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Creatine is a nitrogen based organic compound that is naturally synthesised in the body by the kidney, liver and pancreas. Over the past 2 decades creatine, usually in the form of creatine monohydrate, has become one of the most popular ergogenic aids used by amateur and professional athletes alike. A 2001 study involving over 600 high school students completing who completed surveys regarding the use of creatine. Over 75% of students had knowledge of creatine and its uses, 16% of whom admitted to using creatine as an ergogenic aid to improve athletic performance (Tracy et al,2001). Creatine combines with a phosphate to form phosphocreatine which is a vital way in which cells are able to store energy in the form of adenosine triphosphate (ATP). This is via the reversible creatine kinase reaction, so called as it is catalysed by the enzyme creatine kinase (Sweeney, 1994). Creatine monohydrate supplements are most beneficial in short duration, high intensity exercises lasting less than 30 seconds. The phosphocreatine is broken down to its constituent elements and ATP is resynthesised allowing for improved muscular performance. Taking creatine as a sports supplement is beneficial because it increases the total amount of phosphocreatine stored in resting muscle cells allowing for greater ATP resynthesis in intense activities. As well as being a commonly used sports supplement creatine is a widely researched compound due to its potential benefits in various areas of medicine. Studies have suggested that creatine may provide neuroprotective benefits, often via a similar mechanism, by delaying the onset of motor symptoms and improving survival rates in conditions such as Huntington’s disease and Parkinson’s disease (Wyss and Schulze, 2002). Creatine has also proven its benefits in other neuromuscular diseases where muscular dystrophy is common by improving strength of muscular contractions in key muscles used in everyday exercises such as walking and lifting (Kreider, 1998) . Some research has led scientists to believe that creatine plays a role in atherosclerotic protection against cardiovascular based conditions (Wyss and Schulze, 2002). This might be caused by oral creatine supplementation decreasing levels of the amino acid homocysteine in the blood plasma. Homocysteine is a commonly known risk factor for atherosclerotic disease so this may be the reason creatine can offer atherosclerotic protection. There are risks associated with using creatine as a supplement which could be as minor as trouble with acne or muscular cramping to renal dysfunction or even failure. This is a controversial area with opinions often split on whether creatine does cause renal disorders as there are many studies done concluding opposing outcomes. Further research needs to be done into this area to fully assess the risk factor for using creatine as many of the studies have been relatively short term in their nature.
What is creatine?
Creatine is a nitrogen based organic compound that is most commonly associated with sports supplementation. It is believed to have been first identified by a French chemist named Michel Eugene Chevreul in 1835 (Hultman et al,1996). Chevreul was able to identify the presence of creatine in a meat extract. The compound is not generally regarded a protein but is made up of 3 amino acids and consists of 32% nitrogen (Poortmans and Francaux, 1999). The chemical structure of creatine can be seen in Figure 1.
Figure 1 – Chemical Structure of Creatine
The figure shows the chemical structure of creatine. The molecular formula of creatine is C4H9N3O2.
The amino acids found in creatine are arginine, glycine and methinione. Over the past twenty years creatine has become one of the most popular ergogenic aids taken in the world of sport . An ergogenic aid is defined as “any means of enhancing energy utilisation, including energy production, control and efficiency” (Silver,2001). It is now known that increasing the amount of dietary creatine available leads to an increase in total muscle creatine [TCr]. As well as this, there is also evidence that both total intramuscular creatine increases levels rise as well as levels of phosphocreatine [PCr] (Martini,2006).
During intense exercise phosphocreatine is broken down to creatine and inorganic phosphate (combines with ADP to form ATP) which is the fastest source for the re-synthesis of ATP molecules during the first 10 seconds of high intensity exercise (Mougois,2006). As intense exercise continues and phosphocreatine stores become depleted, ATP is not resynthesised at the same rate and performance levels drop. This is where evidence suggests that creatine can help to increase performance by delaying the inevitable depletion of phosphocreatine stores. Creatine, as a sports supplement, has only been shown to be beneficial during such short duration exercises. These range from sprinting to power lifting so an array of athletes take advantage of the compound including sprinters, rugby players and weight lifters. Creatine is synthesised naturally in the body but only at a rate of 1 to 2 grams per day (McArdle, 2009). This takes place primarily in the liver, pancreas and kidneys. It is therefore important to eat foods rich in creatine as part of a healthy, balanced diet. Such foods include poultry and fish which contain around 5g of creatine per kg of food weight (McArdle, 2006). Approximately half of the creatine used by the body is replaced through the diet with the other half replaced via endogenous synthesis. Approximately 95% of stored creatine is found in skeletal muscle (Spillane et al,2009). As only meat foods contain creatine it is often difficult for vegetarians to obtain ample exogenous creatine via the diet. As a sports supplement, creatine is usually taken in the form of creatine monohydrate (CrH2O). Creatine monohydrate is taken in either capsule or powder form and, nowadays, is readily available online and in high street shops (Kreiber, 1998).
