Molecular and Cellular Biochemistry

, Volume 224, Issue 1–2, pp 169–181 | Cite as

Creatine and the creatine transporter: A review

  • Rodney J. SnowEmail author
  • Robyn M. Murphy


The cellular role of creatine (Cr) and Cr phosphate (CrP) has been studied extensively in neural, cardiac and skeletal muscle. Several studies have demonstrated that alterations in the cellular total Cr (Cr + CrP) concentration in these tissues can produce marked functional and/or structural change. The primary aim of this review was to critically evaluate the literature that has examined the regulation of cellular total Cr content. In particular, the review focuses on the regulation of the activity and gene expression of the Cr transporter (CreaT), which is primarily responsible for cellular Cr uptake. Two CreaT genes (CreaT1 and CreaT2) have been identified and their chromosomal location and DNA sequencing have been completed. From these data, putative structures of the CreaT proteins have been formulated. Transcription products of the CreaT2 gene are expressed exclusively in the testes, whereas CreaT1 transcripts are found in a variety of tissues. Recent research has measured the expression of the CreaT1 protein in several tissues including neural, cardiac and skeletal muscle. There is very little information available about the factors regulating CreaT gene expression. There is some evidence that suggests the intracellular Cr concentration may be involved in the regulatory process but there is much more to learn before this process is understood. The activity of the CreaT protein is controlled by many factors. These include substrate concentration, transmembrane Na+ gradients, cellular location, and various hormones. It is also likely that transporter activity is influenced by its phosphorylation state and by its interaction with other plasma membrane proteins. The extent of CreaT protein glycosylation may vary within cells, the functional significance of which remains unclear.

nutritional supplement neuromuscular diseases genetic regulation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Walker JB: Creatine: Biosynthesis, regulation, and function. Adv Enzymol 50: 177–252, 1979Google Scholar
  2. 2.
    Braissant O, Henry H, Loup M, Eilers B, Bachmann C: Endogenous synthesis and transport of creatine in the rat brain: An in situ hybridization study. Mol Brain Res 86: 193–201, 2001Google Scholar
  3. 3.
    Moore NP: The distribution, metabolism and function of creatine in the male mammalian reproductive tract: A review. Int J Androl 23: 4–12, 2000Google Scholar
  4. 4.
    Balsom PD, Soderlund K, Ekblom B: Creatine in humans with special reference to creatine supplementation. Sports Med 18: 268–280, 1994Google Scholar
  5. 5.
    Hoberman HD, Sims EAH, Peters JH: Creatine and creatinine metabolism in the normal male adult studied with the aid of isotopic nitrogen. J Biol Chem 172: 45–58, 1948Google Scholar
  6. 6.
    Hoogwerf BJ, Laine DC, Greene E: Urine C-peptide and creatinine (Jaffe method) excretion in healthy young adults on varied diets: Sustained effects of varied carbohydrate, protein, and meat content. Am J Clin Nutr 43: 350–360, 1986Google Scholar
  7. 7.
    Borsook H, Dubnoff JW: The hydrolysis of phosphocreatine and the origin of urinary creatinine. J Biol Chem 168: 493–510, 1947Google Scholar
  8. 8.
    Boroujerdi M, Mattocks AM: Metabolism of creatinine in vivo. Clin Chem 29: 1363–1366, 1983Google Scholar
  9. 9.
    Wang E: Clinical and experimental investigations on the creatine metabolism. Acta Med Scand 105(suppl): 66–75, 1939Google Scholar
  10. 10.
    Hultman E, Soderlund K, Timmons JA, Cederblad G, Greenhaff PL: Muscle creatine loading in men. J Appl Physiol 81: 232–237, 1996Google Scholar
  11. 11.
    Harris RC, Soderlund K, Hultman E: Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci 83: 367–374, 1992Google Scholar
  12. 12.
    Daly MM, Seifter S: Uptake of creatine by cultured cells. Arch Biochem Biophys 203: 317–324, 1980Google Scholar
  13. 13.
    Dai WX, Vinnakota S, Qian XJ, Kunze DL, Sarkar HK: Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Arch Biochem Biophys 361: 75–84, 1999Google Scholar
  14. 14.
    Loike JD, Somes M, Silverstein SC: Creatine uptake, metabolism, and efflux in human monocytes and macrophages. Am J Physiol 251: C128–C135, 1986Google Scholar
  15. 15.
