Creatine

Creatine (/ˈkriːətiːn/ or /ˈkriːətɪn/)[1] is an organic compound with the nominal formula (H2N)(HN)CN(CH3)CH2CO2H. This species exists in various modifications (tautomers) in solution. Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate (ATP), the energy currency of the cell, primarily in muscle and brain tissue. Recycling is achieved by converting adenosine diphosphate (ADP) back to ATP via donation of phosphate groups. Creatine also acts as a buffer.[2]

Not to be confused with creatinine.

Creatine
Names
Systematic IUPAC name
2-[Carbamimidoyl(methyl)amino]acetic acid
Other names
N-Carbamimidoyl-N-methylglycine; Methylguanidoacetic acid
Identifiers
3D model (JSmol)
3DMet
907175
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.278
EC Number
  • 200-306-6
240513
KEGG
MeSH Creatine
RTECS number
  • MB7706000
UNII
Properties
C4H9N3O2
Molar mass 131.135 g·mol−1
Appearance White crystals
Odor Odourless
Melting point 255 °C (491 °F; 528 K)
13.3 g L−1 (at 18 °C)
log P −1.258
Acidity (pKa) 3.429
Basicity (pKb) 10.568
Isoelectric point 8.47
Thermochemistry
171.1 J K−1 mol−1 (at 23.2 °C)
189.5 J K−1 mol−1
Std enthalpy of
formation (ΔfH⦵298)
 −538.06–−536.30 kJ mol−1
Std enthalpy of
combustion (ΔcH⦵298)
 −2.3239–−2.3223 MJ mol−1
Pharmacology
C01EB06 (WHO)
Pharmacokinetics:
3 hours
Hazards
GHS pictograms
GHS Signal word Warning
GHS hazard statements
 H315, H319, H335
P261, P305+351+338
Related compounds
Related alkanoic acids
Related compounds
 Dimethylacetamide
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

History

Creatine was first identified in 1832 when Michel Eugène Chevreul isolated it from the basified water-extract of skeletal muscle. He later named the crystallized precipitate after the Greek word for meat, κρέας (kreas). In 1928, creatine was shown to exist in equilibrium with creatinine.[3] Studies in the 1920s showed that consumption of large amounts of creatine did not result in its excretion. This result pointed to the ability of the body to store creatine, which in turn suggested its use as a dietary supplement.[4]

In 1912, Harvard University researchers Otto Folin and Willey Glover Denis found evidence that ingesting creatine can dramatically boost the creatine content of the muscle.[5] In the late 1920s, after finding that the intramuscular stores of creatine can be increased by ingesting creatine in larger than normal amounts, scientists discovered creatine phosphate, and determined that creatine is a key player in the metabolism of skeletal muscle. The substance creatine is naturally formed in vertebrates.[6]

The discovery of phosphocreatine[7][8] was reported in 1927.[9][10][8] In the 1960s, creatine kinase (CK) was shown to phosphorylate ADP using phosphocreatine (PCr) to generate ATP. It follows that ATP, not PCr is directly consumed in muscle contraction. CK uses creatine to "buffer" the ATP/ADP ratio.[11]

While creatine's influence on physical performance has been well documented since the early twentieth century, it came into public view following the 1992 Olympics in Barcelona. An August 7, 1992 article in The Times reported that Linford Christie, the gold medal winner at 100 meters, had used creatine before the Olympics. An article in Bodybuilding Monthly named Sally Gunnell, who was the gold medalist in the 400-meter hurdles, as another creatine user. In addition, The Times also noted that 100 meter hurdler Colin Jackson began taking creatine before the Olympics.[12][13]

Phosphocreatine relays phosphate to ADP.

At the time, low-potency creatine supplements were available in Britain, but creatine supplements designed for strength enhancement were not commercially available until 1993 when a company called Experimental and Applied Sciences (EAS) introduced the compound to the sports nutrition market under the name Phosphagen.[14] Research performed thereafter demonstrated that the consumption of high glycemic carbohydrates in conjunction with creatine increases creatine muscle stores.[15]

The cyclic derivative creatinine exists in equilibrium with its tautomer and with creatine.