When did creatine become popular?
Creatine first came into the public eye after the 1992 Olympic Games in Barcelona. Linford Christie, who won the Gold medal in the 100m event, admitted to taking creatine monohydrate supplements during his training program. The International Olympic Committee does not consider creatine an illegal substance so athletes are free to take it. 30% of high school athletes admitted to using it with the figure for both professional and college athletes is higher still. In terms of nutritional supplementation net annual sales of creatine are nearly 500 million dollars in the USA alone (Metzl et al, 2001) making it the most popular ergogenic aid used legally. In 2004, a new form of creatine supplementation was introduced to the market called creatine ethyl ester. This is now a very commonly used form of the supplement. It is said to be beneficial due to increased absorption rates compared with standard creatine monohydrate.
However, studies have also shown that there is no advantage to be gained from taking creatine ethyl ester (Figure 2) compared with regular creatine monohydrate supplements (Spillane et al,2009). The study focused on claims that using the revolutionary creatine ethyl ester increases the bio-availability of creatine allowing for greater gains in performace. Subjects were randomly assigned in a double blind fashion to either a creatine ethyl ester group, a creatine monohydrate group or a maltodextrose placebo group. During the investigation both the creatine monohydrate subjects and the creatine ethyl ester subjects observed improvements in both muscle strength and muscle power but there was little difference recorded between the two creatine based groups. The authors were able to conclude that despite claims, creatine ethyl ester provides no benefits, as a sports supplement, compared with creatine monohydrate (Spillane et al,2009)
Figure 2 – Creatine ethyl ester
As can clearly be seen from the diagram the chemical structure of creatine ethyl ester is slightly different to that of creatine. The molecular formula is C6H13N3O2.
How to take creatine?
Creatine monohydrate is widely available and is usually found in powder or capsule form. Unlike many protein supplements creatine is not usually flavoured and is just mixed with water. When starting to take creatine as a supplement the athlete must first undergo the ‘loading’ phase which usually lasts no more than a week. This is necessary to elevate intramuscular levels of creatine phosphate and involves taking 5 grams of creatine 4 times a day. Taking 20g a day elevates both free creatine and creatine phosphate levels by between 10 and 30% (McArdle,2009). The short term mass gains experienced by users of creatine are likely to be primarily caused by water retention. Users of creatine should limit their caffeine intake because it is now well known that caffeine counteracts the ergogenic benefits that the substance provides. In 1996 a Belgian study concluded caffeine has the ability to completely eliminate the ergogenic benefit of creatine supplementation (Vandenberghe et al, 1996). Therefore it is vital that athletes who use creatine limit their caffeine intake to a minimum if not exclude caffeine containing drinks from their diet all together to prevent the impact of the supplement being inhibited. It has also been proven that caffeine intake prolongs muscle relaxation time, therefore opposing the action of the creatine which is able to shorten muscular relaxation time (Hespel,2002).
Does creatine possess other benefits?
