IL6 (-174) and TNFA (-308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise

  • Chen Yamin
  • José Alberto Ramos Duarte
  • José Manuel Fernandes Oliveira
  • Offer Amir
  • Moran Sagiv
  • Nir Eynon
  • Michael Sagiv
  • Ruthie E. AmirEmail author
Original Article


Exertional rhabdomyolysis is a complex and poorly understood entity. The inflammatory system has an important role in muscle injury and repair. Serum creatine kinase (CK) is often used as systemic biomarker representing muscle damage. Considerable variation exists in CK response between different subjects. Genetic elements may act as predisposition factors for exertional srhabdomyolysis. Based on their biological activity, we hypothesized that in healthy subjects IL6 G-174C and TNFA G-308A promoter polymorphisms would be associated with CK response to exercise. We determined serum CK activity pre- and post-maximal eccentric contractions of the elbow flexor muscles. IL6 G-174C and TNFA G-308A genotypes were analyzed for possible relationship with changes in serum CK activity. IL6 G-174C genotype was associated with CK activity in a Dose-Dependent fashion. Subjects with one or more of the -174C allele had a greater increase and higher peak CK values than subjects homozygous for the G allele (mean ± SE U/L: GG, 2,604 ± 821; GC, 7,592 ± 1,111; CC, 8,403 ± 3,849, ANOVA = 0.0003 for GG + GC genotypes versus CC genotype, = 0.0005 for linear trend). IL6-174CC genotype was associated with a greater than threefold increased risk of massive CK response (adjusted odds ratio 3.29, 95% confidence interval 1.27–7.85, = 0.009). A milder association (P = 0.06) was noted between TNFA G-308A genotype and CK activity. In conclusion, we found a strong association of the IL6 G-174C genotype with systemic CK response to strenuous exercise. Data suggest that homozygosity for the IL6-174C allele is a clinically important risk factor for exercise-induced muscle injury, further supporting the central role of cytokines in the reactive inflammatory process of muscle damage and repair.


