Effects of dietary creatine supplementation on systemic microvascular density and reactivity in healthy young adults

Nutrition Journal

Eduardo Tibiriçá¹  Beatriz Serpa de Moraes¹  Diogo Van Bavel¹  Roger de Moraes² 

[1] Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Rio de Janeiro, Brazil;School of Physical Education and Sports Sciences of the Estácio de Sá University, Rio de Janeiro, Brazil

关键词: Post-occlusive reactive hyperemia;    Capillary recruitment;    Intra-vital video-microscopy;    Laser speckle contrast imaging;   

Others  :  1132392
DOI  :  10.1186/1475-2891-13-115

 received in 2014-10-16, accepted in 2014-12-09,  发布年份 2014

【 摘 要 】

Background

Dietary creatine supplementation (CrS) is a practice commonly adopted by physically active individuals. However, the effects of CrS on systemic microvascular reactivity and density have never been reported. Additionally, CrS is able to influence blood levels of homocysteine, resulting in presumed effects on vascular endothelial function. Thus, we investigated the effects of CrS on the systemic microcirculation and on homocysteine levels in healthy young individuals.

Methods

This open-label study was performed on a group of 40 healthy male, moderately physically active subjects aged 27.7 ± 13.4 years who received one week of CrS at a dose of 20 g/day of commercially available micronized creatine monohydrate. Laser speckle contrast imaging was used in the evaluation of cutaneous microvascular reactivity, and intra-vital video microscopy was used to evaluate skin capillary density and reactivity, before and after CrS.

Results

CrS did not alter plasma levels of homocysteine, although CrS increased creatinine (p = 0.0001) and decreased uric acid (p = 0.0004) plasma levels. Significant changes in total cholesterol (p = 0.0486) and LDL-cholesterol (p = 0.0027) were also observed along with a reduction in plasma levels of T3 (p = 0.0074) and an increase in T4 levels (p = 0.0003). Skin functional capillary density (p = 0.0496) and capillary recruitment during post-occlusive reactive hyperemia (p = 0.0043) increased after CrS. Increases in cutaneous microvascular vasodilation induced by post-occlusive reactive hyperemia (p = 0.0078) were also observed.

Conclusions

Oral supplementation with creatine in healthy, moderately physically active young adults improves systemic endothelial-dependent microvascular reactivity and increases skin capillary density and recruitment. These effects are not concurrent with changes in plasma homocysteine levels.