    Loike JD, Zalutsky DL, Kaback E, Miranda AF, Silverstein SC: Extracellular creatine regulates creatine transport in rat and human muscle cells. Proc Natl Acad Sci 85: 807–811, 1988Google Scholar
  16. 16.
    Odoom JE, Kemp GJ, Radda GK: The regulation of total creatine content in a myoblast cell line. Mol Cell Biochem 158: 179–188, 1996Google Scholar
  17. 17.
    Guimbal C, Kilimann MW: A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression. J Biol Chem 268: 8418–8421, 1993Google Scholar
  18. 18.
    Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM: Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 281: 21–40, 1992Google Scholar
  19. 19.
    Carpenter CL, Mohan C, Bessman SP: Inhibition of protein and lipid synthesis in muscle by 2,4-dinitrofluorobenzene, an inhibitor of creatine phosphokinase. Biochem Biophys Res Commun 111: 884–889, 1983Google Scholar
  20. 20.
    Ingwall JS: Creatine and the control of muscle-specific protein synthesis in cardiac and skeletal muscle. Circ Res 38: 115–123, 1976Google Scholar
  21. 21.
    Young RB, Denome RM: Effect of creatine on contents of myosin heavy chain and myosin-heavy-chain mRNA in steady state chicken muscle-cell cultures. Biochem J 218: 871–876, 1984Google Scholar
  22. 22.
    Hultman E, Sahlin K: Acid-base balance during exercise. Ex Sport Sci Rev 8: 41–127, 1980Google Scholar
  23. 23.
    Wyss M, Kaddurah-Daouk R: Creatine and creatinine metabolism. Physiol Rev 80: 1107–1213, 2000Google Scholar
  24. 24.
    Felber S, Skladal D, Wyss M, Kremser C, Koller A, Sperl W: Oral creatine supplementation in Duchenne muscular dystrophy: A clinical and 31P magnetic resonance spectroscopy study. Neurol Res 22: 145–150, 2000Google Scholar
  25. 25.
    Vorgerd M, Grehl T, Jager M, Muller K, Freitag G, Patzold T, Bruns N, Fabian K, Tegenthoff M, Mortier W, Luttmann A, Zange J, Malin JP: Creatine therapy in myophosphorylase deficiency (McArdle Disease): A placebo-controlled crossover trial. Arch Neurol 57: 956–963, 2000Google Scholar
  26. 26.
    Willer B, Stucki G, Hoppeler H, Bruhlmann P, Krahenbuhl S: Effects of creatine supplementation on muscle weakness in patients with rheumatoid arthritis. Rheumatology 39: 293–298, 2000Google Scholar
  27. 27.
    van der Knaap MS, Verhoeven NM, Maaswinkel Mooij P, Pouwels PJ, Onkenhout W, Peeters EA, Stockler Ipsiroglu S, Jakobs C: Mental retardation and behavioral problems as presenting signs of a creatine synthesis defect. Ann Neurol 47: 540–543, 2000Google Scholar
  28. 28.
    Leuzzi V, Bianchi MC, Tosetti M, Carducci C, Cerquiglini CA, Cioni G, Antonozzi I: Brain creatine depletion: guanidinoacetate methyltransferase deficiency (improving with creatine supplementation). Neurology 55: 1407–1409, 2000Google Scholar
  29. 29.
    Bianchi MC, Tosetti M, Fornai F, Alessandri MG, Cipriani P, De Vito G, Canapicchi R: Reversible brain creatine deficiency in two sisters with normal blood creatine level. Ann Neurol 47: 511–513, 2000Google Scholar
  30. 30.
    Passaquin A, Renard M, Kay L, Challet C, Mokhtarian A, Wallimann T, Ruegg U: Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice. Neuromus Dis: 2001 (in press)Google Scholar
  31. 31.
    Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF: Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J Neurosci 20: 4389–4397, 2000Google Scholar
  32. 32.
    Shear DA, Haik KL, Dunbar GL: Creatine reduces 3-nitropropionicacid-induced cognitive and motor abnormalities in rats. Clin Neurosci 11: 1833–1837, 2000Google Scholar
  33. 33.
    Wilken B, Ramirez JM, Probst I, Richter DW, Hanefeld F: Anoxic ATP depletion in neonatal mice brainstem is prevented by creatine supplementation. Arch Dis Child Fetal Neonatal Ed 82: F224–F227, 2000Google Scholar
  34. 34.
