Creatine was already known since the last century (Greenhaff, 1995); however, its role in muscle metabolism and physical performance has become a matter of interest in recent years.
In the muscle cell, Creatine in its phosphorylated form, creatine-phosphate (CP), constitutes an energy reserve for the rapid regeneration of adenosine triphosphate (ATP), in high-intensity and short-duration exercises, such as, for example, during a 100m sprint or in a weightlifting sequence in a weightlifting workout.
Organic Creatine has two sources, synthesis by the body itself, from 3 amino acids, and food intake, specifically meat (Redondo et al ., 1996). The organic pool of this substance is located almost entirely (95%) in the skeletal muscles, and its regeneration after intense exercise is a process dependent on the oxidative pathway (Mayes, 1996).
Most creatine supplementation studies have shown the possibility of increasing the organic pool of this compound by 10 to 20%. However, some studies have shown an increase of up to 50% in total levels after supplementation in non-vegetarian individuals (Burke & Berning, 1996). These authors report that in vegetarian athletes, the increase reaches around 60%.
The expansion of the reserve of energy in the muscle through Creatine has improved athletes’ physical performance (Volek et al ., 1997; Ziegenfuss et al ., 1997). However, only some research has shown significant effects after supplementation with this compound (Dawson et al., 1995; Terrillion et al., 1997).
Ergogenic resources are substances (among them Creatine), processes, or procedures that can or are perceived as being able to improve sports performance (Williams, 1998).
The consumption of some of these ergogenic resources may have a positive result for doping tests; therefore, they are vetoed by the International Olympic Committee (IOC). Creatine is off the list of banned substances by the IOC, so its consumption is not considered doping.
In sports, this substance was popularized at the 1992 Olympic Games in Barcelona, when the British runner Linford Christie, winner of the gold medal in the 100m dash, credited his victory to the consumption of Creatine.
There still needs to be a consensus on the side effects of creatine consumption for a long time. There is a need for information and awareness campaigns about consuming supplements for the physically active population that does not practice physical exercise professionally.
This work aims to review some aspects of creatine metabolism and its use as an ergogenic substance in sports.
During a running event, at each step taken by a competitor, an amount close to 10 19 ATP molecules are converted into adenosine diphosphate ADP, with the corresponding transfer of energy for muscular work; in a way, this would mean that a marathon runner could expend the equivalent of 75 kg of ATP during the race (Newsholme et al ., 1994).
As the athlete could not carry this amount of ATP, this fact is resolved by the rapid regeneration of the molecule from ADP and inorganic phosphate and the energy provided by another reserve compound: creatine phosphate (CP).
Anaerobic energy supply: ATP – CP system
During the first few seconds of intense exercise, muscle ATP concentration is maintained at a more or less constant level. The ATP used is quickly replenished from the breakdown of CP. Thus, CP levels rapidly decrease as this compound regenerates ATP.
When physical exercise is carried out to exhaustion, both muscle concentrations of ATP and CP are reduced, making them unavailable for efficiently supplying energy to continue muscle work.
Although there is evidence that muscle ATP concentration can drop to almost zero (horse studies), this situation has not been shown in humans, where total muscle ATP content can drop by approximately 50% at the point of fatigue during high-intensity exercise (Spriet, 1995).
The ATP concentration in most tissues is low, about 3 to 8 mmol/kg. The concentration of CP in muscle is 4 to 5 times that of ATP (on average 18 mmol/kg muscle), representing an approximate amount of 120 g of total Creatine in an adult individual weighing 70 kg (Guerrero-Ontiveros & Wallimann, 1998). This reserve, although limited, is sufficient to act as a temporary ATP buffer until other ATP regenerating processes reach full speed (Houston, 1995).
Together, ATP and CP can provide muscles energy for approximately 3 to 12 seconds (Burke & Berning, 1996).
During the muscle contraction process, the ATP used for energy generation is broken down by the ATPase enzyme in a very fast reaction. The resulting ADP is readily regenerated from CP by the action of another enzyme, creatine kinase (CK).