As well as the much documented use of creatine as a sports supplement, the compound is the basis of intense, scientific research with regards to its possible benefits in other areas. Among these is the potential use of creatine to protect against both neurological and atherosclerotic disease. It is thought that creatine administration may be beneficial in treating chronic obstructive pulmonary disease by increasing muscle mass (Fuld et al, 2005). Creatine supplementation displayed neuroprotective effects in various animal models of both Huntington’s and Parkinson’s disease (Wyss and Schulze, 2002) as well as in McArdle’s disease (Vorgerd et al,2000). Also in this paper, the authors looked into atherosclerotic protection which may be provided by creatine by lowering the concentration, in the blood, of the amino acid homocysteine. Homocysteine has previously been identified as an atherosclerotic risk factor. A 2002 study focused primarily on the effects creatine had on transgenic animal models of Huntington’s disease. Again, this study found creatine to be beneficial in that survival rates increased and delayed the development of motor symptoms associated with the condition (Andreassen et al, 2001). Much research has focused on the possibility of creatine supplementation increasing strength and power in neuromuscular disease patients who often suffer with muscular dystrophy (Tarnospolsky and Martin,1999) . Handgrip and body weight, as well as other measures, were taken and showed significant improvement after the course of supplementation. As well as the potential neuroprotective benefits of creatine, research has also taken place to find other advantages of the creatine compound. Sullivan et al, for example found that creatine can help provide protection against traumatic brain injury (Sullivan et al, 2001). However, this evidence was only gathered using transgenic mice models so further and more extensive studies need to be conducted. Animal models were used during the study and post chronic administration of creatine cortical damage to the mice was reduced by as much as 50%.
The potential use of creatine as a form of treatment in Huntingdon’s disease is revolutionary and vitally important. This is because there is no current effective treatment for the condition so all forms of potential therapy must be explored. A study in 2000 looked into whether, by increasing phosphocreatine levels, creatine could be administered to Hutingdon’s disease sufferers.
Although there has been little research into the matter, there is a possibility that creatine supplementation can influence bone biology (Candow and Chilibeck,2010). Resistance training alone has previously shown to be beneficial, especially to the elderly to help reduce bone loss which in turn decreases the likelihood of bone fractures. Long term creatine supplementation, possibly coupled with resistance training may be a future method in helping to maintain bone structure and reduce the risk of falls and injuries (Candow and Chilbeck,2010).
As well as this the aging process is also responsible for sarcopenia which is essentially a reduction in muscle mass resulting in decreased muscle function and muscle weakness (Evans,1995) (Tarnopolsky and Safdar,2008). Creatine supplementation, combined with resistance training may be able to reduce muscle wastage and increase muscular hypertrophy (Dalbo et al,2009). This is believed to be due to the activation of satellite cells. These were first discovered in 1961 during microscopic studies of muscle fibre tissue (Mauro,1961). Since then much information has been obtained as to their function. Satellite cells are believed to function as progenitor cells to the myofibre nuclei which are involved in muscle cell growth (Campion,1984). Muscle fibres are not able to divide, so new muscle fibres are formed through the division of satellite cells. This contributes to the ability of skeletal muscle tissue to repair itself following an injury (Martini,2006).
Are there any risks to taking creatine in the long term?
Despite the various benefits I have described creatine does have its critics. Numerous studies have focused on the worrying link between its use and renal dysfunction or even complete renal failure. In particular a study by Pritchard and Kalra concluded that creatine had been the underlying factor which led to renal dysfunction in their subject (Pritchard and Kalra,1998) . This was thought to be due largely to the fact that creatine is degraded to creatinine prior to excretion in the urine. This led to further studies on the issue but there is still no definitive answer as to whether the use of creatine as a supplement contributes to renal dysfunction. Another study by Thorsteinsdottir et al in 2006 focused on the alarming case of a healthy 24 year old who was diagnosed with acute renal failure while taking several dietary supplements, including creatine monohydrate. For example, a paper by Poortmans and Francaux (1998) looked into the findings from the Pritchard paper by supplementing subjects for as long as 5 years. They found no link whatsoever between the use of creatine and impaired renal function. The same paper also found there to be no impact on blood pressure either. Despite this it is generally accepted that those suffering with renal disorders should refrain from the use of the supplement. While use of creatine as a supplement for a period up to 8 weeks has shown no detrimental health effects, further work must be done to investigate any long term health implications which may arise. Studies focusing on creatine supplementation in endurance athletes have sometimes found that taking the substance could actually inhibit performance. This is thought to be due to the weight gain sometimes attributed to the use of creatine (Balsom et al,1994). There have also been numerous links between creatine supplementation and increases in acne, especially among adolescent athletes which could be another factor in a performer choosing to avoid supplementation. Creatine use has been linked with outbreaks of acne especially among adolescents. A study by Kaymak in 2008 concluded that between 15-20% of subjects treated had high blood plasma levels of creatine phosphokinase. A clinical report by Landau et al in 2001 also produced similar results with up to 51% of patients being treated with isotretinoin having elevated blood creatine kinase levels.