Genetics Inflammation Polymorphisms Cytokines Eccentric exercise 


  1. Barton BE (1996) The biological effects of interleukin 6. Med Res Rev 16:87–109PubMedCrossRefGoogle Scholar
  2. Bayley JP, Ottenhoff TH, Verweij CL (2004) Is there a future for TNF promoter polymorphisms? Genes Immun 5:315–329PubMedCrossRefGoogle Scholar
  3. Bennermo M, Held C, Stemme S, Ericsson CG, Silveira A, Green F, Tornvall P (2004) Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases? Clin Chem 50:2136–2140PubMedCrossRefGoogle Scholar
  4. Bruunsgaard H, Galbo H, Halkjaer-Kristensen J, Johansen TL, MacLean DA, Pedersen BK (1997) Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage. J Physiol 499:833–841PubMedGoogle Scholar
  5. Cabrera M, Shaw MA, Sharples C, Williams H, Castes M, Convit J, Blackwell JM (1995) Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J Exp Med 182:1259–1264PubMedCrossRefGoogle Scholar
  6. Cannon JG, St Pierre BA (1988) Cytokines in exertion-induced skeletal muscle injury. Mol Cell Biochem 179:159–167CrossRefGoogle Scholar
  7. Clarkson PM, Hoffman EP, Zambraski E, Gordish-Dressman H, Kearns A, Hubal M, Harmon B, Devaney JM (2005) ACTN3 and MLCK genotype associations with exertional muscle damage. J Appl Physiol 99:564–569PubMedCrossRefGoogle Scholar
  8. Dennis RA, Trappe TA, Simpson P, Carroll C, Huang BE, Nagarajan R, Bearden E, Gurley C, Duff GW, Evans WJ, Kornman K, Peterson CA (2004) Interleukin-1 polymorphisms are associated with the inflammatory response in human muscle to acute resistance exercise. J Physiol 560:617–626PubMedCrossRefGoogle Scholar
  9. Devaney JM, Hoffman EP, Gordish-Dressman H, Kearns A, Zambraski E, Clarkson PM (2007) IGF-II gene region polymorphisms related to exertional muscle damage. J Appl Physiol 102:1815–1823PubMedCrossRefGoogle Scholar
  10. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:1369–1376PubMedCrossRefGoogle Scholar
  11. Greiwe JS, Cheng B, Rubin DC, Yarasheski KE, Semenkovich CF (2001) Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans. FASEB J 15:475–482PubMedCrossRefGoogle Scholar
  12. Hamada K, Vannier E, Sacheck JM, Witsell AL, Roubenoff R (2005) Senescence of human skeletal muscle impairs the local inflammatory cytokine response to acute eccentric exercise. FASEB J 19:264–266PubMedGoogle Scholar
  13. Helge JW, Stallknecht B, Pedersen BK, Galbo H, Kiens B, Richter EA (2003) The effect of graded exercise on IL-6 release and glucose uptake in human skeletal muscle. J Physiol 546(1):299–305PubMedCrossRefGoogle Scholar
  14. Heled Y, Bloom MS, Wu TJ, Stephens Q, Deuster PA (2007) CK-MM and ACE genotypes and physiological prediction of the creatine kinase response to exercise. J Appl Physiol 103(2):504–510PubMedCrossRefGoogle Scholar
  15. Hirose L, Nosaka K, Newton M, Laveder A, Kano M, Peake J, Suzuki K (2004) Changes in inflammatory mediators following eccentric exercise of the elbow flexors. Exerc Immunol Rev 10:75–90PubMedGoogle Scholar
  16. Hoppe C, Klitz W, D’Harlingue K, Cheng S, Grow M, Steiner L, Noble J, Adams R, Styles L (2007) Stroke prevention trial in sickle cell anemia (STOP) Investigators. Confirmation of an association between the TNF(-308) promoter polymorphism and stroke risk in children with sickle cell anemia. Stroke 38:2241–2246PubMedCrossRefGoogle Scholar
  17. Hørder M, Jorgensen PJ, Hafkenscheid JC, Carstensen CA, Bachmann C, Bauer K, Neuwald C, Rosalki SB, Foo AY, Vogt W (1999) Creatine kinase determination: a European evaluation of the creatine kinase determination in serum, plasma and whole blood with the Reflotron system. Eur J Clin Chem Clin Biochem 29:691–696Google Scholar
  18. Jamurtas AZ, Theocharis V, Tofas T, Tsiokanos A, Yfanti C, Paschalis V, Koutedakis Y, Nosaka K (2005) Comparison between leg and arm eccentric exercises of the same relative intensity on indices of muscle damage. Eur J Appl Physiol 95:179–185PubMedCrossRefGoogle Scholar
  19. Ling PR, Schwartz JH, Bistrian BR (1997) Mechanisms of host wasting induced by administration of cytokines in rats. Am J Physiol 272:333–339Google Scholar
  20. MacIntyre DL, Sorichter S, Mair J, Berg A, McKenzie DC (2001) Markers of inflammation and myofibrillar proteins following eccentric exercise in humans. Eur J Appl Physiol 84:180–186PubMedCrossRefGoogle Scholar
  21. Malm C, Nyberg P, Engstrom M, Sjodin B, Lenkei R, Ekblom B, Lundberg I (2000) Immunological changes in human skeletal muscle and blood after eccentric exercise and multiple biopsies. J Physiol 529:243–262PubMedCrossRefGoogle Scholar
  22. Malm C, Sjödin TL, Sjöberg B, Lenkei R, Renström P, Lundberg IE, Ekblom B (2004) Leukocytes, cytokines, growth factors and hormones in human skeletal muscle and blood after uphill or downhill running. J Physiol 556:983–100PubMedCrossRefGoogle Scholar
