Editing Creatine (section)

==Metabolic role==
Creatine is a naturally occurring non-protein compound and the primary constituent of phosphocreatine, which is used to regenerate [[Adenosine triphosphate|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.<ref name="pmid22817979">{{cite journal |vauthors=Cooper R, Naclerio F, Allgrove J, Jimenez A |title=Creatine supplementation with specific view to exercise/sports performance: an update |journal=Journal of the International Society of Sports Nutrition |volume=9 |issue=1 |pages=33 |date=July 2012 |pmid=22817979 |pmc=3407788 |doi=10.1186/1550-2783-9-33 |quote=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]. |doi-access=free }}</ref><ref name="pmid26874700">{{cite journal |vauthors=Brosnan ME, Brosnan JT |title=The role of dietary creatine |journal=Amino Acids |volume=48 |issue=8 |pages=1785–91 |date=August 2016 |pmid=26874700 |doi=10.1007/s00726-016-2188-1 |s2cid=3700484 |quote=The daily requirement of a 70-kg male for creatine is about 2&nbsp;g; up to half of this may be obtained from a typical omnivorous diet, with the remainder being synthesized in the body&nbsp;... 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).&nbsp;... Creatine synthesized in liver must be secreted into the bloodstream by an unknown mechanism (Da Silva et al. 2014a)}}</ref> The typical creatine content of skeletal muscle (as both creatine and phosphocreatine) is 120&nbsp;mmol per kilogram of dry muscle mass, but can reach up to 160&nbsp;mmol/kg through supplementation.<ref name=":2">{{cite journal |vauthors=Hultman E, Söderlund K, Timmons JA, Cederblad G, Greenhaff PL |date=July 1996 |title=Muscle creatine loading in men |journal=Journal of Applied Physiology |volume=81 |issue=1 |pages=232–7 |doi=10.1152/jappl.1996.81.1.232 |pmid=8828669}}</ref> 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.<ref name=":2" /><ref>{{cite journal |vauthors=Balsom PD, Söderlund K, Ekblom B |title=Creatine in humans with special reference to creatine supplementation |journal=Sports Medicine |volume=18 |issue=4 |pages=268–80 |date=October 1994 |pmid=7817065 |doi=10.2165/00007256-199418040-00005|s2cid=23929060 }}</ref><ref name=":5">{{cite journal |vauthors=Harris RC, Söderlund K, Hultman E |title=Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation |journal=Clinical Science |volume=83 |issue=3 |pages=367–74 |date=September 1992 |pmid=1327657 |doi=10.1042/cs0830367 }}</ref> An omnivorous diet provides roughly half of this value, with the remainder synthesized in the liver and kidneys.<ref name="pmid22817979" /><ref name="pmid26874700" /><ref name="pmid21387089">{{cite journal |vauthors=Brosnan JT, da Silva RP, Brosnan ME |date=May 2011 |title=The metabolic burden of creatine synthesis |journal=Amino Acids |volume=40 |issue=5 |pages=1325–31 |doi=10.1007/s00726-011-0853-y |pmid=21387089 |quote=Creatinine loss averages approximately 2&nbsp;g (14.6&nbsp;mmol) for 70&nbsp;kg males in the 20- to 39-year age group.&nbsp;... 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<br />Creatine synthesis (mmol/day)&nbsp;&nbsp;&nbsp;8.3 |s2cid=8293857}}</ref>

Creatine is not an [[essential nutrient]].<ref name="Creatine">{{Cite web|url=http://www.bidmc.org/YourHealth/ConditionsAZ.aspx?ChunkID=21706|title=Creatine|publisher=[[Beth Israel Deaconess Medical Center]]|access-date=23 August 2010|archive-date=28 January 2011|archive-url=https://web.archive.org/web/20110128035754/http://www.bidmc.org/YourHealth/ConditionsAZ.aspx?ChunkID=21706|url-status=live}}</ref> It is an amino acid [[Derivative (chemistry)|derivative]], naturally produced in the human body from the [[amino acid]]s [[glycine]] and [[arginine]], with an additional requirement for [[S-Adenosyl methionine|''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, [http://enzyme.expasy.org/EC/2.1.4.1 EC:2.1.4.1]) mediates the reaction of glycine and arginine to form [[guanidinoacetate]]. This product is then [[methylation|methylated]] by [[guanidinoacetate N-methyltransferase|guanidinoacetate ''N''-methyltransferase]] (GAMT, [http://enzyme.expasy.org/EC/2.1.1.2 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.