This freely reversible reaction is inverted during rest in order to favor CP regeneration, using the energy available through the oxidative process, which occurs within the mitochondria (Houston, 1995), suggesting that the initial rate of recovery of CP would be proportional to the mitochondrial rate of oxygen consumption (Thompson et al ., 1995).
Creatine is an amino acid, methyl guanidine-acetic acid (Kreider, 1998), which is present both in food and the human body due to endogenous synthesis.
In food, Creatine is found in greater amounts in meat (all types): cod – 3.0; sole – 2.0; salmon – 4.5; tuna – 4.0; and beef – 4.5 g/kg (Balsom et al ., 1994). It is also found in other foods but in very small amounts.
When synthesized in humans, this nitrogenous compound begins its formation cycle in the kidney in a reaction involving two amino acids: arginine and glycine. This operation, catalyzed by the transaminase enzyme, occurs only in this organ. Subsequently, Creatine completes its synthesis by adding a methyl group supplied by methionine (S-adenosylmethionine).
This reaction takes place in the liver (Rodwell, 1996). The Creatine, thus formed outside the muscle, is then distributed to the various tissues of the organism through the blood.
The plasma concentration of Creatine is very small, between 50 and 100 mmol/L (Balsom et al ., 1994). Only traces of this compound are found in urine.
The final destination of synthesized Creatine is skeletal muscle tissue, which holds approximately 95% of the organic pool; the remaining 5% is distributed among organs such as the heart, brain, retina, and testicles (Balsom et al ., 1994).
Creatine uptake by muscle cells is a saturable process that action occurs against a concentration gradient (sodium-dependent transporter), possibly involving the interaction of Creatine with specific membrane sites that recognize part of the creatine molecule (Greenhaff, 1997).
Some possible regulatory mechanisms of intracellular creatine storage have been suggested: in one of them, in the endogenous synthesis in the kidney and liver, the creatine concentration would influence a negative feedback control in the enzyme that catalyzes the 1stsynthesis reaction (transferase); in another, creatine homeostasis would be regulated by controlling the expression and activity of the creatine transporter protein, which may be affected by several structural analogs of this substance or metabolic inhibitors (Guerrero-Ontiveros & Wallimann, 1998).
Daily, an adult individual with a habitual varied diet (mixed) ingests approximately 1. g of Creatine, and the liver produces a similar amount to reach the daily requirements. This total (about 2. g) is approximately equivalent to the Creatine recycled daily by the body (Greenhaff, 1995).
In skeletal muscle, there is a reversible balance between creatine and creatine phosphate: in the resting condition, approximately two-thirds of the creatine content is in the phosphorylated (PC) form, and the rest is in the free form (Balsom et al ., 1994). As previously mentioned, creatine phosphorylation is an oxygen-dependent process, that is, oxidative phosphorylation (Mayes, 1996).
The rate of CP degradation is higher in type II muscle fibers (fast twitch) compared to type I (slow twitch). The availability of CP as an energy substrate in fast-twitch fibers is considered the possible factor limiting factor for maintaining muscle strength during high-intensity exercise (Balsom et al ., 1994; Greenhaff et al ., 1994).
On the other hand, Gariod et al . (1994) showed that the CP resynthesis rate in type I muscle fibers is faster than in type II muscle fibers, probably due to the greater aerobic potential of slow contraction fibers; therefore, this is an oxygen-dependent process.
After high-intensity exercise, approximately half of the initial CP concentration is regenerated within the first minute of recovery; total CP resynthesis would be completed after approximately 5 minutes (Soderlund & Hultman, 1991).
Although CP is not considered a primary energy source during submaximal exercises, an inverse relationship between exercise intensity and CP level in the exercised muscles has been reported. In individuals submitted to bicycle exercises at an intensity between 60 and 70% of VO 2 max. for 80 minutes, CP levels have been demonstrated to decrease to approximately 40% of baseline values (Broberg & Sahlin, 1989).
Thus, these amounts appear to decrease even during submaximal exercise, but muscle stores are not depleted to the same degree as in high-intensity exercise. According to Willmore & Costill (1994), CP levels can be reduced by 10 – 15% of the initial content after 10 – 12 seconds of intense exercise.