【 授权许可】

   
2014 de Moraes et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Hall M, Trojian TH: Creatine supplementation. Curr Sports Med Rep 2013, 12(4):240-244.
• [2]Sestili P, Martinelli C, Bravi G, Piccoli G, Curci R, Battistelli M, Falcieri E, Agostini D, Gioacchini AM, Stocchi V: Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity. Free Radic Biol Med 2006, 40(5):837-849.
• [3]Kley RA, Tarnopolsky MA, Vorgerd M: Creatine for treating muscle disorders. Cochrane Database Syst Rev 2013, 6:CD004760.
• [4]Allen PJ: Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value? Neurosci Biobehav Rev 2012, 36(5):1442-1462.
• [5]Gualano B, Roschel H, Lancha-Jr AH, Brightbill CE, Rawson ES: In sickness and in health: the widespread application of creatine supplementation. Amino Acids 2012, 43(2):519-529.
• [6]Adhihetty PJ, Beal MF: Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromolecular Med 2008, 10(4):275-290.
• [7]Strumia E, Pelliccia F, D'Ambrosio G: Creatine phosphate: pharmacological and clinical perspectives. Adv Ther 2012, 29(2):99-123.
• [8]Persky AM, Brazeau GA: Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev 2001, 53(2):161-176.
• [9]Gualano B, DE Salles Painneli V, Roschel H, Artioli GG, Neves M Jr, De Sa Pinto AL, Da Silva ME, Cunha MR, Otaduy MC, Leite Cda C, Ferreira JC, Pereira RM, Brum PC, Bonfá E, Lancha AH Jr: Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Med Sci Sports Exerc 2011, 43(5):770-778.
• [10]Nomura A, Zhang M, Sakamoto T, Ishii Y, Morishima Y, Mochizuki M, Kimura T, Uchida Y, Sekizawa K: Anti-inflammatory activity of creatine supplementation in endothelial cells in vitro. Br J Pharmacol 2003, 139(4):715-720.
• [11]Sanchez-Gonzalez MA, Wieder R, Kim JS, Vicil F, Figueroa A: Creatine supplementation attenuates hemodynamic and arterial stiffness responses following an acute bout of isokinetic exercise. Eur J Appl Physiol 2011, 111(9):1965-1971.
• [12]Deminice R, Portari GV, Vannucchi H, Jordao AA: Effects of creatine supplementation on homocysteine levels and lipid peroxidation in rats. Br J Nutr 2009, 102(1):110-116.
• [13]McCarty MF: Supplemental creatine may decrease serum homocysteine and abolish the homocysteine 'gender gap' by suppressing endogenous creatine synthesis. Med Hypotheses 2001, 56(1):5-7.
• [14]Jahangir E, Vita JA, Handy D, Holbrook M, Palmisano J, Beal R, Loscalzo J, Eberhardt RT: The effect of L-arginine and creatine on vascular function and homocysteine metabolism. Vasc Med 2009, 14(3):239-248.
• [15]Deminice R, Rosa FT, Franco GS, da Cunha SF, de Freitas EC, Jordao AA: Short-term creatine supplementation does not reduce increased homocysteine concentration induced by acute exercise in humans. Eur J Nutr 2013, 53(6):1355-1361.
• [16]Holowatz LA, Thompson-Torgerson CS, Kenney WL: The human cutaneous circulation as a model of generalized microvascular function. J Appl Physiol 2008, 105(1):370-372.
• [17]Roustit M, Cracowski JL: Assessment of endothelial and neurovascular function in human skin microcirculation. Trends Pharmacol Sci 2013, 34(7):373-384.
• [18]Cordovil I, Huguenin G, Rosa G, Bello A, Kohler O, de Moraes R, Tibirica E: Evaluation of systemic microvascular endothelial function using laser speckle contrast imaging. Microvasc Res 2012, 83(3):376-379.
• [19]Debbabi H, Uzan L, Mourad JJ, Safar M, Levy BI, Tibirica E: Increased skin capillary density in treated essential hypertensive patients. Am J Hypertens 2006, 19(5):477-483.
• [20]Kaiser SE, Sanjuliani AF, Estato V, Gomes MB, Tibirica E: Antihypertensive treatment improves microvascular rarefaction and reactivity in low-risk hypertensive individuals. Microcirculation 2013, 20(8):703-716.
• [21]Serne EH, de Jongh RT, Eringa EC, IJzerman RJ, Stehouwer CD: Microvascular dysfunction: a potential pathophysiological role in the metabolic syndrome. Hypertension 2007, 50(1):204-211.
• [22]Sposito AC, Caramelli B, Fonseca FA, Bertolami MC, Afiune Neto A, Souza AD, Lottenberg AM, Chacra AP, Faludi AA, Loures-Vale AA, Carvalho AC, Duncan B, Gelonese B, Polanczyk C, Rodrigues Sobrinho CR, Scherr C, Karla C, Armaganijan D, Moriguchi E, Saraiva F, Pichetti G, Xavier HT, Chaves H, Borges JL, Diament J, Guimarães JI, Nicolau JC, dos Santos JE, de Lima JJ, Vieira JL, et al.: [IV Brazilian Guideline for Dyslipidemia and Atherosclerosis prevention: Department of Atherosclerosis of Brazilian Society of Cardiology]. Arq Bras Cardiol 2007, 88(Suppl 1):2-19.