  23. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D (1994) Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 371:508–510PubMedCrossRefGoogle Scholar
  24. McHugh MP (2003) Recent advances in the understanding of the repeated bout effect: the protective effect against muscle damage from a single bout of eccentric exercise. Scand J Med Sci Sports 13:88–97PubMedCrossRefGoogle Scholar
  25. Milne CJ (1988) Rhabdomyolysis, myoglobinuria and exercise. Sports Med 6:93–106PubMedCrossRefGoogle Scholar
  26. Nosaka K, Sakamoto K, Newton M, Sacco P (2001) How long does the protective effect on eccentric exercise-induced muscle damage last? Med Sci Sports Exerc 33:1490–1495PubMedCrossRefGoogle Scholar
  27. Padovani JC, Pazin-Filho A, Simoes MV, Marin-Neto JA, Zago MA, Franco RF (2000) Gene polymorphisms in the TNF locus and the risk of myocardial infarction. Thromb Res 100:263–269PubMedCrossRefGoogle Scholar
  28. Peake J, Nosaka K, Suzuki K (2005) Characterization of inflammatory responses to eccentric exercise in humans. Exerc Immunol Rev 11:64–85PubMedGoogle Scholar
  29. Peake JM, Nosaka K, Muthalib M, Suzuki K (2006) Systemic inflammatory responses to maximal versus submaximal lengthening contractions of the elbow flexors. Exerc Immunol Rev 12:72–85PubMedGoogle Scholar
  30. Pedersen BK, Steensberg A, Keller P, Keller C, Fischer C, Hiscock N, van Hall G, Plomgaard P, Febbraio MA (2003) Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects. Pflugers Arch 446:9–16PubMedGoogle Scholar
  31. Pedersen BK, Toft AD (2000) Effects of exercise on lymphocytes and cytokines. Br J Sports Med 34:246–251PubMedCrossRefGoogle Scholar
  32. Rein T, Forster R, Krause A, Winnacker EL, Zorbas H (1995) Organization of the alpha-globin promoter and possible role of nuclear factor I in an alpha-globin-inducible and a noninducible cell line. J Biol Chem 270:19643–19650PubMedCrossRefGoogle Scholar
  33. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning. Cold Spring Harbor, Cold Spring HarborGoogle Scholar
  34. Sinert R, Kohl L, Rainone T, Scalea T (1994) Exercise-induced rhabdomyolysis. Ann Emerg Med 23:1301–1306PubMedCrossRefGoogle Scholar
  35. Sookoian SC, Gonzalez C, Pirola CJ (2005) Meta-analysis on the G-308A tumor necrosis factor alpha gene variant and phenotypes associated with the metabolic syndrome. Obes Res 12:2122–2131CrossRefGoogle Scholar
  36. Steinberg JG, Ba A, Bregeon F, Delliaux S, Jammes Y (2007) Cytokine and oxidative responses to maximal cycling exercise in sedentary subjects. Med Sci Sports Exerc 39:964–968PubMedGoogle Scholar
  37. Swider C, Schnittger L, Bogunia-Kubik K, Gerdes J, Flad H, Lange A, Seitzer U (1999) TNF-alpha and HLA-DR genotyping as potential prognostic markers in pulmonary sarcoidosis. Eur Cytokine Netw 10:143–146PubMedGoogle Scholar
  38. Terry CF, Loukaci V, Green FR (2000) Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 275:18138–18144PubMedCrossRefGoogle Scholar
  39. Tidball JG (2005) Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol 288:345–353Google Scholar
  40. Toft AD, Jensen LB, Bruunsgaard H, Ibfelt T, Halkjaer-Kristensen J, Febbraio M, Pedersen BK (2002) Cytokine response to eccentric exercise in young and elderly humans. Am J Physiol Cell Physiol 283:289–295Google Scholar
  41. Wilson AG, di Giovine FS, Blakemore AI, Duff GW (1992) Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genet 1:353PubMedCrossRefGoogle Scholar
  42. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW (1997) Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci 94:3195–3199PubMedCrossRefGoogle Scholar
  43. Yamin C, Amir O, Sagiv M, Attias E, Meckel Y, Eynon N, Sagiv M, Amir RE (2007) ACE ID genotype affects blood Creatine Kinase response to eccentric exercise. J Appl Physiol 103:2057–2061PubMedCrossRefGoogle Scholar
  44. Zheng C, Huang DR, Bergenbrant S, Sundblad A, Osterborg A, Björkholm M, Holm G, Yi Q (2000) Interleukin 6, tumour necrosis factor alpha, interleukin 1beta and interleukin 1 receptor antagonist promoter or coding gene polymorphisms in multiple myeloma. Br J Haematol 109:39–45PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Chen Yamin
    • 1
  • José Alberto Ramos Duarte
    • 2
  • José Manuel Fernandes Oliveira
    • 2
  • Offer Amir
    • 3
  • Moran Sagiv
    • 1
  • Nir Eynon
    • 1
  • Michael Sagiv
    • 1
  • Ruthie E. Amir
    • 1
    Email author
  1. 1.Department of Genetics and Molecular BiologyZinman College of Physical Education and Sport Sciences at the Wingate InstituteNetanyaIsrael
  2. 2.CIAFEL, Faculty of SportUniversity of PortoPortoPortugal
  3. 3.Department of CardiologyLady Davis Carmel Medical CenterHaifaIsrael

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