GENE DOPING IN SPORT – PERSPECTIVES AND RISKS

• Authors: E. Brzeziańska , D. Domańska , A. Jegier
• Languages of publication: EN

Abstracts

EN

In the past few years considerable progress regarding the knowledge of the human genome map has been achieved. As a result, attempts to use gene therapy in patients' management are more and more often undertaken. The aim of gene therapy is to replace defective genes in vivo and/or to promote the long-term endogenous synthesis of deficient protein. In vitro studies improve the production of human recombinant proteins, such as insulin (INS), growth hormone (GH), insulin-like growth factor-1 (IGF-1) and erythropoietin (EPO), which could have therapeutic application. Unfortunately, genetic methods developed for therapeutic purposes are increasingly being used in competitive sports. Some new substances (e.g., antibodies against myostatin or myostatin blockers) might be used in gene doping in athletes. The use of these substances may cause an increase of body weight and muscle mass and a significant improvement of muscle strength. Although it is proven that uncontrolled manipulation of genetic material and/or the introduction of recombinant proteins may be associated with health risks, athletes are increasingly turning to banned gene doping. At the same time, anti-doping research is undertaken in many laboratories around the world to try to develop and refine ever newer techniques for gene doping detection in sport. Thanks to the World Anti-Doping Agency (WADA) and other sports organizations there is a hope for real protection of athletes from adverse health effects of gene doping, which at the same time gives a chance to sustain the idea of fair play in sport.

Keywords

EN

WADA; gene doping; methods of gene doping; methods of proteomic profiling; sport

Discipline

• MEDICINE: MEDICINE

• Publisher: Instytut Sportu
• Journal: Biology of Sport
• Year: 2014
• Volume: 31
• Issue: 4
• Pages: 251-259

