Creatine

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Creatine
Skeletal formula of neutral form of creatine CreatineStructure.png
Skeletal formula of neutral form of creatine
Skeletal formula of neutral form of creatine
Skeletal formula of one of zwitterionic forms of creatine CreatineZwitter.png
Skeletal formula of one of zwitterionic forms of creatine
Skeletal formula of one of the zwitterionic forms of creatine
Ball and stick model of creatine Creatine zwitterion ball.png
Ball and stick model of creatine
Ball and stick model of one zwitterionic form of creatine
Names
Systematic IUPAC name
2-[Carbamimidoyl(methyl)amino]acetic acid
Other names
N-Carbamimidoyl-N-methylglycine; Methylguanidoacetic acid; N-amidinosarcosine
Identifiers
3D model (JSmol)
907175
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.278 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 200-306-6
240513
KEGG
MeSH Creatine
PubChem CID
RTECS number
  • MB7706000
UNII
  • InChI=1S/C4H9N3O2/c1-7(4(5)6)2-3(8)9/h2H2,1H3,(H3,5,6)(H,8,9) Yes check.svgY
    Key: CVSVTCORWBXHQV-UHFFFAOYSA-N Yes check.svgY
  • CN(CC(=O)O)C(=N)N
Properties
C4H9N3O2
Molar mass 131.135 g·mol−1
AppearanceWhite crystals
Odor Odourless
Density 1.33 g/cm3
Melting point 255 °C (491 °F; 528 K)
13.3 g L−1 (at 18 °C)
log P −1.258
Vapor pressure 0.001 mmHg
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 (S⦵298)
189.5 J K−1 mol−1
−538.06–−536.30 kJ mol−1
−2.3239–−2.3223 MJ mol−1
Pharmacology
C01EB06 ( WHO )
Pharmacokinetics:
3 hours
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H315, H319, H335
P261, P305+P351+P338
NFPA 704 (fire diamond)
NFPA 704.svgHealth 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
1
0
Flash point 118.1 °C (244.6 °F; 391.2 K)
> 400 °C
Lethal dose or concentration (LD, LC):
> 2000 mg/kg (dermal, rat)
Safety data sheet (SDS) ChemicalBook
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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Creatine ( /ˈkriːətiːn/ or /ˈkriːətɪn/ ) [1] is an organic compound that, in vertebrates, facilitates recycling of adenosine triphosphate (ATP), primarily in muscle and brain tissue. Its phosphorylated form, phosphocreatine, donates phosphate groups to adenosine diphosphate (ADP), turning it back into ATP. Creatine also acts as a buffer. [2] It has the nominal formula (H2N)(HN)CN(CH3)CH2CO2H and in solutions, exists in various tautomers, including a neutral form and zwitterionic forms.

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] [6] The discovery of phosphocreatine was reported in 1927. [7] [8]

In the 1960s, the enzyme 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. [9]

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 (however, it should also be noted that Christie was found guilty of doping later in his career). [10] 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. [11] [12]

Phosphocreatine relays phosphate to ADP. Phosphocreatine.svg
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. [13] In 1996, researchers found that carbohydrate consumption augments the effects of creatine supplementation on skeletal muscle creatine accumulation. [14]

The cyclic derivative creatinine exists in equilibrium with its tautomer and with creatine. Creatinine-tautomerism-2D-skeletal.svg
The cyclic derivative creatinine exists in equilibrium with its tautomer and with creatine.

Metabolic role

Creatine is a naturally occurring non-protein compound and the primary constituent of phosphocreatine, which is used to regenerate ATP within the cell. 95% of the human body's total creatine and phosphocreatine stores are found in skeletal muscle, while the remainder is distributed in the blood, brain, testes, and other tissues. [15] [16] The typical creatine content of skeletal muscle (as both creatine and phosphocreatine) is 120 mmol per kilogram of dry muscle mass, but can reach up to 160 mmol/kg through supplementation. [17] Approximately 1–2% of intramuscular creatine is degraded per day and an individual would need about 1–3 grams of creatine per day to maintain average (unsupplemented) creatine storage. [17] [18] [19] An omnivorous diet provides roughly half of this value, with the remainder synthesized in the liver and kidneys. [15] [16] [20]

Biosynthesis

Creatine is not an essential nutrient. [21] It is an amino acid derivative, naturally produced in the human body from the amino acids glycine and arginine, with an additional requirement for S-adenosyl methionine (a derivative of methionine) to catalyze the transformation of guanidinoacetate to creatine. In the first step of the biosynthesis, the enzyme arginine:glycine amidinotransferase (AGAT, EC:2.1.4.1) mediates the reaction of glycine and arginine to form guanidinoacetate. This product 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.

