate a potential benefit for treating this neurodegenerative disease.

My refutation to the counterargument for creatine’s effect on ALS is based on the fact that I have also researched the origin of motor neuron loss in your disease and the neuroprotective properties of creatine. There appears to be a connection, which can be seen in Table 3, between ALS and creatine that further supports my claim. I conclude that creatine can help you based on my study of this literature. Following are four indirect connections to the benefit of creatine for ALS. They are indirect because they were not tested on ALS; however, they where discovered by various scientific experiments with strong study designs, which makes their findings acceptable to discuss.

First, oxidative damage from reactive oxygen species [called free radicals, which have been implicated in aging, cancer, cardiovascular disease and other kinds of oxidative damage to the body] appears to play a role in the destruction of motor neurons in ALS. This is because motor neurons have high metabolic activity (use a lot of energy); therefore, they are particularly sensitive to oxidative damage. Approximately 25% of ALS patients possess a defect in a gene called SOD-1, which acts as an antioxidant against the free radicals that form in the body from toxic exposures (Rowland and Shneider, 2001). Furthermore, it is believed that this defect actually increases oxidative damage to cells. A recent study found creatine to have major antioxidant-scavenging activity, indicating it to have direct antioxidant properties (Lawler, Barnes and Wu, 2002). This indicates that creatine can protect motor neurons from damage by free radicals, which is one way it can help reduce the progression of your decreasing muscle control.

Second, motor neuron degeneration involves mitochondrial dysfunction. As already mentioned, the primary function of mitochondria is the production of ATP (biological energy); therefore, mitochondrial damage results in energy deficiency that can result in cell death. Increased creatine levels means increased reserves of ATP. In addition, the mitochondrial creatine promotes the transport of ATP from the mitochondria to the cytosol (fluid inside the cell) where it can be used (Wyss and Wallimann, 1994). This increase in energy reserves inside the cell may help to offset the high energy demands of motor neurons, thereby reducing your cell death.

Third, according to Klivenyi (1999), abnormal calcium handling inside the cell is also part of the development of ALS symptoms. Studies have shown a direct link between the creatine system and calcium regulation inside the cell. In one animal study with mutations for creatine, its absence disrupted both calcium release and uptake by the sarcoplasmic reticulum (Steeghs, Benders and Oerlemans, 1997). Again, the sarcoplasmic reticulum is the membrane structure in muscle that is involved in the control of calcium concentration and hence muscle contraction. Another animal study demonstrated the importance of creatine in the delivery of ATP to the sarcoplasmic reticulum (de Groof, Fransen and Errington, 2002). Thus, the neuroprotective property of creatine to increase delivery of ATP to the sarcoplasmic reticulum helps amend the imbalance of calcium homeostasis for muscle contraction.

Finally, glutamate is produced by the body and plays an essential role in human metabolism and in initiating and transmitting nerve impulses (Persky and Brazeau, 2001). As previously noted in the study by Andreassen et al (2001), glutamate excitotoxicity, which is over stimulation of nerve cells by nerve impulses that often leads to cell death, is another factor involved in the development of ALS symptoms. Because removal of glutamate from the nerve cell requires energy, creatine may aid this process by increasing energy reserves in the cell. Therefore, creatine can increase your muscle contraction and give you more strength by removing excess glutamate from muscle cells.

Now that you have an understanding of the connection between the origin of motor neuron loss in ALS and the neuroprotective properties of creatine, you should appreciate the possible benefit of creatine for you.

Conclusion: Creatine Can Help You!

Supplementation with oral creatine appears safe and effective in improving exercise performance and lean mass in healthy populations. The increase in energy due to creatine along with associated increases in lean muscle mass also hold promise for the treatment of neurodegenerative diseases, like ALS, which are characterized by muscle weakness and muscle atrophy. Creatine also possess neuroprotective properties that could improve mitochondrial stabilization, calcium handling in side the cell, glutamate reuptake into synaptic vesicles and antioxidant properties, all of which are potentially beneficial in the treatment of ALS.

