Advertisement

European Journal of Applied Physiology

, Volume 112, Issue 1, pp 183–192 | Cite as

Creatine kinase MM TaqI and methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms influence exercise-induced C-reactive protein levels

  • Ana Luisa Miranda-VilelaEmail author
  • Arthur K. Akimoto
  • Graciana S. Lordelo
  • Luiz C. S. Pereira
  • Cesar K. Grisolia
  • Maria de Nazaré Klautau-Guimarães
Original Article

Abstract

Physical training induces beneficial adaptations, but exhausting exercise increases reactive oxygen species, which can cause muscular injuries with consequent inflammatory processes, implying jeopardized performance and possibly overtraining. Acute strenuous exercise almost certainly exceeds the benefits of physical activity; it can compromise performance and may contribute to increased future risk of cardiovascular disease (CVD) in athletes. Polymorphisms in the muscle-type creatine kinase (CK-MM) gene may influence performance and adaptation to training, while many potentially significant genetic variants are reported as risk factors for CVD. Therefore, we investigated the influence of polymorphisms in CK-MM TaqI and NcoI, methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and C-reactive protein (CRP G1059C) genes on exercise-induced damage and inflammation markers. Blood samples were taken immediately after a race (of at least 4 km) that took place outdoors on flat tracks, and were submitted to genotyping and biochemical evaluation of aspartate aminotransferase (AST), CK, CRP and high-sensitivity CRP (hs-CRP). CK-MM TaqI polymorphism significantly influenced results of AST, CK and hs-CRP, and an association between MTHFR C677T and A1298C with CRP level was found, although these levels did not exceed reference values. Results indicate that these polymorphisms can indirectly influence performance, contribute to higher susceptibility to exercise-induced inflammation or protection against it, and perhaps affect future risks of CVD in athletes.

Keywords

Exercise-induced oxidative damage Biochemical damage markers C-reactive protein Creatine kinase Gene polymorphisms 

Abbreviations

CVD

Cardiovascular disease

CAD

Coronary artery disease

CK-MM

Muscle-type creatine kinase

MTHFR

Methylenetetrahydrofolate reductase

CK

Creatine kinase

AST

Aspartate aminotransferase

CRP

C-reactive protein

hs-CRP

High-sensitivity C-reactive protein

SNPs

Single nucleotide polymorphisms

PCR

Polymerase chain reaction

RFLP

Restriction fragment length polymorphism

HWE

Hardy–Weinberg equilibrium

ROS

Reactive oxygen species

Hcy

Homocysteine

Notes

Acknowledgments

The authors gratefully acknowledge the subjects who participated in this research, Sabin Institute/Sabin Laboratories and Farmacotécnica for technical support. They also thank the National Council for Technological and Scientific Development (CNPq), the Coordination for Further Training of Graduate Staff (CAPES) and the Scientific and Technological Enterprises Foundation (FINATEC) for financial support.

Conflict of interest

None.