    Sullivan PG, Geiger JD, Mattson MP, Scheff SW: Dietary supplement creatine protects against traumatic brain injury. Ann Neurol 48: 723–729, 2000Google Scholar
  35. 35.
    Brewer GJ, Wallimann TW: Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J Neurochem 74: 1968–1978, 2000Google Scholar
  36. 36.
    Brustovetsky N, Brustovetsky T, Dubinsky JM: On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem 76: 425–434, 2001Google Scholar
  37. 37.
    Demant TW, Rhodes EC: Effects of creatine supplementation on exercise performance. Sports Med 28: 49–60, 1999Google Scholar
  38. 38.
    Haff GG, Kirksey KB: Creatine supplementation. Strength and conditioning 21: 13–23, 1999Google Scholar
  39. 39.
    Juhn MS: Oral creatine supplementation separating fact from hype. Physician Sports Med 27: 47–57, 1999Google Scholar
  40. 40.
    Silber ML: Scientific facts behind creatine monohydrate as sport nutrition supplement. J Sports Med Phys Fitness 39: 179–188, 1999 179Google Scholar
  41. 41.
    Feldman EB: Creatine: A dietary supplement and ergogenic aid. Nutr Rev 57: 45–50, 1999Google Scholar
  42. 42.
    Greenhaff PL: Creatine and its application as an ergogenic aid. Int J Sport Nutr 5: S100–S110, 1995Google Scholar
  43. 43.
    Greenhaff PL: Creatine supplementation: Recent developments. Br J Sports Med 30: 276–281, 1996Google Scholar
  44. 44.
    Greenhaff PL: The nutritional biochemistry of creatine. J Nutr Biochem 8: 610–618, 1997Google Scholar
  45. 45.
    Jacobs I: Dietary creatine monohydrate supplementation. Can J Appl Physiol 24: 503–514, 1999Google Scholar
  46. 46.
    Kraemer WJ, Volek JS: Creatine supplementation. Its role in human performance. Clin Sports Med 18: 651–666, 1999Google Scholar
  47. 47.
    Kreider R: Creatine supplementation: Analysis of ergogenic value, medical safety, and concerns. J Exerc Physiol 1: online, 1998Google Scholar
  48. 48.
    Mujika I, Padilla S: Creatine supplementation as an ergogenic aid for sports performance in highly trained athletes: a critical review. Int J Sports Med 18: 491–496, 1997Google Scholar
  49. 49.
    Plisk SS, Kreider RB: Creatine controversy? Strength and Conditioning 21: 14–23, 1999Google Scholar
  50. 50.
    Williams MH, Branch JD: Creatine supplementation and exercise performance: An update. J Am Coll Nutr 17: 216–234, 1998Google Scholar
  51. 51.
    Wyss M, Wallimann T: Creatine metabolism and the consequences of creatine depletion in muscle. Mol Cell Biochem 133/4: 51–66, 1994Google Scholar
  52. 52.
    Dodd JR, Zheng T, Christie DL: Creatine accumulation and exchange by HEK293 cells stably expressing high levels of creatine transporter. Biochim Biophys Acta 1472: 128–136, 1999Google Scholar
  53. 53.
    Tarnopolsky MA, Parshad A, Walzel B, Schlattner U, Wallimann T: Creatine transporter and mitochondrial creatine kinase protein content in myopathies. Muscle Nerve: 24: 682–688, 2001Google Scholar
  54. 54.
    Eichler EE, Lu F, Shen Y, Antonacci R, Jurecic V, Doggett NA, Moyzis RK, Baldini A, Gibbs RA, Nelson DL: Duplication of a gene-rich cluster between 16p11.1 and Xq28: A novel pericentrometric-directed mechanism for paralogous genome evolution. Hum Mol Gen 5: 899–912, 1996Google Scholar
  55. 55.
    Gregor P, Nash SR, Caron MG, Seldin MF, Warren ST: Assignment of the creatine transporter gene (SLC6A8) to human chromosome Xq28 telomeric to G6PD. Genomics 25: 332–333, 1995Google Scholar
  56. 56.
    Iyer GS, Krahe R, Goodwin LA, Doggett NA, Siciliano MJ, Funanage VL, Proujansky R: Identification of a testis-expressed creatine transporter gene at 16p11.2 and confirmation of the X-linked locus to Xq28. Genomics 34: 143–146, 1996Google Scholar
  57. 57.