Dates

published

2014

Contributors

author

E. Brzeziańska

author

D. Domańska

author

A. Jegier

References

• 1. Unal M, Ozer Unal D.Gene doping in sports. Sports Med. 2004;34:357–62.
• 2. DeFrancesco L.The faking of champions. Nat Biotechnol. 2004;22:1069–71.
• 3. Azzazy HM, Mansour MM, Christenson RH. Doping in the recombinant era: strategies and counterstrategies. Clin Biochem. 2005;38:959–65.
• 4. Haisma HJ, de Hon O.Gene doping. Int J Sports Med. 2006;27:257–66.
• 5. Azzazy HM, Mansour MM. Rogue athletes and recombinant DNA technology: challenges for doping control. Analyst. 2007;132:951–57.
• 6. Baoutina A, Alexander IE, Rasko JE, Emslie KR. Potential use of gene transfer in athletic performance enhancement. Mol Ther. 2007;15:1751–66.
• 7. Pokrywka A, Kaliszewski P, Majorczyk E, Zembroń-Łacny A.Genes in sport and doping. Biol Sport. 2013;30:155-161.
• 8. WADA2008. The World Anti–Doping Code: The 2008 Prohibited List international Standard 2008.
• 9. WADA2013. The World Anti–Doping Code: The 2013 Prohibited List international Standard 2013.
• 10. Lundstrom K, Boulikas T.Viral and non–viral vectors in gene therapy: technology development and clinical trials. Technol Cancer Res Treat. 2003;2:471–86.
• 11. Inesi G, Lewis D, Sumbilla C, Nandi A, Strock C, Huff KW, Rogers TB, Johns DC, Kessler PD, Ordahl CP. Cell–specific promoter in adenovirus vector for transgenic expression of SERCA1 ATPase in cardiac myocytes. Am J Physiol. 1998;274:645–53.
• 12. Jager L, Ehrhardt A.Emerging adenoviral vectors for stable correction of genetic disorders. Curr Gene Ther. 2007;74:272–83.
• 13. Kung HJ, Liu J.L.Retroviral oncogenesis. Philadelphia: Lippineott–RavenPublishers 1997;235–266.
• 14. Crystal R.Transfer of genes to humans: early lessons and obstacles to success. Science. 1995;270:404–10.
• 15. Hackett C, Geurts A, Hackett. P. Predicting preferential DNA vector insertion sites: implications for functional genomics and gene therapy. Genome Biol. 2007;8:S12.
• 16. Lentz T, Gray S, Samulski J.Viral vectors for gene delivery to the central nervous system. Neurobiol Dis. 2012;48:179– 188.
• 17. Fallahi A, Ravasi A, Farhud D.Genetic doping and health damages. Iran J Public Health. 2011;40:1–14.
• 18. Lemkine GF, Demeneix BA. Polyethylenimines for in vivo gene delivery. Curr Opin Mol Ther. 2001;3:178–82.
• 19. Yew NS, Zhao H, Wu IH, Song A, Tousignant JD, Przybylska M, Cheng SH. Reduced inflammatory response to plasmid DNA vectors by elimination and inhibition of immunostimulatory CpG motifs. Mol Ther. 2000;1:255–26.
• 20. Liu F, Conwell CC, Yuan X, Shollenberger LM, Huang L.Novel nonviral vectors target cellular signaling pathways: regulated gene expression and reduced toxicity. J Pharmacol Exp Ther. 2007;321:777–83.
• 21. Kaiser J.Gene therapy. Seeking the cause of induced leukemias in X–SCID trial. Science. 2003;24:5495–606.
• 22. Shyu KG, Chang H, Wang BW, Kuan P.Intramuscular vascular endothelial growth factor gene therapy in patients with chronic critical leg ischemia. Am J Med2003;1:85–92.
• 23. Wang YX, Zhang CL, Yu RT. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol. 2004;2:294.
• 24. Lee S, Barton ER, Sweeney HL, Farrar RP. Viral expression of insulin–like growth factor–I enhances muscle hypertrophy in resistance–trained rats. J Appl Physiol. 2004;96:1097–104.
• 25. Hakimi P, Yang J, Casadesus G, Massillon D, Tolentino-Silva F, Nye CK, Cabrera ME, Hagen DR, Utter CB, Baghdy Y, Johnson DH, Wilson DL, Kirwan JP, Kalhan SC, Hanson RW. Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse. J Biol Chem. 2007;9:32844–55.
• 26. Khan AS, Brown PA, Draghia–Akli R.Plasmid–based growth hormone– releasing hormone supplementation and its applications. Curr Opin Mol Ther. 2005;7:306–16.
• 27. Diamanti–Kandarakis E, Konstantinopoulos PA, Papailiou J, Kandarakis SA, Andreopoulos A, Sykiotis GP. Erythropoietin abuse and erythropoietin gene doping: detection strategies in the genomic era. Sports Med. 2005;35:831–40.