[[File:CreatineSynthesis(en).png|500px|center|class=skin-invert-image]]

===Phosphocreatine system===
[[File:Creatine kinase and phosphocreatine energy shuttle.png|thumb|464x464px|class=skin-invert-image|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 [[adenosine triphosphate|ATP]] in skeletal muscle is usually 2–5&nbsp;mM, which would result in a muscle contraction of only a few seconds.<ref name="ncbi.nlm.nih.gov">{{cite journal | vauthors = Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM | title = Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis | journal = The Biochemical Journal | volume = 281 ( Pt 1) | issue = Pt 1 | pages = 21–40 | date = January 1992 | pmid = 1731757 | pmc = 1130636 | doi = 10.1042/bj2810021 }}</ref> During times of increased energy demands, the [[phosphagen]] (or ATP/PCr) system rapidly resynthesizes ATP from [[adenosine diphosphate|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&nbsp;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.<ref name="ncbi.nlm.nih.gov" /> A proposed representation has been illustrated by Krieder et al.<ref name=":3" /> 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.<ref>{{cite journal | vauthors = Spillane M, Schoch R, Cooke M, Harvey T, Greenwood M, Kreider R, Willoughby DS | title = The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels | journal = Journal of the International Society of Sports Nutrition | volume = 6 | issue = 1 | pages = 6 | date = February 2009 | pmid = 19228401 | pmc = 2649889 | doi = 10.1186/1550-2783-6-6 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wallimann T, Tokarska-Schlattner M, Schlattner U | title = The creatine kinase system and pleiotropic effects of creatine | journal = Amino Acids | volume = 40 | issue = 5 | pages = 1271–96 | date = May 2011 | pmid = 21448658 | pmc = 3080659 | doi = 10.1007/s00726-011-0877-3 }}.</ref><ref>T. Wallimann, M. Tokarska-Schlattner, D. Neumann u.&nbsp;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.ch7}}C</ref>

Creatine supplementation appears to increase the number of [[myonuclei]] that satellite cells will 'donate' to damaged [[muscle fiber]]s, 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.<ref>{{cite journal | vauthors = Hespel P, Eijnde BO, Derave W, Richter EA | title = Creatine supplementation: exploring the role of the creatine kinase/phosphocreatine system in human muscle | journal = Canadian Journal of Applied Physiology | volume = 26 Suppl | pages = S79-102 | year = 2001 | pmid = 11897886 | doi = 10.1139/h2001-045 }}</ref>

===Genetic deficiencies===
Genetic deficiencies in the creatine biosynthetic pathway lead to various [[cerebral creatine deficiency|severe neurological defects]].<ref>{{Cite web |url=https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602360 |title=L-Arginine:Glycine Amidinotransferase |access-date=16 August 2010 |archive-date=24 August 2013 |archive-url=https://web.archive.org/web/20130824195046/http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602360 |url-status=live }}</ref> Clinically, there are three distinct disorders of creatine metabolism, termed [[Cerebral creatine deficiency|cerebral creatine deficiencies]]. Deficiencies in the two synthesis enzymes can cause [[Arginine:glycine amidinotransferase|L-arginine:glycine amidinotransferase deficiency]] caused by variants in ''[[GATM (gene)|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 is inherited in a X-linked manner. This condition is related to the transport of creatine into the brain.<ref name="creatinedefects">{{cite journal | vauthors = Braissant O, Henry H, Béard E, Uldry J | title = Creatine deficiency syndromes and the importance of creatine synthesis in the brain | journal = Amino Acids | volume = 40 | issue = 5 | pages = 1315–24 | date = May 2011 | pmid = 21390529 | doi = 10.1007/s00726-011-0852-z | s2cid = 13755292 | url = https://serval.unil.ch/resource/serval:BIB_CE3937F9A69E.P001/REF.pdf | access-date = 8 July 2019 | archive-date = 10 March 2021 | archive-url = https://web.archive.org/web/20210310001947/https://serval.unil.ch/resource/serval:BIB_CE3937F9A69E.P001/REF.pdf | url-status = live }}</ref>

===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.<ref>{{cite journal |vauthors=Rogerson D |title=Vegan diets: practical advice for athletes and exercisers |journal=J Int Soc Sports Nutr |volume=14 |issue= |pages=36 |date=2017 |pmid=28924423 |pmc=5598028 |doi=10.1186/s12970-017-0192-9 |doi-access=free |url=}}</ref>