Metabolic role

Creatine is a naturally occurring non-protein amino acid of which the primary metabolic role is to combine creatine with a phosphoryl group to generate phosphocreatine, which is used to regenerate ATP or Adenosine Triphosphate. Most of the human body's total creatine and phosphocreatine stores are found in skeletal muscle (95%), while the remainder is distributed in the blood, brain, testes, and other tissues.[16][17] The average amount of total creatine (creatine and phosphocreatine) stored in the body is approximately 120 mmol/kg of dry muscle mass.[18] However the upper limit of creatine storage post supplementation and dietary intervention is believed to be around 160 mmol/kg.[18] Studies have also shown that 1–2% of intramuscular creatine is degraded per day and an individual would need to consume about 1–3g of creatine per day to maintain average (unsupplemented) creatine storage.[18][19][20] For most individuals about half (1g/day) of this daily need is consumed from an omnivorous diet,[21][17] while the remaining amount is synthesized in the liver and kidneys.

Biosynthesis

Creatine synthesis primarily occurs in the liver and kidneys.[2][21] On average, it is produced endogenously at an estimated rate of about 8.3 mmol or 1 gram per day in young adults.[21][16]

Creatine is not an essential nutrient[22] as it is naturally produced in the human body from the amino acids glycine and arginine, with an additional requirement for methionine to catalyze the transformation of guanidinoacetate to creatine. In the first step of the biosynthesis these two amino acids are combined by the enzyme arginine:glycine amidinotransferase (AGAT, EC:2.1.4.1) to form guanidinoacetate, which is then methylated by guanidinoacetate N-methyltransferase (GAMT, EC:2.1.1.2), using S-adenosyl methionine as the methyl donor. Creatine itself can be phosphorylated by creatine kinase to form phosphocreatine, which is used as an energy buffer in skeletal muscles and the brain. A cyclic form of creatine, called creatinine, exists in equilibrium with its tautomer and with creatine.

Phosphocreatine system
Proposed creatine kinase/phosphocreatine (CK/PCr) energy shuttle. CRT = creatine transporter; ANT = adenine nucleotide translocator; ATP = adenine triphosphate; ADP = adenine diphosphate; OP = oxidative phosphorylation; mtCK = mitochondrial creatine kinase; G = glycolysis; CK-g = creatine kinase associated with glycolytic enzymes; CK-c = cytosolic creatine kinase; CK-a = creatine kinase associated with subcellular sites of ATP utilization; 1 – 4 sites of CK/ATP interaction.

Creatine is transported through the blood and taken up by tissues with high energy demands, such as the brain and skeletal muscle, through an active transport system. The concentration of ATP in skeletal muscle is usually 2–5 mM, which would result in a muscle contraction of only a few seconds.[23] During times of increased energy demands, the phosphagen (or ATP/PCr) system rapidly resynthesizes ATP from ADP with the use of phosphocreatine (PCr) through a reversible reaction catalysed by the enzyme creatine kinase (CK). The phosphate group is attached to an NH center of the creatine. In skeletal muscle, PCr concentrations may reach 20–35 mM or more. Additionally, in most muscles, the ATP regeneration capacity of CK is very high and is therefore not a limiting factor. Although the cellular concentrations of ATP are small, changes are difficult to detect because ATP is continuously and efficiently replenished from the large pools of PCr and CK.[23] A proposed representation has been illustrated by Krieder et al.[24] Creatine has the ability to increase muscle stores of PCr, potentially increasing the muscle's ability to resynthesize ATP from ADP to meet increased energy demands.[25][26][27]

Creatine supplementation appears to increase the number of myonuclei that satellite cells will 'donate' to damaged muscle fibers, which increases the potential for growth of those fibers. This increase in myonuclei probably stems from creatine's ability to increase levels of the myogenic transcription factor MRF4.[28]

Genetic deficiencies

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects.[29] Clinically, there are three distinct disorders of creatine metabolism. Deficiencies in the two synthesis enzymes can cause L-arginine:glycine amidinotransferase deficiency caused by variants in GATM and guanidinoacetate methyltransferase deficiency, caused by variants in GAMT. Both biosynthetic defects are inherited in an autosomal recessive manner. A third defect, creatine transporter defect, is caused by mutations in SLC6A8 and inherited in a X-linked manner. This condition is related to the transport of creatine into the brain.[30]

Vegetarians

Some studies suggest that total muscle creatine is significantly lower in vegetarians than non-vegetarians.[31][32][30][17] This finding has been postulated to be due to an omnivorous diet being the primary source of creatine. Research shows that supplementation is needed to raise lacto-ovo vegetarian or vegan muscle creatine concentrations up to non-vegetarian levels.[31]