Creatine in phosphorylated form, as a reserve of high-energy phosphates, not only allows the maintenance of intracellular ATP levels in conditions of muscular work but also, in the resting condition (recovery), acts in the muscle as a transporter of phosphate groups of high energy from the mitochondria to the cytoplasm (Mayes, 1996).
In skeletal and cardiac muscle cells, this mechanism allows the rapid displacement of high-energy phosphates from the mitochondrial matrix, which is produced from oxidative phosphorylation to the cytosol.
CP is also used during intermediate anaerobic (lactic) work – 15 seconds to a few minutes when its breakdown will help buffer the intracellular acidic environment caused by lactate accumulation. The greater amount of CP in the muscle cell means a greater buffering capacity and, thus, a greater time of resistance to fatigue (Soderlund et al ., 1994).
The creatine cycle ends when it is converted into creatinine by a continuous and irreversible dehydration reaction (non-enzymatic), excreted in the urine. The amount of creatinine recycled and eliminated is constant daily and is produced in proportion to an individual’s muscle mass (Devlin, 1992).
According to Forbes (1991), in individuals who consume a mixed diet (without consumption of creatine supplements), the relationship between muscle mass (MM) and creatinine excretion (Cr) is as follows: MM (kg) = 14.3 Cr (g/d) + 3.6.
Factors related to creatine storage in muscle
It is not yet clear whether there are differences due to sex for the concentration of CP stored in muscle. In a study by Soderlund (1992), with 20 men and 25 women, no statistically significant difference was observed between the mean creatine concentrations according to sex (127.7±2.1 and 131.4±2.4 mmol/kg of dry muscle, respectively).
Regarding age, McCully & Posner (1992) reported that the CP resynthesis rate after an exercise tends to decrease with time, approximately 8% every 10 years after 30 years of age.
Reduction in the size of muscle mass, decrease in the diameter of type II fibers, and decrease in mitochondrial enzymatic activity and metabolism of high-energy phosphates are some of the age-related changes that are associated with the decline in muscle strength and physical resistance capacity, which occurs with aging (Smith et al ., 1998).
Moller et al . (1980) found no difference in the total amount of Creatine between the elderly (between 52 and 79 years) and young subjects (between 18 and 36 years). Despite this finding, a lower amount of CP and a higher amount of free Creatine was observed in the elderly compared to the young population.
The authors suggested that this result is a consequence of the physical inactivity of older individuals. The hypothesis was reaffirmed with later research, in which an inversion of the CP and free creatine proportions was found, without having had any change in the total concentration of Creatine in the muscle, when a training program was introduced (Moller & Brandt, 1981).
Smith et al . (1998) conducted a study with a group of 5 young subjects (mean age 30 years) and 4 adults (mean age 58 years) who were supplemented with Creatine (0.3 g/kg/d) for 5 days. Before supplementation, juveniles had a significantly higher muscle CP concentration and initial resynthesis rate than adults.
After supplementation, resting CP concentration increased by 15% in juveniles and 30% in adults, resulting in both groups having a similar initial rate of CP resynthesis.
The determination of the composition of muscle fiber types varies not only from one muscle to another but also between individuals. This is why some are better sprinters and endurance runners (Newsholme et al ., 1994).
According to techniques for separating muscle fibers of types I and II from samples of frozen and dry muscle tissue, type II fibers (fast contraction), at rest, had a higher concentration of CP muscle than type I fibers (slow twitch) (Soderlund et al ., 1992). Confirming these results, Edström et al .. (1982) demonstrated significantly lower CP concentration in the soleus muscle in humans (containing approximately 65% of type I fibers) compared to the vastus lateralis muscle (with approximately 41% of type I fibers).
Supplemental Creatine does not appear to increase resting muscle ATP concentration but appears to help maintain ATP levels during maximal physical exertion (Greenhaff et al ., 1993). Supplementation with this compound increases the body’s creatine pool, potentially facilitating the generation of a greater amount of CP.
The ergogenic effect may be specific for certain types of physical exertion, such as repetitive (intermittent) exercises, of high intensity, short duration, and with very short recovery periods (American College…, 1999). It is also possible that creatine supplementation allows the athlete to engage in more intense physical training, which eventually could translate into improved physical performance (Kreider, 1998; Williams, 1998).