• [23]Jager R, Purpura M, Shao A, Inoue T, Kreider RB: Analysis of the efficacy, safety, and regulatory status of novel forms of creatine. Amino Acids 2011, 40(5):1369-1383.
• [24]Graham AS, Hatton RC: Creatine: a review of efficacy and safety. J Am Pharm Assoc 1999, 39(6):803-810. quiz 875-807
• [25]Souza EG, De Lorenzo A, Huguenin G, Oliveira GM, Tibirica E: Impairment of systemic microvascular endothelial and smooth muscle function in individuals with early-onset coronary artery disease: studies with laser speckle contrast imaging. Coron Artery Dis 2014, 25(1):23-28.
• [26]Tibirica E, Rodrigues E, Cobas RA, Gomes MB: Endothelial function in patients with type 1 diabetes evaluated by skin capillary recruitment. Microvasc Res 2007, 73(2):107-112.
• [27]Antonios TF, Rattray FE, Singer DR, Markandu ND, Mortimer PS, MacGregor GA: Maximization of skin capillaries during intravital video-microscopy in essential hypertension: comparison between venous congestion, reactive hyperaemia and core heat load tests. Clin Sci (Lond) 1999, 97(4):523-528.
• [28]Wong BJ, Wilkins BW, Holowatz LA, Minson CT: Nitric oxide synthase inhibition does not alter the reactive hyperemic response in the cutaneous circulation. J Appl Physiol (1985) 2003, 95(2):504-510.
• [29]Cracowski JL, Gaillard-Bigot F, Cracowski C, Sors C, Roustit M, Millet C: Involvement of cytochrome epoxygenase metabolites in cutaneous postocclusive hyperemia in humans. J Appl Physiol (1985) 2013, 114(2):245-251.
• [30]Lorenzo S, Minson CT: Human cutaneous reactive hyperaemia: role of BKCa channels and sensory nerves. J Physiol 2007, 585(Pt 1):295-303.
• [31]Wang H, Long C, Duan Z, Shi C, Jia G, Zhang Y: A new ATP-sensitive potassium channel opener protects endothelial function in cultured aortic endothelial cells. Cardiovasc Res 2007, 73(3):497-503.
• [32]Long CL, Qin XC, Pan ZY, Chen K, Zhang YF, Cui WY, Liu GS, Wang H: Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia. J Hypertens 2008, 26(12):2326-2338.
• [33]Selivanov VA, Alekseev AE, Hodgson DM, Dzeja PP, Terzic A: Nucleotide-gated KATP channels integrated with creatine and adenylate kinases: amplification, tuning and sensing of energetic signals in the compartmentalized cellular environment. Mol Cell Biochem 2004, 256–257(1–2):243-256.
• [34]Shi WW, Yang Y, Shi Y, Jiang C: K(ATP) channel action in vascular tone regulation: from genetics to diseases. Sheng li xue bao 2012, 64(1):1-13.
• [35]Prass K, Royl G, Lindauer U, Freyer D, Megow D, Dirnagl U, Stockler-Ipsiroglu G, Wallimann T, Priller J: Improved reperfusion and neuroprotection by creatine in a mouse model of stroke. J Cereb Blood Flow Metab 2007, 27(3):452-459.
• [36]Braissant O: Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers. J Inherit Metab Dis 2012, 35(4):655-664.
• [37]Decking UK, Alves C, Wallimann T, Wyss M, Schrader J: Functional aspects of creatine kinase isoenzymes in endothelial cells. Am J Physiol Cell Physiol 2001, 281(1):C320-C328.
• [38]Ceddia RB, Sweeney G: Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells. J Physiol 2004, 555(Pt 2):409-421.
• [39]Tonkonogi M, Harris B, Sahlin K: Mitochondrial oxidative function in human saponin-skinned muscle fibres: effects of prolonged exercise. J Physiol 1998, 510(Pt 1):279-286.
• [40]Eijnde BO, Derave W, Wojtaszewski JF, Richter EA, Hespel P: AMP kinase expression and activity in human skeletal muscle: effects of immobilization, retraining, and creatine supplementation. J Appl Physiol (1985) 2005, 98(4):1228-1233.
• [41]Schoch RD, Willoughby D, Greenwood M: The regulation and expression of the creatine transporter: a brief review of creatine supplementation in humans and animals. J Int Soc Sports Nutr 2006, 3:60-66. BioMed Central Full Text
• [42]Gualano B, Ugrinowitsch C, Artioli GG, Benatti FB, Scagliusi FB, Harris RC, Lancha AH Jr: Does creatine supplementation improve the plasma lipid profile in healthy male subjects undergoing aerobic training? J Int Soc Sports Nutr 2008, 5:16. BioMed Central Full Text
• [43]Mullur R, Liu YY, Brent GA: Thyroid hormone regulation of metabolism. Physiol Rev 2014, 94(2):355-382.
• [44]Araujo RL, Andrade BM, Padron AS, Gaidhu MP, Perry RL, Carvalho DP, Ceddia RB: High-fat diet increases thyrotropin and oxygen consumption without altering circulating 3,5,3'-triiodothyronine (T3) and thyroxine in rats: the role of iodothyronine deiodinases, reverse T3 production, and whole-body fat oxidation. Endocrinology 2010, 151(7):3460-3469.