    Sandoval N, Bauer D, Brenner V, Coy JF, Drescher B, Kioschis P, Korn B, Nyakatura G, Poustka A, Reichwald K, Rosenthal A, Platzer M: The genomic organization of a human creatine transporter (CRTR) gene located in Xq28. Genomics 35: 383–385, 1996Google Scholar
  58. 58.
    Mayser W, Schloss P, Betz H: Primary structure and functional expression of a choline transporter expressed in the rat nervous system. FEBS Lett 305: 31–36, 1992Google Scholar
  59. 59.
    Nash SR, Giros B, Kingsmore SF, Rochelle JM, Suter ST, Gregor P, Seldin MF, Caron MG: Cloning, pharmacological characterization, and genomic localization of the human creatine transporter. Receptors Channels 2: 165–174, 1994Google Scholar
  60. 60.
    Saltarelli MD, Bauman AL, Moore KR, Bradley CC, Blakely RD: Expression of the rat brain creatine transporter in situ and in transfected HeLa cells. Dev Neurosci 18: 524–534, 1996Google Scholar
  61. 61.
    Sora I, Richman J, Santoro G, Wei H, Wang Y, Vanderah T, Horvath R, Nguyen M, Waite S, Roeske WR, Yamamura HI: The cloning and expression of a human creatine transporter. Biochem Biophys Res Commun 204: 419–427, 1994Google Scholar
  62. 62.
    Ades LC, Gedeon AK, Wilson MJ, Latham M, Partington MW, Mulley JC, Nelson J, Lui K, Sillence DO: Barth syndrome: Clinical features and confirmation of gene localisation to distal Xq28. Am J Med Genet 45: 327–334, 1993Google Scholar
  63. 63.
    Bolhuis PA, Hensels GW, Hulsebos TJ, Baas F, Barth PG: Mapping of the locus for X-linked cardioskeletal myopathy with neutropenia and abnormal mitochondria (Barth syndrome) to Xq28. Am J Hum Genet 48: 481–485, 1991Google Scholar
  64. 64.
    Consalez GG, Thomas NS, Stayton CL, Knight SJ, Johnson M, Hopkins LC, Harper PS, Elsas LJ, Warren ST: Assignment of Emery-Dreifuss muscular dystrophy to the distal region of Xq28: The results of a collaborative study. Am J Hum Genet 48: 468–480, 1991Google Scholar
  65. 65.
    Thomas NS, Williams H, Cole G, Roberts K, Clarke A, Liechti Gallati S, Braga S, Gerber A, Meier C, Moser H, Harper PS: X linked neonatal centronuclear/myotubular myopathy: Evidence for linkage to Xq28 DNA marker loci. J Med Genet 27: 284–287, 1990Google Scholar
  66. 66.
    Guerrero-Ontiveros ML, Wallimann T: Creatine supplementation in health and disease. Effects of chronic creatine ingestion in vivo: Downregulation of the expression of creatine transporter isoforms in skeletal muscle. Mol Cell Biochem 184: 427–437, 1998Google Scholar
  67. 67.
    Xu W, Liu L, Gorman PA, Sheer D, Emson PC: Assignment of the human creatine transporter type 2 (SLC6A10) to chromosome band 16p11.2 by in situ hybridization. Cytogenet Cell Genet 76: 19, 1997Google Scholar
  68. 68.
    Schloss P, Mayser W, Betz H: The putative rat choline transporter CHOT1 transports creatine and is highly expressed in neural and muscle-rich tissues. Biochem Biophys Res Commun 198: 637–645, 1994Google Scholar
  69. 69.
    Guimbal C, Kilimann MW: A creatine transporter cDNA from Torpedo illustrates structure/function relationships in the GABA/noradrenaline transporter family. J Mol Biol 241: 317–324, 1994Google Scholar
  70. 70.
    Neubauer S, Remkes H, Spindler M, Horn M, Wiesmann F, Prestle J, Walzel B, Ertl G, Hasenfuss G, Wallimann T: Downregulation of the Na(+)-creatine cotransporter in failing human myocardium and in experimental heart failure. Circulation 100: 1847–1850, 1999Google Scholar
  71. 71.
    Wallimann T, Schlattner U, Guerrero L, Dolder M: The phosphocreatine circuit and creatine supplementation, both come of age! In: A. Mori, M. Ishida, J.F. Clark (eds). Guanidino Compounds. Blackwell Science Asia, Australia, 1994, pp. 117–129Google Scholar
  72. 72.