Supplementation for athletes is in the form of creatine monohydrate, a water-soluble white powder. The amount of Creatine stored during supplementation is highly variable between individuals; these variations suggest that the uptake of this substance is dependent on different factors, including differences in diet composition, initial muscle content of this compound, sex, and muscle fiber composition (GuerreiroOntiveros & Wallimann, 1998).
Vegetarian athletes benefit most from creatine supplementation. Their diets do not contain sources of this compound; therefore, they have low levels of this element in the body. The consumption of supplements of this substance has shown the possibility of an increase in muscle creatine concentration of approximately 60% compared to another group fed a mixed diet (10 20%) (Burke & Berning, 1996).
Consumption of Creatine with glucose, around 100 g, increases the muscle content of this compound by approximately 10%, as shown by Green et al . (1996). There is an increase in creatine uptake by the muscle fiber; consequently, ingestion of this simple carbohydrate can increase the ergogenic effect.
The process seems to be mediated by insulin, which would stimulate the ATPase enzyme of the Na + /K + pump, which in turn would promote a simultaneous transport of Na + /Creatine (two molecules of sodium for each of Creatine) to maintain or restore the normal Na + gradient and membrane potential (Odoom et al ., 1996).
After ingesting 5 g of Creatine, the plasmatic level increases from 50 and 100 mmol/L to more than 500 mmol/L one hour after its consumption (Harris et al ., 1992). Daily doses of 20 g (divided into 4 or 5 times) for a period of 5 to 7 days generally increase the total content of this substance in the muscle by about 10 to 20% (Grindstaff et al ., 1997; Kreider, 1998 ).
However, recently, smaller amounts, 3 g/day for 30 days, have shown the same effect (American College…, 1999). Thus, high doses (20 g/day) would be unnecessary to increase the content of this compound in the muscle. Approximately one-third of the extra Creatine that enters the muscle is phosphorylated (Balsom et al .., 1995; Burke & Berning, 1996), and the rest predominate in free form (Vandenberghe et al ., 1997).
Vandenberghe et al . (1996) hypothesized that oral consumption of Creatine combined with some adrenergic stimulus – for example, caffeine consumption – might facilitate muscle accumulation of Creatine. Caffeine has been shown to directly stimulate ATPase activity of the muscle Na + /K + pump and increase plasma levels of epinephrine, direct stimuli for the activity of said mechanism.
Surprisingly, initial results indicated that caffeine did not improve the efficiency of oral creatine supplementation, increase muscle CP levels, or improve physical performance. Caffeine would have completely suppressed the ergogenic effect of creatine supplementation.
On the one hand, there are several studies showing improvement in physical performance and changes in body composition in athletes as a result of creatine supplementation (Balsom et al ., 1995; Vandenberghe et al ., 1996; Grindstaff et al ., 1997; Vandenberghe et al ., 1997; Volek et al ., 1997; Ziegenfuss et al ., 1997). On the other hand, well-controlled studies have not shown significant changes in performance after this supplementation (Dawson et al ., 1995; Redondo et al ., 1996; Terrillion et al ., 1997).
Consequently, although some advantages may be evidenced from supplementation with this compound, only some individuals who consume such a substance will necessarily benefit from better sports performance.
In an extensive review of studies in this regard, Kreider (1998) reports less effective results from creatine supplementation in the following situations: when it was consumed in amounts lower than 20 g/d for a period of fewer than 5 days; when it was consumed in low doses (2-3 g/d), without the initial loading period (high dose); in studies with a limited number of subjects; and when maximal exercise ( sprint ) was performed with very short or very long recovery periods between sprints.
Untrained women who consumed Creatine (20 g/d) for 4 days, followed by a consumption of 5 g daily for 66 days, associated with strength training, had a significantly greater gain in lean mass (1.0 kg ) when compared with the control group, according to Vandenberghe et al . (1997).
Williams (1998) refers that although researchers have shown an increase between 0.9 and 2.2 kg of body mass gain after a week of creatine supplementation, this increase, as expected, due to the short period, it is not muscle mass.