References

  1. Abbassi-Ghanavati M, Greer LG, Cunningham FG (2009) Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol 114:1326–1331PubMedCrossRefGoogle Scholar
  2. Akimoto AK, Miranda-Vilela AL, Alves PCZ, Pereira LCS, Lordelo GS, Hiragi CO, Silva ICR, Grisolia CK, Klautau-Guimarães MN (2010) Evaluation of gene polymorphisms in exercise-induced oxidative stress and damage. Free Rad Res 44:322–331CrossRefGoogle Scholar
  3. Anderson JL, Muhlestein JB, Horne BD, Carlquist JF, Bair TL, Madsen TE, Pearson RR (2000) Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation 102:1227PubMedGoogle Scholar
  4. Apple FS, Rogers MA, Ivy JL (1986) Creatine kinase isoenzyme MM variants in skeletal muscle and plasma from marathon runners. Clin Chem 32:41–44PubMedGoogle Scholar
  5. Araújo F, Pereira AC, Mota GF, Latorre Mdo R, Krieger JE, Mansur AJ (2004) The influence of tumor necrosis factor -308 and C-reactive protein G1059C gene variants on serum concentration of C-reactive protein: evidence for an age-dependent association. Clin Chim Acta 349(1–2):129–134PubMedCrossRefGoogle Scholar
  6. Barbosa TM, Magalhães PM, Lopes VP, Neuparth M, Duarte JA (2003) Comparação da variação da actividade neuromuscular, da creatina quinase e da força isométrica máxima voluntária entre dois protocolos exaustivos e inabituais. Rev Port Cien Desp 3:7–15Google Scholar
  7. Benedini S, Caimi A, Alberti G, Terruzzi I, Dellerma N, La Torre A, Luzi L (2010) Increase in homocysteine levels after a half-marathon running: a detrimental metabolic effect of sport? Sport Sci Health 1:35–42CrossRefGoogle Scholar
  8. Biselli PM, Guerzoni AR, Goloni-Bertollo EM, de Godoy MF, Abou-Chahla JAB, Pavarino-Bertelli EC (2009) Variabilidade genética MTHFR no desenvolvimento da doença arterial coronária. Rev Assoc Med Bras 55:274–278PubMedCrossRefGoogle Scholar
  9. Borrione P, Rizzo M, Spaccamiglio A, Salvo RA, Dovio A, Termine A, Parisi A, Fagnani F, Angeli A, Pigozzi F (2008) Sport-related hyperhomocysteinaemia: a putative marker of muscular demand to be noted for cardiovascular risk. Br J Sports Med 42:894–900PubMedCrossRefGoogle Scholar
  10. Bouchard C, Malina RM, Pérusse L (1997) Genetics of fitness and physical performance. Human Kinetics, Champaign, ILGoogle Scholar
  11. Brancaccio P, Maffulli N, Limongelli FM (2007) Creatine kinase monitoring in sport medicine. Br Med Bull 81(82):209–230PubMedCrossRefGoogle Scholar
  12. Bruce R, Todd JK, Le Dune L (1958) Serum transaminase: its clinical use in diagnosis and prognosis. Br Med J 2:1125–1128PubMedCrossRefGoogle Scholar
  13. Brull DJ, Serrano N, Zito F, Jones L, Montgomery HE, Rumley A, Sharma P, Lowe GDO, World MJ, Humphries SE, Hingorani AD (2003) Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol 23:2063–2069PubMedCrossRefGoogle Scholar
  14. Cao H, Hegele RA (2000) Human C-reactive protein (CRP) 1059G/C polymorphism. J Hum Genet 45:100–101PubMedCrossRefGoogle Scholar
  15. Carlson DL, Mawdsley RH (1986) Sports anemia: a review of the literature. Am J Sports Med 14:109–112PubMedCrossRefGoogle Scholar
  16. Cortese C, Motti C (2001) MTHFR gene polymorphism, homocysteine and cardiovascular Disease. Public Health Nutr 4:493–497PubMedCrossRefGoogle Scholar
  17. Cruzat VF, Rogero MM, Borges MC, Tirapegui J (2007) Aspectos atuais sobre estresse oxidativo, exercícios físicos e suplementação. Rev Bras Med Esp 13(5):336–342CrossRefGoogle Scholar