Creatine has been shown to be effective in neurodegenerative diseases other than ALS, such as Huntington’s disease, which has similar neurodegenerative symptoms. Evidence for the efficacy in animals appears promising. This is because these highly controlled studies indicate creatine to be effective in decreasing the degenerative process of motor control, decreasing muscle atrophy, and decreasing muscle weakness. However, this is not the end all be all of the effect of creatine on ALS. You can not live in a box like an animal. Therefore, it is necessary to make sure you take creatine daily as recommended by your neurologist so that you can comply with the timing of doses. In addition, it is necessary that your neurologist recommend a healthy diet and a light exercise routine. This will give you the power to control for these variables (compliance and timing of doses, diet, and exercise) that the human studies were unable to control. Limited evidence from the clinical trials in ALS has shown little benefit (Drory and Gross, 2002, Groeneveld, Veldink, and Tweel, 2003 and Shefner, Cudkowiez, and Colombo, 2003). Therefore, it is evident that future clinical trial research is still needed with highly controlled study designs using large subject populations and longer treatment durations.

In conclusion, I believe you should consider creatine supplementation to help delay the symptoms of this neurodegenerative disease especially since studies indicate it to be safe and well tolerated by the body.



References

Andreassen, O., Jenkins, B., Dedeoglu, A., Ferrante, K., Bogdanov, M., Kaddurah-Daouk, R., and Beal, M. (2001). Increases in cortical glutamate concentration in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. Journal of Neurochemistry, 77, 383-390.

Bogdanis, G., Nevill, M. and Boobis, L. (1996). Contribution of phosphocreatine and aerobic metabolism to energy supply during repeated sprint exercise. Journal of Sports Medicine and Physical Fitness, 80, (3), 876-884.

Cluskey, S. and Ramsden, D. (2001). Mechanisms of neurodegeneration in amyotrophic lateral sclerosis. Journal of Clinical Pathology, 54, 386-392.

De Groof, A., Fransen, J. and Errington, R. (2002). The creatine kinase system is essential for optimal refill of the sarcoplasmic reticulum Ca2+ store in skeletal muscle. Journal of Biological Chemistry, 277, 5275-5284.

Derave, W., Bosch, L., Lemmens, G., Eijnde, B., Robberecht, W., and Hespel, P. (2003). Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: effects of creatine treatment. Journal of Neurobiology of Disease, 13, 264-272.

Derave, W., Eijnde, B., and Hespel, P. (2003). Creatine supplementation in health and disease: What is the evidence for long-term efficacy? Molecular and Cellular Biochemistry, 244, 49-558.

Drory, V and Gross, D. (2002). No effect of creatine on respiratory distress in amyotrophic lateral sclerosis. ALS and other motor neuron disorders, 3, 43-46.

Groeneveld, G., Veldink, J., Tweel, I., Kalmijn, S., Beijer, C., Visser, M., Wokke, J., Franssen, H and Berg, L. (2003). A Randomized Sequential Trial of Creatine in Amyotrophic Lateral Sclerosis. Annual Neurology, 53, 437-445.

Ikeda, K., Iwasaki, Y. and Kinoshita, M. (2000). Oral administration of creatine monohydrate retards progression of motor neuron disease in the wobbler mouse. ALS and Other Motor Neuron Diseases, 1, 207-212.

Klivenyi, P., Ferrante, R., Matthews, R., Bogdanov, M., Klein, A., Andreassen, O., Mueller, G., Wermer, M., Kaddurah-Daouk, R. and Beal, M. (1999). Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Journal of Nature Medicine, 5, (3), 347-350.

Lawler, J., Barnes, W., Wu, G., Song, W. and Demaree, S. (2002). Direct antioxidant properties of creatine. Biochemical and Biophysical Research Communications, 290, 47-52.

Mazzini, L., Balzarini, C., Colombo, R., Mora, G., Pastore, I., Ambrogio, R. and Caligari, M. (2001). Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. Journal of the Neurological Sciences, 191, 139-144.

Persky, A. and Brazeau, G. (2001). Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacological Reviews, 53, 161-176.

Rowland, L. and Shneider, N. (2001). Amyotrophic Lateral Sclerosis. The New England Journal of Medicine, 344, (22), 1688-1700.

Shefner, J., Cudkowiez, M. and Colombo, R. (2003). A clinical trial of creatine in patients with amyotrophic lateral sclerosis. ALS and Other Motor Neuron Disorders, 4, 28-29.

Stegers, K., Benders, A. and Oelemans, F. (1997). Altered CA2+ responses in muscles with combined mitochondrial and cystolic creatine kinase deficiencies. The Journal of Cell Biology, 89, 93-103.

Wyss, M. and Walliman, T. (1994). Creatine metabolism and the consequence of creatine depletion in muscle. Molecular and Cellular Biochemistry, 133, 51-66.







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