Pharmacokinetics

Most of the research to-date on creatine has predominantly focused on the pharmacological properties of creatine, yet there is a lack of research into the pharmacokinetics of creatine. Studies have not established pharmacokinetic parameters for clinical usage of creatine such as volume of distribution, clearance, bioavailability, mean residence time, absorption rate, and half life. A clear pharmacokinetic profile would need to be established prior to optimal clinical dosing.[33]

Dosing

Loading phase

Taking creatine monohydrate in supplemental powder form showed that an initial loading dose of 5g creatine taken four times a day in equally spaced intervals (total of 20g/day) per day resulted in a rapid (20%) increase in total muscle creatine stores after 6 days.[18] Alternatively, an approximation of 0.3g/kg/day divided into 4 equal spaced intervals has also been suggested since creatine needs may vary based on body weight.[24][18] It has also been shown that taking a lower dose of 3g four times a day for a total of 12g/day for 28 days can also increase total muscle creatine storage to the same amount as the rapid loading dose of 20g/day for 6 days.[18] However, a 28 day loading phase does not allow for ergogenic benefits of creatine supplementation to be realized until fully saturated muscle storage.

Supplementing creatine with carbohydrates or carbohydrates and protein has been shown to augment creatine retention.[34][15]

This elevation in muscle creatine storage has been correlated with ergogenic benefits discussed in the therapeutic uses section. However, higher doses for longer periods of time are being studied to offset creatine synthesis deficiencies and mitigating diseases.[35][36][30]

Maintenance phase

After the 5–7 day loading phase, muscle creatine stores are fully saturated and supplementation only needs to cover the amount of creatine broken down per day. This maintenance dose was originally reported to be around 2–3g/day (or 0.03g/kg/day),[18] however, recent studies have suggested 3–5g/day maintenance dose to maintain saturated muscle creatine.[15][20][37][38]

Absorption
This graph shows the mean plasma creatine concentration (measured in μmol/L) over an 8-hour period following ingestion of 4.4 grams of creatine in the form of creatine monohydrate (CrM), tri-creatine citrate (CrC), or creatine pyruvate (CrPyr).[39]

Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 g (5000 mg) oral dose in healthy adults results in a peak plasma creatine level of approximately 120 mg/L at 1–2 hours post-ingestion. Creatine has a fairly short elimination half life, averaging just less than 3 hours, so to maintain an elevated plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day.

Clearance

It has been shown that once supplementation of creatine stops, muscle creatine stores return to baseline in 4–6 weeks.[18][40][38]

Therapeutic usage

Creatine supplements are marketed in ethyl ester, gluconate, monohydrate, and nitrate forms.[41]

Potential ergogenic benefits of creatine supplementation

Exercise performance

Creatine as a performance enhancing supplement has received support from the Journal of the International Society of Sports Nutrition,[42] and in joint position stands from the American College of Sports Medicine, Academy of Nutrition and Dietetics, and Dietitians in Canada.[43]

Examples of sport events that may be enhanced by creatine supplementation

Potential Creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5 to 15%.[44][45][46] Creatine has no significant effect on aerobic endurance, though it will increase power during short sessions of high-intensity aerobic exercise.[47][48]

A survey of 21,000 college athletes showed that 14% of athletes take creatine supplements to improve performance.[49] Non-athletes report taking creatine supplements to improve appearance.[49]

Creatine is reported to increase cognitive performance,[50] especially in individuals with inadequate intakes in their diet and is claimed by some sources[51][52] to be a nootropic supplement.

Preventative health

A clinical study has shown that the intake of pure, high-quality creatine alone, or in combination with exercise, may reduce and delay age-related muscle atrophy, by improving fat-free body mass, muscle strength and endurance, while simultaneously improving bone density.[53]

Muscular disease

A meta-analysis found that creatine treatment increased muscle strength in muscular dystrophies, and potentially improved functional performance.[54] Creatine treatment does not appear to improve muscle strength in people who have metabolic myopathies.[54] High doses of creatine lead to increased muscle pain and an impairment in activities of daily living when taken by people who have McArdle disease.[54]

According to a clinical study focusing on people with various muscular dystrophies, using a pure form of creatine monohydrate can be beneficial in rehabilitation after injuries and immobilization.[55]

Mitochondrial diseases

Parkinson's disease

Creatine's impact on mitochondrial function has led to research on its efficacy and safety for slowing Parkinson's disease. As of 2014, the evidence did not provide a reliable foundation for treatment decisions, due to risk of bias, small sample sizes, and the short duration of trials.[56]

Huntington's disease

Several primary studies[57][58][59] have been completed but no systematic review on Huntington's disease has been completed yet.