• 28. Machelska H, Schroff M, Oswald D, Binder W, Sitte N, Mousa SA, Rittner HL, Brack A, Labuz D, Busch M, Wittig B, Schäfer M, Stein C.Peripheral non-viral MIDGE vector-driven delivery of beta-endorphin in inflammatory pain. Mol Pain. 2009;14:5:72.
• 29. Bergestrom J.New aspects of erythropoietin treatment. J Int Med. 1993;233:1–18.
• 30. Caldini A, Moneti G, Fanelli A, Bruschettini A, Mercurio S, Pieraccini G, Cini E, Ognibene A, Luceri F, Messeri G. Epoetin alpha, epoetin beta and darbepoetin alfa:two–dimensional gel electrophoresis isoforms characterization and mass spectrometry analysis. Proteomics. 2003;3:937–41.
• 31. Pascual JA, Belalcazar V, de Bolos C, Gutiérrez R, Llop E, Segura J. Recombinant erythropoietin and analogues: a challenge for doping control. Ther Drug Monit. 2004;26:175–79.
• 32. Wilber RL. Detection of DNA– recombinant human epoetin–alfa as a pharmacological ergogenic aid. Sports Med. 2002;32:125–42.
• 33. Schertzer JD, Lynch GS. Comparative evaluation of IGF–I gene transfer and IGF–I protein administration for enhancing skeletal muscle regeneration after injury. Gene Ther. 2006;13:1657–64.
• 34. Tentori L, Graziani G. Doping with growth hormone/IGF–1, anabolic steroids or erythropoietin: is there a cancer risk?Pharmacol Res. 2007;55:359–69.
• 35. Ma J, Sawai H, Matsuo Y, Yasuda A, Ochi N, Takahashi H, Wakasugi T, Funahashi H, Sato M, Takeyama M.IGF-1 and PTEN regulate the proliferation and invasiveness of colon cancer cells through opposite effects on PI3K/Akt signaling. Arch Med Sci. 2009;5:195-206.
• 36. Lu Y, Zi X, Zhao Y, Pollak M.Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells. Biochem Biophys Res Commun. 2004;313:709- 15.
• 37. Boyne MS, Thame M, Bennett F, Osmond C, Miell JP, Forrester TE. The relationship among circulating insulin– like growth factor (IGF)–I, IGF–binding proteins–1 and –2, and birth anthropometry: a prospective study. J Clin Endocrinol Metab. 2003;88:1687– 1691.
• 38. Petersenn S, Schulte HM. Structure and function of the growth–hormone– releasing hormone receptor. Vitam Horm. 2000;59:35–69.
• 39. Kniess A, Ziegler E, Thieme D, Müller RK. Intra-individual variation of GH- dependent markers in athletes: comparison of population based and individual thresholds for detection of GH abuse in sports. J Pharm Biomed Anal. 2013;84:201-8.
• 40. Cox HD, Rampton J, Eichner D.Quantification of insulin-like growth factor-1 in dried blood spots for detection of growth hormone abuse in sport. Anal Bioanal Chem. 2013;405:1949-58.
• 41. Harridge SD, Velloso CP. IGF–I and GH: potential use in gene doping. Growth Horm IGF Res. 2009;19:378–82.
• 42. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5:343– 354.
• 43. Lippi G, Guidi GC. Gene manipulation and improvement of athletic performances: new strategies in blood doping. Br J Sports Med. 2004;38:641.
• 44. Döring F, Onur S, Fischer A, Boulay MR, Pérusse L, Rankinen T, Rauramaa R, Wolfarth B, Bouchard C.A common haplotype and the Pro582Ser polymorphism of the hypoxia–inducible factor–1alpha (HIF1A) gene in elite endurance athletes. J Appl Physiol. 2010;108:1497–500.
• 45. Marx J.HowCells Endure Low Oxygen. Cell Biology2004;5:1454–56.
• 46. Chakravarthy MV, Pan Z, Zhu Y, Tordjman K, Schneider JG, Coleman T, Turk J, Semenkovich CF. New hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab. 2005;1:309– 22.
• 47. Reilly SM, Lee CH. PPAR delta as a therapeutic target in metabolic disease. FEBS Lett. 2008;582:26–31.
• 48. Hautala AJ, Leon AS, Skinner JS, Rao DC, Bouchard C, Rankinen T.Peroxisome proliferator–activated receptor–delta polymorphisms are associated with physical performance and plasma lipids: the HERITAGE Family Study. Am J Physiol Heart Circ Physiol2007;292:2498–505.
• 49. Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM, Gonzalez FJ, Ham J, Kang H, Peters JM, Evans RM. PPARδ regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci. 2006;103:3444–9.
• 50. Grimaldi PA. Regulatory role of peroxisome proliferator–activated receptor delta (PPAR delta) in muscle metabolism. A new target for metabolic syndrome treatment? Biochimie. 2005;87:5–8.
