Creatine

Creatine (/ˈkrətn/ or /ˈkrətɪn/)[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]

Creatine
Names
Systematic IUPAC name
2-[Carbamimidoyl(methyl)amino]acetic acid
Other names
N-Carbamimidoyl-N-methylglycine; Methylguanidoacetic acid
Identifiers
3D model (JSmol)
3DMet
Beilstein Reference
907175
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.278
EC Number
  • 200-306-6
Gmelin Reference
240513
KEGG
MeSH Creatine
RTECS number
  • MB7706000
UNII
CompTox Dashboard (EPA)
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)
Std molar
entropy (So298)
189.5 J K−1 mol−1
−538.06–−536.30 kJ mol−1
Std enthalpy of
combustion cH298)
−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
GHS precautionary statements
P261, P305+351+338
Related compounds
Related alkanoic acids
  • Sarcosine
  • Dimethylglycine
  • Glycocyamine
  • N-Methyl-D-aspartic acid
  • beta-Methylamino-L-alanine
  • Guanidinopropionic acid
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.

Biosynthesis

Creatine synthesis primarily occurs in the liver and kidneys.[2][16] On average, it is produced endogenously at an estimated rate of about 8.3 mmol or 1 gram per day in young adults.[16][17] Most of the human body's total creatine and phosphocreatine stores are found in skeletal muscle, while the remainder is distributed in the blood, brain, and other tissues.[17][18] Creatine is also obtained through the diet at a rate of about 1 gram per day from an omnivorous diet.[16][18] Some small studies suggest that total muscle creatine is significantly lower in vegetarians than non-vegetarians, as expected since foods of animal origin are the primary source of creatine. However, subjects happened to show the same levels after using supplements.[19] Creatine supplements are marketed in ethyl ester, gluconate, monohydrate, and nitrate forms.[20]

Creatine is not an essential nutrient[21] 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

Creatine, which is synthesized in the liver and kidneys, 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.[22] 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.[22] 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.[23][24][25]

Genetic deficiencies

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects.[26] 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.[27]

Pharmacokinetics

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).[28]

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. After the "loading dose" period (1–2 weeks, 12–24 g a day), it is no longer necessary to maintain a consistently high serum level of creatine. As with most supplements, each person has their own genetic "preset" amount of creatine they can hold. The rest is eliminated as waste. A typical post-loading dose is 2–5 g daily.[29][30][31]

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.[32]

Therapeutic Usage

Exercise performance

Creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5 to 15%.[33][34][35] Creatine has no significant effect on aerobic endurance, though it will increase power during short sessions of high-intensity aerobic exercise.[36][37]

A survey of 21,000 college athletes showed that 14% of athletes take creatine supplements to improve performance.[38] Non-athletes report taking creatine supplements to improve appearance.[38]

Creatine is reported to increase cognitive performance,[39] especially in individuals with inadequate intakes in their diet and is claimed by some sources [40][41] to be a nootropic supplement.

Medical use

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.[42]

Muscular disease

A meta-analysis found that creatine treatment increased muscle strength in muscular dystrophies, and potentially improved functional performance.[43] Creatine treatment does not appear to improve muscle strength in people who have metabolic myopathies.[43] 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.[43]

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.[44]

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.[45]

Huntington's Disease

Several primary studies[46][47][48] 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.[49]

Adverse effects

Side effects include:[50][51]

  • 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.[52]

A 2009 systematic review discredited concerns that creatine supplementation could affect hydration status and heat tolerance and lead to muscle cramping and diarrhea.[53][54]

Renal Function

A 2019 systematic review published by the National Kidney Foundation investigated whether creatine supplementation had adverse effects on renal function.[55] 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[56] and post-menopausal women,[57] bodybuilders,[58] athletes,[59] and resistance trained populations.[60][61][62] The study also discussed 3 case studies where there were reports that creatine affected renal function.[63][64][65]

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.[66]

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.[67]

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.[68] 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.[69]

Interactions

Creatine taken with medications that can harm the kidney can increase the risk of kidney damage:[70]

A National Institutes of Health study suggests that caffeine interacts with creatine to increase the rate of progression of Parkinson's Disease.[71]

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).[72] Such a reaction happens when grilling or pan-frying meat.[73] Creatine content (as a percentage of crude protein) can be used as an indicator of meat quality.[74]

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.[75]

See also

  • Beta-Alanine
  • Creatine methyl ester

References

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