    Bennett SE, Bevington A, Walls J: Regulation of intracellular creatine in erythrocytes and myoblasts: Influence of uraemia and inhibition of Na,K-ATPase. Cell Biochem Funct 12: 99–106, 1994Google Scholar
  73. 73.
    Ku CP, Passow H: Creatine and creatinine transport in old and young human red blood cells. Biochim Biophys Acta 600: 212–227, 1980Google Scholar
  74. 74.
    Syllm-Rapoport I, Daniel A, Rapoport S: Creatine transport into red blood cells. Acta Biol Med Ger 39: 771–779, 1980Google Scholar
  75. 75.
    Syllm-Rapoport I, Daniel A, Starck H, Gotze W, Hartwig A, Gross J, Rapoport S: Creatine in red cells: Transport and erythropoietic dynamics. Acta Biol Med Ger 40: 653–659, 1981Google Scholar
  76. 76.
    Murphy R, McConell G, Cameron-Smith D, Watt K, Ackland L, Walzel B, Wallimann T, Snow R: Creatine transporter gene expression and protein localization in rat skeletal muscle. Am J Physiol (Cell) 280: C415–C422, 2001Google Scholar
  77. 77.
    Delp MD, Duan C: Composition and size of type I, IIA, IID/X, and IIB fibers and citrate synthase activity of rat muscle. J Appl Physiol 80: 261–270, 1996Google Scholar
  78. 78.
    Willott CA, Young ME, Leighton B, Kemp GJ, Boehm EA, Radda GK, Clarke K: Creatine uptake in isolated soleus muscle: Kinetics and dependence on sodium, but not on insulin. Acta Physiol Scand 166: 99–104, 1999Google Scholar
  79. 79.
    Op't Eijnde R, Richter EA, Kiens B, Hespel P: Effect of creatine on glucose disposal in rat skeletal muscle. J Sports Sci 17: 561–562, 1999Google Scholar
  80. 80.
    McMillen J, Donovan CM, Messer JI, Willis WT: Energetic driving forces are maintained in resting rat skeletal muscle after dietary creatine supplementation. J Appl Physiol 90: 62–66, 2001Google Scholar
  81. 81.
    Casey A, Constantin Teodosiu D, Howell S, Hultman E, Greenhaff PL: Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol 271: E31–E37, 1996 180Google Scholar
  82. 82.
    Kreis R, Kamber M, Koster M, Felblinger J, Slotboom J, Hoppeler H, Boesch C: Creatine supplementation - Part II: In vivo magnetic resonance spectroscopy. Med Sci Sports Exerc 31: 1770–1777, 1999Google Scholar
  83. 83.
    Johnson MA, Polgar J, Weightman D, Appleton D: Data on the distribution of fibre types in thirty-six human muscles: An autopsy study. J Neurol Sci 18: 111–129, 1973Google Scholar
  84. 84.
    Kekelidze T, Khait I, Togliatti A, Holtzman D: Brain creatine kinase and creatine transporter proteins in normal and creatine-treated rabbit pups. Dev Neurosci 22: 437–443, 2000Google Scholar
  85. 85.
    Tran TT, Dai W, Sarkar HK: Cyclosporin A inhibits creatine uptake by altering surface expression of the creatine transporter. J Biol Chem 275: 35708–35714, 2000Google Scholar
  86. 86.
    Walzel B, Straumann N, Hornemann T, Magyar J, Kay L, Kristiansen S, Richter EA, Wallimann T: In: 2nd Colloquium on Mitochondria and Myopathies. Halle/Saale, 2000Google Scholar
  87. 87.
    Moller A, Hamprecht B: Creatine transport in cultured cells of rat and mouse brain. J Neurochem 52: 544–550, 1989Google Scholar
  88. 88.
    Fitch CD, Shields RP: Creatine metabolism in skeletal muscle. I. Creatine movement across muscle membranes. J Biol Chem 241: 3611–3614, 1966Google Scholar
  89. 89.
    Fitch CD, Shields RP, Payne WF, Dacus JM: Creatine metabolism in skeletal muscle. III. Specificity of the creatine entry process. J Biol Chem 243: 2024–2027, 1968Google Scholar
  90. 90.