CreatineSynthesis(en).png

Phosphocreatine system

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. [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]

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. [26]

Genetic deficiencies

Genetic defects in the creatine biosynthetic pathway enzymes lead to various severe neurological defects. [27] Defects in the two synthesis enzymes cause L-arginine:glycine amidinotransferase deficiency and guanidinoacetate methyltransferase deficiency. Both biosynthetic defects are inherited in an autosomal recessive manner. Creatine transporter defect, characterized by insufficient transport of creatine to the brain, is caused by mutations in SLC6A8 and is inherited in an X-linked manner. [28]

Vegans and vegetarians

Vegan and vegetarian diets are associated with lower levels of muscle creatine, and athletes on these diets may benefit from creatine supplementation. [29]

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. [30]

Dosing

Loading phase

Approximate muscle total creatine levels in mmol/kg dry weight muscle reported in the literature for vegetarians, individuals following a normal diet, and in response to creatine loading with or without carbohydrate (CHO) or CHO and protein (PRO). Dietary supplementation of creatine serves to increase muscle creatine and PCr by 20-40%. Muscle Total Creatine Stores.png
Approximate muscle total creatine levels in mmol/kg dry weight muscle reported in the literature for vegetarians, individuals following a normal diet, and in response to creatine loading with or without carbohydrate (CHO) or CHO and protein (PRO). Dietary supplementation of creatine serves to increase muscle creatine and PCr by 20–40%.

An approximation of 0.3 g/kg/day divided into 4 equal spaced intervals has been suggested since creatine needs may vary based on body weight. [31] [17] It has also been shown that taking a lower dose of 3 grams a day for 28 days can also increase total muscle creatine storage to the same amount as the rapid loading dose of 20 g/day for 6 days. [17] However, a 28-day loading phase does not allow for ergogenic benefits of creatine supplementation to be realized until fully saturated muscle storage.

This elevation in muscle creatine storage has been correlated with ergogenic benefits discussed in the research section. However, higher doses for longer periods of time are being studied to offset creatine synthesis deficiencies and mitigating diseases. [32] [33] [28]

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 2–3 g/day (or 0.03 g/kg/day), [17] however, some studies have suggested 3–5 g/day maintenance dose to maintain saturated muscle creatine. [14] [19] [34] [35]

Absorption

This graph shows the mean plasma creatine concentration (measured in mmol/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). Plasma creatine concentration over time.jpg
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).

Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 gram (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.

Exercise and sport

Creatine supplements are marketed in ethyl ester, gluconate, monohydrate, and nitrate forms. [37]

Creatine supplementation for sporting performance enhancement is considered safe for short-term use but there is a lack of safety data for long term use, or for use in children and adolescents. [38]

According to a 2018 review article in the Journal of the International Society of Sports Nutrition creatine monohydrate is the most effective nutritional supplement to increase high intensity exercise capacity and muscle mass during training. [39]

Creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5% to 15%. [40] [41] [42] Creatine supplementation exerts positive ergogenic effects on single and multiple bouts of short-duration, high-intensity exercise activities, in addition to potentiating exercise training adaptations. [43] Creatine has no significant effect on aerobic endurance. [44] [ obsolete source ] [45] [ obsolete source ]

A 2014 survey of 21,000 US college athletes showed that 14% of athletes take creatine supplements. [46]

Research

Cognitive performance

Creatine is sometimes reported to have a beneficial effect on brain function and cognitive processing, although the evidence is difficult to interpret systematically and the appropriate dosing is unknown. [47] [48] The greatest effect appears to be in individuals who are stressed (due, for instance, to sleep deprivation) or cognitively impaired. [47] [48] [49]

A 2018 systematic review found that "generally, there was evidence that short-term memory and intelligence/reasoning may be improved by creatine administration", whereas for other cognitive domains "the results were conflicting". [50]