  18. Dedoussis GV, Panagiotakos DB, Pitsavos C, Chrysohoou C, Skoumas J, Choumerianou D, Stefanadis C, ATTICA Study Group (2005) An association between the methylenetetrahydrofolate reductase (MTHFR) C677T mutation and inflammation markers related to cardiovascular disease. Int J Cardiol 100(3):409–414PubMedCrossRefGoogle Scholar
  19. Defoor J, Martens K, Matthijs G, Zieliñska D, Schepers D, Philips T, Vlietinck R, Fagard R, Vanhees L (2005) The CAREGENE Study: muscle-specific creatine kinase gene and aerobic power in coronary artery disease. Eur J Cardiovasc Prev Rehabil 12:415–417PubMedCrossRefGoogle Scholar
  20. Dewar HA, Rowell NR, Smith AJ (1958) Serum glutamic oxalacetic transaminase in acute myocardial infarction. Br Med J 2:1121–1125PubMedCrossRefGoogle Scholar
  21. Dufaux B, Order U, Geyer H, Hollmann W (1984) C-reactive protein serum concentrations in well-trained athletes. Int J Sports Med 5(2):102–106PubMedCrossRefGoogle Scholar
  22. Eikelboom JW, Lonn E, Genest J, Hankey G, Yusuf F (1999) Homocysteine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 131:363–375PubMedGoogle Scholar
  23. Ferreira F, Ferreira R, Duarte JA (2007) Stress oxidativo e dano oxidativo muscular esquelético: influência do exercício agudo inabitual e do treino físico. Rev Port Cien Desp 7(2):257–275Google Scholar
  24. Fortunato G, Fattoruso O, De Caterina M, Mancini A, Di Fiore R, Alfieri A, Tafuri D, Buono P (2007) RAS and MTHFR gene polymorphisms in a healthy exercise-trained population: association with the MTHFR (TT) genotype and a lower hemoglobin level. Int J Sports Med 28(2):172–177PubMedCrossRefGoogle Scholar
  25. Foschini D, Prestes J, Charro MA (2007) Relação entre exercício físico, dano muscular e dor muscular de início tardio. Rev Bras Cineantropom Desempenho Hum 9:101–106Google Scholar
  26. Freire LMD, Sodré FL, Oliveira RA, Castilho LN, Faria EC (2008) Controle de qualidade laboratorial pré-analítico: avaliação de solicitações médicas de exames bioquímicos no Hospital de Clínicas da Universidade Estadual de Campinas, São Paulo, Brasil. Rev Bras Anal Clin 40:143–145Google Scholar
  27. Fujimura H, Kawasaki T, Sakata T, Ariyoshi H, Kato H, Monden M, Miyata T (2000) Common C677T polymorphism in the methylenetetrahydrofolate reductase gene increases the risk for deep vein thrombosis in patients with predisposition of thrombophilia. Thromb Res 98(1):1–8PubMedCrossRefGoogle Scholar
  28. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis RJ, Boers GH, Sheahan RG, Israelsson B, Uiterwaal CS, Melead R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales Luis AC, Parrot-Roulaud FM, Tan KS, Higgins I, Garcon D, Medrano MJ, Candito M, Evans AE, Andria G (1997) Plasma homocysteine as a risk factor for cardiovascular disease: the European concerted action project. J Am Med Assoc 277:1775–1781CrossRefGoogle Scholar
  29. Griffiths PD (1964) Serum levels of creatine phosphokinase. J Clin Pathol 17:56–57PubMedCrossRefGoogle Scholar
  30. Heled Y, Bloom MS, Wu TJ, Stephens Q, Deuster PA (2007) CM-MM and ACE genotypes and physiological prediction of the creatine kinase response to exercise. J Appl Physiol 103:504–510PubMedCrossRefGoogle Scholar
  31. Hornemann T, Kempa S, Himmel M, Hayess K, Fürst DO, Wallimann T (2003) Muscle-type creatine kinase interacts with central domains of the M-band proteins myomesin and M-protein. J Mol Biol 332:877–887PubMedCrossRefGoogle Scholar
  32. Ji LL, Leichtweis S (1997) Exercise and oxidative stress: sources of free radicals and their impact on antioxidant systems. Age 20:91–106CrossRefGoogle Scholar
  33. Judge S, Leeuwenburgh C (2007) Cardiac mitochondrial bioenergetics, oxidative stress, and aging. Am J Physiol Cell Physiol 292:1983–1992CrossRefGoogle Scholar