• 51. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. AMPK and PPARδ agonists are exercise mimetics. Cell. 2008;134:405–415.
• 52. Thevis M, Beuck S, Thomas A, Kortner B, Kohler M, Rodchenkov G, Schänzer W.Doping control analysis of emerging drugs in human plasma – identification of GW501516, S–107, JTV–519, and S–40503. Rapid Commun Mass Spectrom. 2009;23:1139–1146.
• 53. Winder WW, Hardie DG. AMP–activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol. 1999;277:E1–E10
• 54. Rantzau C, Christopher M, Alford FP. Contrasting effects of exercise, AICAR, and increased fatty acid supply on in vivo and skeletal muscle glucose metabolism. J Appl Physiol. 2008;104:363–370.
• 55. Carnac G, Ricaud S, Vernus B, Bonnieu A.Myostatin: biology and clinical relevance. Mini Rev Med Chem. 2006;6:765–70.
• 56. Whittemore LA, Song K, Li X, Aghajanian J, Davies M, Girgenrath S, Hill JJ, Jalenak M, Kelley P, Knight A, Maylor R, O’Hara D, Pearson A, Quazi A, Ryerson S, Tan XY, Tomkinson KN, Veldman GM, Widom A, Wright JF, Wudyka S, Zhao L, Wolfman NM. Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun. 2003;24:965–71.
• 57. Furalyov VA, Kravchenko IV, Khotchenkov VP, Popov VO. SiRNAs targeting mouse myostatin. Biochemistry. 2008;7:342–45.
• 58. Paynea J, Montgomery H.Angiotensinconverting enzyme and human physical performance. Equine and Comp Exerc Physiol. 2004;1:255–60.
• 59. Thompson J, Raitt J, Hutchings L, Drenos F, Bjargo E, Loset A, Grocott M, Montgomery H, Caudwell Xtreme Everest Research Group. Angiotensin–Converting Enzyme Genotype and Successful Ascent to Extreme High Altitude. High Alt Med Biol. 2007;28:278–85.
• 60. Gayagay G, Yu B, Hambly B, Boston T, Hahn A, Celermajer DS, Trent RJ. Elite endurance athletes and the ACE I allele–the role of genes in athletic performance. Hum Genet. 1998;103:48–50.
• 61. Woods D, Hickman M, Jamshidi Y, Brull D, Vassiliou V, Jones A, Humphries S, Montgomery H. Elite swimmers and the Dallele of the ACE I/D polymorphism. Hum Genet. 2001;108:230–32.
• 62. Hernandez D, de la Rosa A, Barragan A, Barrios Y, Salido E, Torres A, Martín B, Laynez I, Duque A, De Vera A, Lorenzo V, González A.The ACE/DD genotype is associated with the extent of exercise– induced left ventricular growth in endurance athletes. J Am Coll Cardiol. 2003;42:527–32.
• 63. Drozdovska S, Dosenko V, Ahmetov I, Ilyin V.The association of gene polymorphisms with athlete status in Ukrainians. Biol Sport. 2013;30:163– 167.
• 64. Ahmetov I, Donnikov A, Trofimov DY. ACTN3 genotype is associated with testosterone levels of athletes. Biol Sport. 2014;31:105–108.
• 65. Busquets S, Figueras M, Almendro V, López-Soriano FJ, Argilés JM. Interleukin– 15 increases glucose uptake in skeletal muscle. An antidiabetogenic effect of the cytokine. Biochim Biophys Acta2006;1760:1613–17.
• 66. Thomas A, Beuck S, Eichoff JC, Guddat S, Krug O, Kamber M, Schänzer W, Thevis M. Quantification of urinary AICAR concentrations as a matter of doping control. Anal Bioanal Chem. 2010;396:2899-2908.
• 67. Baoutina A, Alexander IE, Rasko J, Emslie KR. Developing strategies for detection of gene doping. J Gene Med. 2008;10:3–20.
• 68. Joos L, Eryuksel E, Brutsche. MH Functional genomics and gene microarrays – the use in research and clinical medicine. Swiss Med Wkly. 2003;133:31–38.
• 69. Chaudhuri J.D. Genes arrayed out for you: the amazing world of microarrays. Med Sci Monit. 2005;11:RA52–RA62.
• 70. Issaq HJ, Veenstra TD, Conrads TP, Felschow D. The SELDI-TOF MS approach to proteomics: protein profiling and biomarker identification. Biochem Biophys Res Commun. 2002;292:587–592.
• 71. Chung L, Clifford D, Buckley M, Baxter RC. Novel biomarkers of human growth hormone actionfrom serum proteomic profiling using protein chip mass spectrometry. J Clin Endocrinol Metab. 2006;91:671–677.
• 72. Lasne F, Martin L, de Ceaurriz J, Larcher T, Moullier P, Chenuaud P. Genetic doping with erythropoietin cDNA in primate muscle is detectable. Mol Ther. 2004;10:409–410.

• Document Type: article