A 2023 meta-analysis including 8 randomized controlled trials found that creatine supplementation improved memory performance with dosing parameters such as intake amounts and duration having no additional effects. [51] Any positive effects on cognition from creatine supplementation seem to be greater for older adults. [51]

A 2024 systematic review found no significant effect for healthy, unstressed individuals and mixed results for people under stress, suggesting that more research is needed to determine optimal dosing parameters and quantify changes in brain creatine levels during supplementation. [52]

A 2024 randomized trial involving 15 sleep-deprived subjects found that a single large dose of creatine (0.35 g/kg) may partially restore cognitive performance and resolve aberrant brain metabolism parameters. [53]

In a 2024 scientific opinion article, the European Food Safety Authority Panel on Nutrition, Novel Foods and Food Allergens determined that a cause and effect relationship cannot be established between creatine supplementation and increased cognitive function based on existing studies. [54] In particular, it ruled that there is currently insufficient evidence on the mechanisms by which creatine can impact cognition.

Muscular disease

A meta-analysis found that creatine treatment increased muscle strength in muscular dystrophies, and potentially improved functional performance. [55] Creatine treatment does not appear to improve muscle strength in people who have metabolic myopathies. [55] 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. [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]

Testosterone

A 2021 systemic review of studies found that "the current body of evidence does not indicate that creatine supplementation increases total testosterone, free testosterone, DHT or causes hair loss/baldness". [61]

Cardiovascular disease

A 2011 systematic review evaluated the effectiveness of creatine and creatine analogues in adults with cardiovascular disease, including heart failure and myocardial infarction. The studies assessed the use of various creatine-based compounds—such as creatine, creatine phosphate, and phosphocreatinine—administered via oral, intravenous, or intramuscular routes, typically as adjuncts to standard therapy.

The analysis found no conclusive evidence that creatine or its analogues significantly affect mortality, myocardial infarction progression, or ejection fraction. However, some studies suggested a potential improvement in cardiac dysrhythmias and dyspnoea. The trials varied considerably in terms of drug formulation, dosage, treatment duration, and patient populations. Notably, no studies were identified that examined the effects of these compounds in patients with essential hypertension.

Due to the small sample sizes, clinical heterogeneity, and inconsistent outcomes across trials, the authors concluded that more rigorous and larger-scale studies are necessary to establish the clinical utility of creatine analogues in cardiovascular care. [62]

Adverse effects

Side effects include: [63] [64]

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 by means of osmosis. [65]

A 2009 systematic review discredited concerns that creatine supplementation could affect hydration status and heat tolerance and lead to muscle cramping and diarrhea. [66] [67]

Despite weight gain due to water retention and potential cramps being two seemingly "common" side effects, new research indicates that these side effects are likely not the result of creatine usage. In addition, the initial water retention is attributed to more short-term creatine use (the "loading" phase). Studies have shown that creatine usage does not necessarily affect total body water relative to muscle mass in the long-term. [68]

Renal function

A 2019 systematic review published by the National Kidney Foundation investigated whether creatine supplementation had adverse effects on renal function. [69] They identified 15 studies from 1997 to 2013 that looked at standard creatine loading and maintenance protocols of 4–20 g/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 [70] and post-menopausal women, [71] bodybuilders, [72] athletes, [73] and resistance trained populations. [74] [75] [76] The study also discussed 3 case studies where there were reports that creatine affected renal function. [77] [78] [79]

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. [80]

The most recent position stand on creatine from the Journal of International Society of Sports Nutrition states that creatine is safe to take in healthy populations from infants to the elderly to performance athletes. They also state that long term (5 years) use of creatine has been considered safe. [31]

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. [81] 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. [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]