As creatine use became more prominent links began to be forged that the person taking the supplement could be more prone to muscular cramping and spasms, particularly during exercise (Poortmans,2000).
However, there is also evidence to the contrary. In 2001 a study was carried out using 26 athletes from various sports (Schilling et al, 2001) . Although the authors focused on the long term clinical markers of creatine use they were able to conclude that there was no increased risk of muscular cramping through use of the supplement. These findings were backed up in 2003 when a paper was published following a 3 year study using elite college athletes (Greenwood et al, 2003). The data was collected between 1998 and 2000 and the authors looked into whether creatine use had any affect over the rate of muscular cramping and injury. Their results showed no significant difference between the placebo group and the creatine taking group allowing them to conclude that creatine had no effect over cramping rate. Similiar conclusions were made in a study by Dalbo et al(2008).
Although the majority of evidence gathered suggests that using creatine monohydrate as a nutritional supplement does lead to performance improvements in high intensity, short duration exercise there is some evidence to the contrary. A 1995 study concluded that there is no benefit to using creatine during short term, high intensity bicycle riding (Cooke et al,1995). There was no difference between the power output of the control group compared with the group who had taken the supplement. These findings are interesting due to the large amount of research which concluded that creatine supplementation was advantageous during this manner of exercise.
Creatine and endurance events
Most of the evidence gathered has suggested that creatine is only beneficial in short, power based activities and has no known
advantages with regards to endurance events. This is partly thought to be due to the weight gain attributed to creatine supplementation due to water retention. However in 2004 a novel experiment was conducted which investigated the potential use of creatine to reduce inflammatory and muscle soreness markers during a 30km bicycle race (Santos et al,2004) . The markers the scientists measured were creatine kinase (CK), lacate dehydrogenase (LDH), prostaglandin E2 (PGE2) and tumor necrosis factor alpha. The subjects used were all experienced road runners whose personal best times for a marathon distance ranged from 2.5 to 3 hours. The subjects undertook the standard creatine loading phase, as well as a small dose of maltodextrin, in the fortnight leading up to the race. Maltodextrin is a commonly used food additive that is used in both the creatine subjects and the placebo subjects so there is no difference in the flavour of the compounds taken. Santos et al found that, in their subjects, the markers of muscle soreness were significantly higher in the control group (who took maltodextrine but not creatine) than in those who had taken creatine. This implies that although creatine has not yet to prove any performance benefits during endurance events it may be beneficial in reducing soreness and improving recovery post exercise by reducing cell damage (Santos, R et al, 2004).
In this project I will look into the array of benefits creatine can provide as well as investigating its negative aspects. I then hope to conclude in what situations the benefits outweigh the potential risks as well as where the risk factor may be too high to warrant using the substance.
Creatine as a sports supplement
As I have already mentioned, it is now known that creatine monohydrate supplements work by increasing the total amount of phosphocreatine available to resting muscle cells. During intense exercise this is broken down to its constituent elements (Phosphate and creatine) and the energy released is used to drive the re-synthesis of ATP, the universal energy currency (Kreider, RB, 1998). As only a very small amount (approximately 2g per day) is synthesised naturally by the liver, pancreas and kidneys extra phosphocreatine in the muscle cells serves to reduce fatigue during high intensity, short duration activities like sprinting.
A study by Kerksick et al in 2007 investigated the impact of various different protein sources and creatine on the human body following a 12 weeks high intensity resistance program. 49 subjects were used who regularly attended the gym to carry out weight lifting exercises. Some subjects were administered with a colostrum protein blend, which is formed from the mild delivered by cows in the days following giving birth. Other subjects were given colostrums combined with creatine administration. A protein control group was put in place and Kerksick et al predicted that the inclusion of creatine with the colostrums blend would bring about greater improvements in both body composition and power than those taking colostrum alone. The resistance training program led to mass gains for all subjects but the greatest lean mass gains were achieved by those taking a blend of creatine and colostrums protein. However, there was no significant improvement in subject’s one repetition maximum on the bench press between the protein control group, the c colostrum group or the colostrums/creatine group. Due to the increased availability of phosphocreatine it would have been predicted that the colostrum/creatine group would have achieved the greatest improvements in this exercise over the 12 week study.