• [45]Araujo RL, Carvalho DP: Bioenergetic impact of tissue-specific regulation of iodothyronine deiodinases during nutritional imbalance. J Bioenerg Biomembr 2011, 43(1):59-65.
• [46]Snow RJ, Murphy RM: Creatine and the creatine transporter: a review. Mol Cell Biochem 2001, 224(1–2):169-181.
• [47]Ranka R, Mathur R: Serum creatine phosphokinase in thyroid disorders. Indian J Clin Biochem 2003, 18(1):107-110.
• [48]Hekimsoy Z, Oktem IK: Serum creatine kinase levels in overt and subclinical hypothyroidism. Endocr Res 2005, 31(3):171-175.
• [49]Gaede JT: Serum enzyme alterations in hypothyroidism before and after treatment. J Am Geriatr Soc 1977, 25(5):199-201.
• [50]Queiroz MS, Shao Y, Berkich DA, Lanoue KF, Ismail-Beigi F: Thyroid hormone regulation of cardiac bioenergetics: role of intracellular creatine. Am J Physiol Heart Circ Physiol 2002, 283(6):H2527-H2533.
• [51]Odoom JE, Kemp GJ, Radda GK: The regulation of total creatine content in a myoblast cell line. Mol Cell Biochem 1996, 158(2):179-188.
• [52]Kurahashi M, Kuroshima A: Mechanism of thyroid-induced creatinuria in rat, with special reference to creatine synthesis in liver and creatine loss from skeletal muscle. Jpn J Physiol 1976, 26(3):279-288.
• [53]Basu G, Mohapatra A: Interactions between thyroid disorders and kidney disease. Indian J Endocrinol Metab 2012, 16(2):204-213.
• [54]Willis J, Jones R, Nwokolo N, Levy J: Protein and creatine supplements and misdiagnosis of kidney disease. BMJ 2010, 340:b5027.
• [55]Pline KA, Smith CL: The effect of creatine intake on renal function. Ann Pharmacother 2005, 39(6):1093-1096.
• [56]Souza WM, Heck TG, Wronski EC, Ulbrich AZ, Boff E: Effects of creatine supplementation on biomarkers of hepatic and renal function in young trained rats. Toxicol Mech Methods 2013, 23(9):697-701.
• [57]Gualano B, Ugrinowitsch C, Novaes RB, Artioli GG, Shimizu MH, Seguro AC, Harris RC, Lancha AH Jr: Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial. Eur J Appl Physiol 2008, 103(1):33-40.
• [58]Lugaresi R, Leme M, de Salles PV, Murai IH, Roschel H, Sapienza MT, Lancha Junior AH, Gualano B: Does long-term creatine supplementation impair kidney function in resistance-trained individuals consuming a high-protein diet? J Int Soc Sports Nutr 2013, 10(1):26. BioMed Central Full Text
• [59]Groeneveld GJ, Beijer C, Veldink JH, Kalmijn S, Wokke JH, van den Berg LH: Few adverse effects of long-term creatine supplementation in a placebo-controlled trial. Int J Sports Med 2005, 26(4):307-313.
• [60]Poortmans JR, Auquier H, Renaut V, Durussel A, Saugy M, Brisson GR: Effect of short-term creatine supplementation on renal responses in men. Eur J Appl Physiol Occup Physiol 1997, 76(6):566-567.
• [61]Poortmans JR, Francaux M: Adverse effects of creatine supplementation: fact or fiction? Sports Med 2000, 30(3):155-170.
• [62]Kim HJ, Kim CK, Carpentier A, Poortmans JR: Studies on the safety of creatine supplementation. Amino Acids 2011, 40(5):1409-1418.
• [63]Yu PH, Deng Y: Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance. Med Hypotheses 2000, 54(5):726-728.
• [64]Souza RA, Miranda H, Xavier M, Lazo-Osorio RA, Gouvea HA, Cogo JC, Vieira RP, Ribeiro W: Effects of high-dose creatine supplementation on kidney and liver responses in sedentary and exercised rats. J Sports Sci Med 2009, 8(4):672-681.
• [65]Roustit M, Millet C, Blaise S, Dufournet B, Cracowski JL: Excellent reproducibility of laser speckle contrast imaging to assess skin microvascular reactivity. Microvasc Res 2010, 80(3):505-511.
• [66]Roustit M, Cracowski JL: Non-invasive assessment of skin microvascular function in humans: an insight into methods. Microcirculation 2012, 19(1):47-64.
• [67]Humeau-Heurtier A, Guerreschi E, Abraham P, Mahe G: Relevance of laser Doppler and laser speckle techniques for assessing vascular function: state of the art and future trends. IEEE Trans Biomed Eng 2013, 60(3):659-666.
• [68]Baumgartner A, Pinna G, Hiedra L, Gaio U, Hessenius C, Campos-Barros A, Eravci M, Prengel H, Thoma R, Meinhold H: Effects of lithium and carbamazepine on thyroid hormone metabolism in rat brain. Neuropsychopharmacology 1997, 16(1):25-41.
• [69]Dong BJ: How medications affect thyroid function. West J Med 2000, 172(2):102-106.