See also

References

  1. ↑ Stout JR, Antonio J, Kalman E, eds. (2008). Essentials of Creatine in Sports and Health. Humana. ISBN   978-1-59745-573-2.
  2. ↑ Barcelos RP, Stefanello ST, Mauriz JL, Gonzalez-Gallego J, Soares FA (2016). "Creatine and the Liver: Metabolism and Possible Interactions". Mini Reviews in Medicinal Chemistry. 16 (1): 12–8. doi:10.2174/1389557515666150722102613. PMID   26202197. The process of creatine synthesis occurs in two steps, catalyzed by L-arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT), which take place mainly in kidney and liver, respectively. This molecule plays an important energy/pH buffer function in tissues, and to guarantee the maintenance of its total body pool, the lost creatine must be replaced from diet or de novo synthesis.
  3. ↑ Cannan RK, Shore A (1928). "The creatine-creatinine equilibrium. The apparent dissociation constants of creatine and creatinine". The Biochemical Journal. 22 (4): 920–9. doi:10.1042/bj0220920. PMC   1252207 . PMID   16744118.
  4. ↑ Volek JS, Ballard KD, Forsythe CE (2008). "Overview of Creatine Metabolism". In Stout JR, Antonio J, Kalman E (eds.). Essentials of Creatine in Sports and Health. Humana. pp. 1–23. ISBN   978-1-59745-573-2.
  5. ↑ Folin O, Denis W (1912). "Protein metabolism from the standpoint of blood and tissue analysis". Journal of Biological Chemistry. 12 (1): 141–61. doi: 10.1016/S0021-9258(18)88723-3 . Archived from the original on 3 May 2018. Retrieved 8 May 2018.
  6. ↑ Antonio, Jose (8 February 2021). "Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show?". Journal of the International Society of Sports Nutrition. 18 (1): 13. doi: 10.1186/s12970-021-00412-w . PMC   7871530 . PMID   33557850.
  7. ↑ Eggleton P, Eggleton GP (1927). "The Inorganic Phosphate and a Labile Form of Organic Phosphate in the Gastrocnemius of the Frog". The Biochemical Journal. 21 (1): 190–5. doi:10.1042/bj0210190. PMC   1251888 . PMID   16743804.
  8. ↑ Fiske CH, Subbarow Y (April 1927). "The nature of the 'inorganic phosphate' in voluntary muscle". Science. 65 (1686): 401–3. Bibcode:1927Sci....65..401F. doi:10.1126/science.65.1686.401. PMID   17807679.
  9. ↑ Wallimann T (2007). "Introduction – Creatine: Cheap Ergogenic Supplement with Great Potential for Health and Disease". In Salomons GS, Wyss M (eds.). Creatine and Creatine Kinase in Health and Disease . Springer. pp.  1–16. ISBN   978-1-4020-6486-9.
  10. ↑ "Shadow over Christie's reputation". 22 August 2000.
  11. ↑ "Supplement muscles in on the market". National Review of Medicine. 30 July 2004. Archived from the original on 16 November 2006. Retrieved 25 May 2011.
  12. ↑ Passwater RA (2005). Creatine. McGraw Hill Professional. p. 9. ISBN   978-0-87983-868-3. Archived from the original on 19 June 2022. Retrieved 8 May 2018.
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  14. 1 2 Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL (November 1996). "Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans". The American Journal of Physiology. 271 (5 Pt 1): E821-6. doi:10.1152/ajpendo.1996.271.5.E821. PMID   8944667.
  15. 1 2 Cooper R, Naclerio F, Allgrove J, Jimenez A (July 2012). "Creatine supplementation with specific view to exercise/sports performance: an update". Journal of the International Society of Sports Nutrition. 9 (1): 33. doi: 10.1186/1550-2783-9-33 . PMC   3407788 . PMID   22817979. Creatine is produced endogenously at an amount of about 1 g/d. Synthesis predominately occurs in the liver, kidneys, and to a lesser extent in the pancreas. The remainder of the creatine available to the body is obtained through the diet at about 1 g/d for an omnivorous diet. 95% of the bodies creatine stores are found in the skeletal muscle and the remaining 5% is distributed in the brain, liver, kidney, and testes [1].