In some cases as little as one week of supplementation can be enough to produce performance improvements (Volek et al,1997). Volek used 14 active, male subjects in a double blind fashion where 7 where unknowingly the placebo group and 7 were administered with oral creatine monohydrate supplement. Bench press and squat jumps were the chosen exercises to measure the effect of creatine on performance. As well as increases in the weight subjects could bench press, and increases in power output for the squat jumps there was also a noticeable increase in lean body mass among the subjects of up to 2.7 kg, possibly due to the water retention attributed to creatine use.
Despite all the evidence which has been gathered implying that creatine does play a role in helping enhance ATP resynthesis during short term, high intensity exercises there is some evidence to the contrary. In particular a paper by Cooke et al in 1995 concluded that their subjects had experienced no benefit whatsoever to using the supplement for their high intensity, intermittent bicycle sprints. The authors focused primarily on the power output the subjects were able to exert as well as fatigue levels experienced. 12 healthy yet untrained male subjects were used for the study, 6 of which were the placebo group with the other 6 making up the supplemented group. The supplemented subjects used the loading phase technique to increase the levels of phosphocreatine in resting muscle cells faster, but the phase only lasted for 5 days. This may have been too short a period of time to load them as most manufacturers suggest a 2 week loading phase. However, as I have mentioned Volek et al, 1997 found performance improvements could occur in as little as a week. Cooke et al found there to be no significant difference between the power output between the two groups, prior to or after the supplementation period. This led the authors to conclude that use of creatine as an ergogenic aid has no positive effect over a person’s ability to exert more power in muscular contraction, which opposes much of the evidence gathered in other studies.
Creatine and its neuroprotective effects
In some studies creatine has demonstrated neuroprotective effects. In some animal models creatine has provided neurological protection against the onset of symptoms in both Parkinson’s and Huntington’s disease (Wyss and Schulze,2002). There are three main steps involved in creatine metabolism with one being creatine transporter. The others are, firstly, AGAT which is L-arginine :glycine amidinotransferase. This forms precursors to the creatine molecule itself. Also, GAMT is involved in the biosynthesis of creatine molecules. Deficiency of either AGAT or GAMT leads to a deficiency in both creatine and phosphocreatine in the brain, which can lead to severe mental retardation (Schutz and Stockler, 2007). In the studies carried out by Wyss and Schulze there was a noticeable improvement in clinical symptoms of both AGAT and GAMT deficiencies but there was no change with the creatine transporter disorders. Dechent et al, 1999 also found that oral creatine monohydrate supplementation also increased creatine levels in the brain.
Furthermore, in transgenic mouse models of Huntington’s disease, creatine administration has shown to improve survival rates, as well as prevent the inevitable onset of symptoms. (Andreassen et al,2001). This was concluded to be via a similar method to how creatine operates as an ergogenic aid, but by increasing phosphocreatine levels in the brain, rather than in muscle cells. A minimal dietary administration, of just 2% creatine was enough to provide positive results in the study and provide neurological protection. Huntington’s disease is often associated with loss in weight and the creatine presence also helped to minimise weight loss in the animal subjects.
In 2002 a revolutionary study was carried out by Jacobs et al into the possibility of using oral creatine monohydrate to assist the recovery of patients with spinal cord injuries at the cervical vertebrae level. Sixteen subjects were used for the study who had suffered injuries between the C5 and C7 vertebrae. Results showed that VO2 max, VCO2 max, and time to fatigue were all greater in the supplemented group compared with the placebo group and Jacobs concluded that there is definite benefit in using creatine to assist with training in the rehabilitation of such severe spinal injuries. This again demonstrates the potential uses that creatine supplementation has in providing neurological protection and rehabilitation.
Creatine supplementation may also be beneficial in patients suffering with amyotrophic lateral sclerosis (Rosenfeld, 2008). This is a neurodegenerative progressive disorder which is characterised by muscular dystrophy and can be fatal. An advantage of this trial was the large sample size, which was over 100 subjects. While creatine did not significantly improve motor or respiratory capacity there was a definitive trend toward increased survival rates among the creatine supplemented subject group. Rosenfeld called for further research to be considered into the increases survival rates that were linked to the use of creatine.