ALS

It is ineffective as a treatment for amyotrophic lateral sclerosis.[60]

Adverse effects

Side effects include:[61][62]

  • Weight gain due to extra water retention to the muscle
  • Potential muscle cramps / strains / pulls
  • Upset stomach
  • Diarrhea
  • Dizziness
  • High blood pressure due to extra water consumption

One well-documented effect of creatine supplementation is weight gain within the first week of the supplement schedule, likely attributable to greater water retention due to the increased muscle creatine concentrations.[63]

A 2009 systematic review discredited concerns that creatine supplementation could affect hydration status and heat tolerance and lead to muscle cramping and diarrhea.[64][65]

Renal function

A 2019 systematic review published by the National Kidney Foundation investigated whether creatine supplementation had adverse effects on renal function.[66] They identified 15 studies from 1997 - 2013 that looked at standard creatine loading and maintenance protocols of 4-20g/day of creatine versus placebo. They utilized serum creatinine, creatinine clearance, and serum urea levels as a measure of renal damage. While in general creatine supplementation resulted in slightly elevated creatinine levels that remained within normal limits, supplementation did not induce renal damage (P value< 0.001). Special populations included in the 2019 Systematic review included type 2 diabetic patients[67] and post-menopausal women,[68] bodybuilders,[69] athletes,[70] and resistance trained populations.[71][72][73] The study also discussed 3 case studies where there were reports that creatine affected renal function.[74][75][76]

In a joint statement between the American College of Sports Medicine, Academy of Nutrition and Dietetics, and Dietitians in Canada on performance enhancing nutrition strategies, creatine was included in their list of ergogenic aids and they do not list renal function as a concern for use.[43]

The most recent position stand on creatine from the Journal of International Society of Sports Nutrition states that creatine is safe to take in health populations from infants to the elderly to performance athletes. They also state that long term (5 years) use of creatine has been considered safe.[24].

At this occasion, it is important to mention that kidneys themselves, for normal physiological function, need Phospho-Creatine and Creatine and indeed kidneys express significant amounts of Creatine Kinases (BB-CK and u-mtCK isoenzymes)[77]. At the same time, the first of two steps for endogenous Creatine synthesis takes place in the kidneys itself. Patients with kidney disease and those undergoing dialysis treatment generally show significantly lowe levels of Creatine in their organs, since the pathological kidney are 1) hampered in creatine synthesis capability and 2) in back-resoption of Creatine from the urine in the distal tubules. In addition, dialysis patients are losing Creatine due to wash out by the very dialysis treatment and thus become chronically Creatine-depleted. This situation is ascerbated by tha fact that dialysis patients generally consume less meat and fish, the alimentary sources of Creatine. Therefore, to alleviate chronic Creatine depletion in these patients and allow to refill-up the organ pools of Creatine, it was recently proposed to supplement dialysis patients with extra Creatine, preferably by intra-dialytic Creatine supplementation. Such a supplementation with Creatine of dialysis patients is expected to significantly improve the health and quality of the patients by improving muscle strengh, coordination of movement, brain function and to aleviate depressions and chronic fatigue that are common in this patients. [78].

Safety

Contamination

A 2011 survey of 33 supplements commercially available in Italy found that over 50% of them exceeded the European Food Safety Authority recommendations in at least one contaminant. The most prevalent of these contaminants was creatinine, a breakdown product of creatine also produced by the body.[79] Creatinine was present in higher concentrations than the European Food Safety Authority recommendations in 44% of the samples. About 15% of the samples had detectable levels of dihydro-1,3,5-triazine or a high dicyandiamide concentration. Heavy metals contamination was not found to be a concern, with only minor levels of mercury being detectable. Two studies reviewed in 2007 found no impurities.[80]

Interactions

Creatine taken with medications that can harm the kidney can increase the risk of kidney damage:[81]

A National Institutes of Health study suggests that caffeine interacts with creatine to increase the rate of progression of Parkinson's Disease.[82]

Food and cooking

When creatine is mixed with protein and sugar at high temperatures (above 148 °C), the resulting reaction produces carcinogenic heterocyclic amines (HCAs).[83] Such a reaction happens when grilling or pan-frying meat.[84] Creatine content (as a percentage of crude protein) can be used as an indicator of meat quality.[85]

Dietary considerations

Creatine-monohydrate is suitable for vegetarians and vegans, as the raw materials used for the production of the supplement have no animal origin.[86]

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See also

References
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    Creatine synthesis (mmol/day)   8.3
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