Two theories prevail to try to explain the effects of creatine supplementation: the first assumes that creatine supplementation would promote water retention, probably linked to this substance, and the decrease in urine production associated with this supplementation, found in some studies, would constitute an indirect marker of fluid retention in the body; the second assumes that supplementation would promote increased protein synthesis. Therefore, more studies are needed to ensure the contribution of each of the processes through which weight gain was achieved (Kreider, 1998; Williams, 1998).
Supplementation with Creatine has not been proven effective in increasing physical performance in endurance sports (American College…, 1999).
Risks and disadvantages of supplementation
Information about the side effects of creatine supplementation comes mainly from anecdotal communications, without a solid scientific foundation; therefore, any discussion of possible negative effects of supplementation deserves careful consideration.
Kreider (1998) summarizes and analyzes some facts found in publications intended for lay people: supplementation can promote muscle tension; when consumed during training, in hot weather, it can cause muscle cramps, and creatine consumption increases the risk of kidney function problems and gastrointestinal disorders.
According to the same author, regarding the first point, the gain in strength and body mass (resulting mainly from training) originates from additional stress on bones and ligaments, although no study has documented an increase in the incidence of injuries. Resulting from creatine supplementation, even in athletes with periods of intense training.
Regarding the second point, the possibility of cramps occurring due to the consumption of Creatine has been attributed to changes in the concentrations of water and mineral salts in the muscle fibers. However, no study has shown that supplementation with this compound can cause cramps, dehydration, or changes in intramuscular concentrations of electrolytes.
These situations may be more related to muscle fatigue and dehydration from training in hot weather. The body has a very large capacity to eliminate an extra amount of Creatine (from supplementation) without difficulty (Poortmans et al ., 1997). It can be eliminated in the form of Creatine or creatinine.
As for the third point, no studies were found showing clinically significant damage to liver or kidney function caused by oral supplementation with Creatine (American College…, 1999).
Suppression of endogenous creatine synthesis ( feedback mechanism ) by oral consumption of this compound has been known for some time (Walker, 1979), but this situation can be reversed when supplementation is discontinued.
Research has indicated the need for approximately 4 weeks, after interrupting creatine intake, for the muscle content of this substance and CP to return to normal values (Hultman et al ., 1996; Vandenberghe et al ., 1997); however, it is still unclear whether the muscle content of these compounds drops below normal (baseline) levels at a later period.
In rats, chronic creatine supplementation suppresses creatine transporter protein expression. This result can be extrapolated to individuals (athletes) who chronically ingest this compound. Human muscle has a maximum limit for storing this substance, 150 – 160 mmol/kg of dry muscle (Guerrero-Ontiveros & Wallimann, 1998).
This suggests the influence of its chronic consumption on endogenous synthesis, aiming to prevent an excessive accumulation of intramuscular Creatine. This suppression of the expression of the transporter protein of this compound can be interpreted as a side effect of the supplementation. Consumption for a long time is not advisable, and 1 month without creatine consumption is recommended after 3 months of continuous supplementation (Guerrero-Ontiveros & Wallimann, 1998).
Optimum nutrition Creatine supplementation could be a disadvantage for some athletes. The fact that this compound can increase body weight has been considered. A disadvantage is aerobic sports is that the increase in weight would imply an additional energy cost to move the runner’s weight (Williams, 1998).
The side effects resulting from chronic creatine supplementation still need to be clearly defined. Consequently, more research is needed.
Consumption of Creatine, an ergogenic substance not considered doping by the International Olympic Committee, is effective in improving sports performance; however, in specific exercise conditions, mainly in short-duration, high-intensity modalities and short recovery periods. This effect would be due to the increase in muscle creatine levels, which could potentiate the rapid regeneration of ATP.
Supplementation would be more effective in those individuals with low initial levels of this compound in the muscles, such as vegetarians and the elderly. The ergogenic effects of this substance can be increased when consumed with glucose, but the number of carbohydrates must be large. It is important to point out that many well-controlled studies do not demonstrate a significant benefit from creatine consumption. There is not yet conclusive evidence on the side effects of its use. There is also a need for further studies to determine whether the weight gain resulting from its consumption is due to water retention or a true increase in protein synthesis.