  16. 1 2 Brosnan ME, Brosnan JT (August 2016). "The role of dietary creatine". Amino Acids. 48 (8): 1785–91. doi:10.1007/s00726-016-2188-1. PMID   26874700. S2CID   3700484. The daily requirement of a 70-kg male for creatine is about 2 g; up to half of this may be obtained from a typical omnivorous diet, with the remainder being synthesized in the body ... More than 90% of the body's creatine and phosphocreatine is present in muscle (Brosnan and Brosnan 2007), with some of the remainder being found in the brain (Braissant et al. 2011). ... Creatine synthesized in liver must be secreted into the bloodstream by an unknown mechanism (Da Silva et al. 2014a)
  17. 1 2 3 4 5 Hultman E, Söderlund K, Timmons JA, Cederblad G, Greenhaff PL (July 1996). "Muscle creatine loading in men". Journal of Applied Physiology. 81 (1): 232–7. doi:10.1152/jappl.1996.81.1.232. PMID   8828669.
  18. ↑ Balsom PD, Söderlund K, Ekblom B (October 1994). "Creatine in humans with special reference to creatine supplementation". Sports Medicine. 18 (4): 268–80. doi:10.2165/00007256-199418040-00005. PMID   7817065. S2CID   23929060.
  19. 1 2 Harris RC, Söderlund K, Hultman E (September 1992). "Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation". Clinical Science. 83 (3): 367–74. doi:10.1042/cs0830367. PMID   1327657.
  20. ↑ Brosnan JT, da Silva RP, Brosnan ME (May 2011). "The metabolic burden of creatine synthesis". Amino Acids. 40 (5): 1325–31. doi:10.1007/s00726-011-0853-y. PMID   21387089. S2CID   8293857. Creatinine loss averages approximately 2 g (14.6 mmol) for 70 kg males in the 20- to 39-year age group. ... Table 1 Comparison of rates of creatine synthesis in young adults with dietary intakes of the three precursor amino acids and with the whole body transmethylation flux
    Creatine synthesis (mmol/day)   8.3
  21. ↑ "Creatine". Beth Israel Deaconess Medical Center. Archived from the original on 28 January 2011. Retrieved 23 August 2010.
  22. 1 2 Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (January 1992). "Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis". The Biochemical Journal. 281 ( Pt 1) (Pt 1): 21–40. doi:10.1042/bj2810021. PMC   1130636 . PMID   1731757.
  23. ↑ Spillane M, Schoch R, Cooke M, Harvey T, Greenwood M, Kreider R, Willoughby DS (February 2009). "The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels". Journal of the International Society of Sports Nutrition. 6 (1): 6. doi: 10.1186/1550-2783-6-6 . PMC   2649889 . PMID   19228401.
  24. ↑ Wallimann T, Tokarska-Schlattner M, Schlattner U (May 2011). "The creatine kinase system and pleiotropic effects of creatine". Amino Acids. 40 (5): 1271–96. doi:10.1007/s00726-011-0877-3. PMC   3080659 . PMID   21448658..
  25. ↑ T. Wallimann, M. Tokarska-Schlattner, D. Neumann u. a.: The Phosphocreatine Circuit: Molecular and Cellular Physiology of Creatine Kinases, Sensitivity to Free Radicals, and Enhancement by Creatine Supplementation. In: Molecular System Bioenergetics: Energy for Life. 22. November 2007. doi : 10.1002/9783527621095.ch7C
  26. ↑ Hespel P, Eijnde BO, Derave W, Richter EA (2001). "Creatine supplementation: exploring the role of the creatine kinase/phosphocreatine system in human muscle". Canadian Journal of Applied Physiology. 26 Suppl: S79-102. doi:10.1139/h2001-045. PMID   11897886.
  27. ↑ "L-Arginine:Glycine Amidinotransferase". Archived from the original on 24 August 2013. Retrieved 16 August 2010.
  28. 1 2 Braissant O, Henry H, Béard E, Uldry J (May 2011). "Creatine deficiency syndromes and the importance of creatine synthesis in the brain" (PDF). Amino Acids. 40 (5): 1315–24. doi:10.1007/s00726-011-0852-z. PMID   21390529. S2CID   13755292. Archived (PDF) from the original on 10 March 2021. Retrieved 8 July 2019.
  29. ↑ Rogerson D (2017). "Vegan diets: practical advice for athletes and exercisers". J Int Soc Sports Nutr. 14: 36. doi: 10.1186/s12970-017-0192-9 . PMC   5598028 . PMID   28924423.
  30. ↑ Persky AM, Brazeau GA (June 2001). "Clinical pharmacology of the dietary supplement creatine monohydrate". Pharmacological Reviews. 53 (2): 161–76. PMID   11356982.
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