    Seppet EK, Adoyaan AJ, Kallikorm AP, Chernousova GB, Lyulina NV, Sharov VG, Severin VV, Popovich MI, Saks VA: Hormone regulation of cardiac energy metabolism. I. Creatine transport across cell membranes of euthyroid and hyperthyroid rat heart. Biochem Med 34: 267–279, 1985Google Scholar
  91. 91.
    Marescau B, De Deyn P, Wiechert P, Van Gorp L, Lowenthal A: Comparative study of guanidino compounds in serum and brain of mouse, rat, rabbit, and man. J Neurochem 46: 717–720, 1986Google Scholar
  92. 92.
    Snow RJ, McKenna MJ, Selig SE, Kemp J, Stathis CG, Zhao S: Effect of creatine supplementation on sprint exercise performance and muscle metabolism. J Appl Physiol 84: 1667–1673, 1998Google Scholar
  93. 93.
    Brannon TA, Adams GR, Conniff CL, Baldwin KM: Effects of creatine loading and training on running performance and biochemical properties of rat skeletal muscle. Med Sci Sports Exerc 29: 489–495, 1997Google Scholar
  94. 94.
    Brzezinska Z, Nazar K, Kaciuba Uscilko H, Falecka Wieczorek I, Wojcik Ziolkowska E: Effect of a short-term dietary creatine supplementation on high-energy phosphates in the rat myocardium. J Physiol Pharmacol 49: 591–595, 1998Google Scholar
  95. 95.
    Febbraio MA, Flanagan TR, Snow RJ, Zhao S, Carey MF: Effect of creatine supplementation on intramuscular TCr, metabolism and performance during intermittent, supramaximal exercise in humans. Acta Physiol Scand 155: 387–395, 1995Google Scholar
  96. 96.
    McKenna MJ, Morton J, Selig SE, Snow RJ: Creatine supplementation increase muscle total creatine, but not maximal intermittent exercise performance. J Appl Physiol 87: 2244–2252, 1999Google Scholar
  97. 97.
    Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL: Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol 271: E821–E826, 1996Google Scholar
  98. 98.
    Rossiter HB, Cannell ER, Jakeman PM: The effect of oral creatine supplementation on the 1000-m performance of competitive rowers. J Sports Sci 14: 175–179, 1996Google Scholar
  99. 99.
    Maganaris CN, Maughan RJ: Creatine supplementation enhances maximum voluntary isometric force and endurance capacity in resistance trained men. Acta Physiol Scand 163: 279–287, 1998Google Scholar
  100. 100.
    Peyrebrune MC, Nevill ME, Donaldson FJ, Cosford DJ: The effects of oral creatine supplementation on performance in single and repeated sprint swimming. J Sports Sci 16: 271–279, 1998Google Scholar
  101. 101.
    Robinson TM, Sewell DA, Hultman E, Greenhaff PL: Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle. J Appl Physiol 87: 598–604, 1999Google Scholar
  102. 102.
    Halestrap AP, Price NT: The proton-linked monocarboxylate transporter (MCT) family: Structure, function and regulation. Biochem J 343: 281–299, 1999Google Scholar
  103. 103.
    Ruiz-Montasell B, Gomez-Angelats M, Casado FJ, Felipe A, McGivan JD, Pastor-Anglada M: Evidence for a regulatory protein involved in the increased activity of system A for neutral amino acid transport in osmotically stressed mammalian cells. Proc Natl Acad Sci USA 91: 9569–9573, 1994Google Scholar
  104. 104.
    Gomez-Angelats M, Lopez-Fontanals M, Felipe A, Casado FJ, Pastor-Anglada M: Cytoskeletal-dependent activation of system A for neutral amino acid transport in osmotically stressed mammalian cells: A role for system A in the intracellular accumulation of osmolytes. J Cell Physiol 173: 343–350, 1997Google Scholar
  105. 105.
    Clausen T: Clinical and therapeutic significance of the Na+,K+ pump. Clin Sci 95: 3–17, 1998Google Scholar
  106. 106.
    Steenge GR, Lambourne J, Casey A, Macdonald IA, Greenhaff PL: Stimulatory effect of insulin on creatine accumulation in human skeletal muscle. Am J Physiol 38: E974–E979, 1998Google Scholar
  107. 107.
    Haugland RB, Chang DT: Insulin effect on creatine transport in skelatal muscle. Proc Soc Exp Biol Med 148: 1–4, 1975Google Scholar
  108. 108.