  34. Kang S-S, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N (1991) Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 48:536–645PubMedGoogle Scholar
  35. Kasapis C, Thompson PD (2005) The effects of physical activity on serum C-reactive protein and inflammatory markers. J Am Coll Cardiol 45(10):1563–1569PubMedCrossRefGoogle Scholar
  36. Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143PubMedCrossRefGoogle Scholar
  37. MacArthur DG, North KN (2005) Genes and human elite athletic performance. Hum Genet 116:331–339PubMedCrossRefGoogle Scholar
  38. Miller DT, Zee RY, Suk DJ, Kozlowski P, Chasman DI, Lazarus R, Cook NR, Ridker PM, Kwiatkowski DJ (2005) Association of common CRP gene variants with CRP levels and cardiovascular events. Ann Hum Genet 69:623–638PubMedCrossRefGoogle Scholar
  39. Miranda-Vilela AL, Akimoto AK, Alves PCZ, Pereira LCS, Gonçalves CA, Klautau-Guimarães MN, Grisolia CK (2009) Dietary carotenoid-rich oil improves plasma lipid peroxidation and damages in runners: evidence for an association with MnSOD genetic variant –Val9Ala. Genet Mol Res 8:1481–1495PubMedCrossRefGoogle Scholar
  40. Misawa AK, Suzuki H, Maia Júnior OO, Bonanomi MTBC, Melo CSN (2008) Obstrução arterial retiniana periférica associada com hiperhomocisteinemia: relato de caso. Arq Bras Oftalmol 71(5):729–733PubMedCrossRefGoogle Scholar
  41. Montaner J, Fernandez-Cadenas I, Molina CA, Ribó M, Huertas R, Rosell A, Penalba A, Ortega L, Chacón P, Alvarez-Sabín J (2006) Poststroke C-reactive protein is a powerful prognostic tool among candidates for thrombolysis. Stroke 37(5):1205–1210PubMedCrossRefGoogle Scholar
  42. Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Sindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y (1997) Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation 95:2032–2036PubMedGoogle Scholar
  43. Mougios V (2007) Reference intervals for serum creatine kinase in athletes. Br J Sports Med 41:674–678PubMedCrossRefGoogle Scholar
  44. Nascimben L, Ingwall JS, Pauletto P, Friedrich J, Gwathmey JK, Saks V, Pessina AC, Allen PD (1996) Creatine kinase system in failing and nonfailing human myocardium. Circulation 94:1894–1901PubMedGoogle Scholar
  45. Ostrander EA, Huson HJ, Ostrander GK (2009) Genetics of athletic performance. Annu Rev Genomics Hum Genet 10:407–429PubMedCrossRefGoogle Scholar
  46. Persky AM, Green PS, Stubley L, Howell CO, Zaulyanov L, Brazeau GA, Simpkins JW (2000) Protective effect of estrogens against oxidative damage to heart and skeletal muscle in vivo and in vitro. Proc Soc Exp Biol Med 223:59–66PubMedCrossRefGoogle Scholar
  47. Putney S, Herlihy W, Royal N, Pang H, Aposhian HV, Pickering L, Belagaje R, Biemann K, Page D, Kuby S, Schimmel P (1984) Rabbit muscle creatine phosphokinase. J Biol Chem 259:14317–14320PubMedGoogle Scholar
  48. Radak Z, Kumagai S, Nakamoto H, Asto S (2007) 8-Oxoguanosine and uracil repair of nuclear and mitochondrial DNA in red and white skeletal muscle of exercise-trained old rats. J Appl Physiol 102:1696–1701PubMedCrossRefGoogle Scholar
  49. Rankinen T, Wolfarth B, Simoneau J-A, Maier-Lenz D, Rauramaa R, Rivera MA, Boulay MR, Chagnon YC, Pérusse L, Keul J, Bouchard C (2000) No association between the angiotensin-converting enzyme ID polymorphism and elite endurance athlete status. J Appl Physiol 88:1571–1575PubMedGoogle Scholar
  50. Rifai N, Ridker PM (2003) Population distributions of C-reactive protein in apparently healthy men and women in the United States: implication for clinical interpretation. Clin Chem 49(4):666–669PubMedCrossRefGoogle Scholar