Creatine and renal failure
It has been predicted that a long term nitrogen rich diet lends itself to cause both structural and functional deformities of the kidney and may eventually cause renal hyperfiltration (Poortmans and Francaux,1999). Due to the high nitrogen content of creatine much research has been done into whether there is a long term danger to using the supplement.
In 1998 a rather controversial paper was published by Pritchard and Kalra which researched into the possible links between use of creatine as a sports supplement, following the death of 3 American college wrestlers who were taking the substance. The article was published in the Lancet and became the topic of much debate in years to come. Pritchard and Kalra concluded that “there was strong circumstantial evidence to suggest that creatine was responsible for the deterioration in renal function” (Pritchard and Kalra,1998). The subject suffered with focal segmental glomerulosclerosis but despite this all markers of renal function were normal, such as creatinine clearance values. However, when the 25 year old subject was studied 8 years later creatinine clearance had decreased considerably. The male admitted to using creatine based supplements during a pre season football training program which Pritchard and Kalra felt was an underlying factor in the deterioration in the man’s renal functioning. This paper was a topic for much debate, due largely to the fact that the patient investigated by Pritchard and Kalra had underlying renal issues prior to the study, which the authors seem to ignore in their conclusions. The size of the study is also questionable due to the fact that there was only a sole participant therefore no a repeat or variety in results taken. There were also just 4 references noted at the end of the article suggesting that Pritchard and Kalra may not have taken into full account all other evidence that had been obtained by other studies.
Due to the ever increasing popularity of creatine supplementation, along with it’s continued link with renal failure there have been a vast number of studies in this area. A study by Edmunds et al in 2000 focused on the progression of renal disease in Han:Sprague-Dawley (SPRD) rat models with cystic kidney disease. The rats undertook the loading phase of supplementation which I described in the introduction. This is the same technique used in humans to increase the amount of free phosphocreatine. Obviously, the intake of creatine was reduced, in comparison with humans, to 2g/kg of diet for the one week loading phase, followed by a 5 week period where the dosage administered was 0.4g/kg of diet to compare. The authors measured the progression of renal disease my taking kidney size records as well as determining cyst scores. The cysts often develop in chronic cases where the cysts grow and inhibit the blood filtering capabilities of the organ (Parker,2007).Edmunds hypothesis stated that due to the relatively short life span of the animals used, any impact that creatine supplementation has on renal function could be more readily detected. The findings supported this hypothesis as the rats that had been administered with creatine suffered greater renal disease progression than the control group. The kidney sizes were as much as 10% larger, in some cases, than the control group which is an indicator of further progression of the condition. The creatine was administered in a creatine/glutamine mixture which supplement manufacturers often do as glutamine is believed to significantly improve absorption of creatine. As expected all other markers of renal function agreed with the hypothesis. Creatinine serum clearance was 23% lower in the supplemented group and cyst scored were 23% greater compared with the control group. At the time of Edmunds paper there had still not been a long term controlled study into the effect creatine supplementation may have on renal function. Although the findings seem conclusive I feel it is important to consider that animal models were used as oppose to humans, although this was partially due to the time restrictions. Also the sample sizes are adequate but by no means large with 14 males and just 12 females making up the creatine supplemented groups. As well as this the length of the study is quite short with the supplementing period lasting 6 weeks in total. Therefore it remains unclear as to the long term risks that can be associated with creatine and renal issues. In spite of this, the paper exacerbates the advice that athletes with any form of renal condition should avoid using creatine as an ergogenic aid.
In contrast there numerous studies have taken place which have focused on the potential link between creatine and renal disorders and concluded that there is no health risk to taking the substance. In 1999, Poortmans and Francaux conducted a long term study on the issue. This was important because some of the investigations done around this time were short term and didn’t account for the potential long term health risks, if creatine were to be taken over a substantial period of time. Poortmans and Francaux refer to the controversial Lancet publication by Pritchard and Kalra in their introduction and used this to form their hypothesis that “short and medium term creatine supplementation in men does not have any detrimental e
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