    Koszalka TR, Andrew CL, Brent RL: Effect of insulin on the uptake of creatine-1-14C by skeletal muscle in normal and x-irradiated rats. Proc Soc Exp Biol Med 139: 1265–1271, 1972Google Scholar
  109. 109.
    Steenge GR, Simpson EJ, Greenhaff PL: Protein-and carbohydrateinduced augmentation of whole body creatine retention in humans. J Appl Physiol 89: 1165–1171, 2000Google Scholar
  110. 110.
    Varki A: Biological roles of oligosaccharides. Glycobiology 3: 97–130, 1993Google Scholar
  111. 111.
    Tate CG, Blakely RD: The effect of N-linked glycosylation on activity of the Na(+)-and Cl(-)-dependent serotonin transporter expressed using recombinant baculovirus in insect cells. J Biol Chem 269: 26303–26310, 1994Google Scholar
  112. 112.
    Olivares L, Aragon C, Gimenez C, Zafra F: The role of N-glycosylation in the targeting and activity of the GLYT1 glycine transporter. J Biol Chem 270: 9437–9442, 1995Google Scholar
  113. 113.
    Kornfeld S: Diseases of abnormal protein glycosylation: An emerging area. J Clin Invest 101: 1293–1295, 1998Google Scholar
  114. 114.
    Rajab P, Greenhaff PL, Constantin-Teodosiu D, Bennett A, Anderton KA, White DA, Mayer RJ, Gardiner SM, Bennett T: Dietary creatine supplementation increases creatine transporter mRNA content and 26S proteasome activity in rat myocardium. J Physiol 515: 64P, 1999Google Scholar
  115. 115.
    Kelso TB, Hodgson DR, Visscher AR, Gollnick PD: Some properties of different skeletal muscle fiber types: Comparison of reference bases. J Appl Physiol 62: 1436–1441, 1987Google Scholar
  116. 116.
    Spriet LL: ATP utilization and provision in fast-twitch skeletal muscle during tetanic contractions. Am J Physiol 257: E595–E605, 1989Google Scholar
  117. 117.
    Spriet LL: Anaerobic ATP provision, glycogenolysis and glycolysis in rat slow-twitch muscle during tetanic contractions. Pflügers Arch 417: 278–284, 1990Google Scholar
  118. 118.
    Yaspelkis BB III, Castle AL, Ding Z, Ivy JL: Attenuating the decline in ATP arrests the exercise training-induced increases in muscle GLUT4 protein and citrate synthase activity. Acta Physiol Scand 165: 71–79, 1999Google Scholar
  119. 119.
    Ponticos M, Lu QL, Morgan JE, Hardie DG, Partridge TA, Carling D: Dual regulation of the AMP-activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle. EMBO J 17: 1688–1699, 1998Google Scholar
  120. 120.
    Kemp BE, Mitchelhill KI, Stapleton D, Michell BJ, Chen ZP, Witters LA: Dealing with energy demand: The AMP-activated protein kinase. Trends Biochem Sci 24: 22–25, 1999 181Google Scholar
  121. 121.
    Constantin-Teodosiu D, Greenhaff PL, Gardiner SM, Randall MD, March JE, Bennett T: Attenuation by creatine of myocardial metabolic stress in Brattleboro rats caused by chronic inhibition of nitric oxide synthase. Br J Pharmacol 116: 3288–3292, 1995Google Scholar
  122. 122.
    Horn M, Frantz S, Remkes H, Laser A, Urban B, Mettenleiter A, Schnackerz K, Neubauer S: Effects of chronic dietary creatine feeding on cardiac energy metabolism and on creatine content in heart, skeletal muscle, brain, liver and kidney. J Mol Cell Cardiol 30: 277–284, 1998Google Scholar
  123. 123.
    Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah Daouk R, Beal MF: Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. J Neurosci 18: 156–163, 1998Google Scholar
  124. 124.
    Dechent P, Pouwels PJW, Wilken B, Hanefeld F, Frahm J: Increase of total creatine in human brain after oral supplementation of creatinemonohydrate. Am J Physiol 46: R698–R704, 1999Google Scholar
  125. 125.
    Hiel H, Happe HK, Warr WB, Morley BJ: Regional distribution of a creatine transporter in rat auditory brainstem: An in-situ hybridization study. Hear Res 98: 29–37, 1996 182Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  1. 1.School of Health SciencesDeakin UniversityBurwoodAustralia

Personalised recommendations