  51. Rifai N, Tracy RP, Ridker PM (1999) Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin Chem 45(12):2136–2141PubMedGoogle Scholar
  52. Rivera MA, Dionne FT, Wolfarth B, Chagnon M, Simoneau J-A, Pérusse L, Boulay MR, Gagnon J, Song TMK, Keul J, Bouchard C (1997) Muscle-specific creatine kinase gene polymorphisms in elite endurance athletes and sedentary controls. Med Sci Sports Exerc 29:1444–1447PubMedCrossRefGoogle Scholar
  53. Santos-Silva A, Rebelo MI, Castro EM, Belo L, Guerra A, Rego C, Quintanilha A (2001) Leukocyte activation, erythrocyte damage, lipid profile and oxidative stress imposed by high competition physical exercise in adolescents. Clin Chim Acta 306:119–126PubMedCrossRefGoogle Scholar
  54. Schoenfelder M (2010) Genetics-based performance talent research: polymorphisms as predictors of endurance performance. J Appl Physiol 108:1454–1455PubMedCrossRefGoogle Scholar
  55. Schumann G, Klauke R (2003) New IFCC reference procedures for the determination of catalytic activity concentrations of five enzymes in serum: preliminary upper reference limits obtained in hospitalized subjects. Clin Chim Acta 327:69–79PubMedCrossRefGoogle Scholar
  56. Suk HJ, Ridker PM, Cook NR, Zee RYL (2005) Relation of polymorphism within the C-reactive protein gene and plasma CRP levels. Atherosclerosis 178:139–145PubMedCrossRefGoogle Scholar
  57. Sureda A, Tauler P, Aguiló A, Cases N, Fuentespina E, Córdova A, Tur JA, Pons A (2005) Relation between oxidative stress markers and antioxidant endogenous defences during exhaustive exercise. Free Rad Res 39:1317–1324CrossRefGoogle Scholar
  58. Thompson PD, Franklin BA, Balady GJ, Blair SN, Corrado D, Estes NAM, Fulton JE, Gordon N, Haskell WL, Link MS, Maron BJ, Mittleman MA, Pelliccia A, Wenger NK, Willich SN, Costa F (2007) Exercise and acute cardiovascular events. Circulation 115:2358–2368PubMedCrossRefGoogle Scholar
  59. Traber MG (2006) Relationship of vitamin E metabolism and oxidation in exercising human subjects. Br J Nutr 96:S34–S37PubMedCrossRefGoogle Scholar
  60. Urso ML, Clarkson PM (2003) Oxidative stress, exercise, and antioxidant supplementation. Toxicology 189:41–54PubMedCrossRefGoogle Scholar
  61. van Bockxmeer FM, Mamotte CDS, Vasikaran SD, Taylor RR (1997) Methylenetetrahydrofolate reductase gene and coronary artery disease. Circulation 95:21–23PubMedGoogle Scholar
  62. Yi P, Pogribny IP, James SJ (2002) Multiplex PCR for simultaneous detection of 677 C→T and 1298 A→C polymorphisms in methylenetetrahydrofolate reductase gene for population studies of cancer risk. Cancer Lett 181:209–213PubMedCrossRefGoogle Scholar
  63. Zhou DQ, Hu Y, Liu G, Wu J, Gong L (2005) An A/G polymorphism in muscle-specific creatine kinase gene in Han population in northern China. Yi Chuan 27:535–538PubMedGoogle Scholar
  64. Zhou DQ, Hu Y, Liu G, Gong L, Xi Y, Wen L (2006) Muscle-specific creatine kinase gene polymorphism and running economy responses to an 18-week 5000-m training programme. Br J Sports Med 40:988–991PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ana Luisa Miranda-Vilela
    • 1
    Email author
  • Arthur K. Akimoto
    • 1
  • Graciana S. Lordelo
    • 1
  • Luiz C. S. Pereira
    • 2
  • Cesar K. Grisolia
    • 1
  • Maria de Nazaré Klautau-Guimarães
    • 1
  1. 1.Laboratório de Genética, Departamento de Genética e Morfologia, Instituto de Ciências BiológicasUniversidade de BrasíliaBrasília, DFBrazil
  2. 2.Laboratório Sabin de Análises ClínicasBrasília, DFBrazil

Personalised recommendations