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Gaming the System: Doping in Sports - Max gassmann
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Gaming the System: Doping in Sports - Max gassmann

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  • 1. San Francisco Prof. Max Gassmann Erythropoietin’s impact onand exercise performance Chairman of the Institute of Veterinary Physiology, Vetsuisse Faculty, and of the Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich Gaming the System: Doping in Sports swissnex San Francisco August 20, 2012 Chart 1
  • 2. circulation reduced oxygen Epo Epo anti-apoptotic effect bone on erythroid oxygen marrow precursor cells sensing: HIF-2 + neg.Feedback - Epo-synthesis Hb-O2 erythrocytes O2 oxygen uptake + hematocrit +Institute of Veterinary Physiology Chart 2
  • 3. rhEpo has been developed to treat anemic patients and not to dope cheating athletesInstitute of Veterinary Physiology Chart 3
  • 4. Mouse models to study the impact of acute and chronically elevated Epo levels • rhEpo injection (i.p.) into wild type mouse • transgenic mouse constitutively overexpressing human Epo in brain only (tg21) • transgenic mouse constitutively overexpressing human Epo (26 fold) in brain and reaching a 12 fold increase in plasma Epo levels (tg6)  excessive erythrocytosis Ruschitzka et al., PNAS 2000 Wiessner et al., JCBF&M 2001Institute of Veterinary Physiology Chart 4
  • 5. Epo-overexpressing transgenic mouse lines tg21 and tg6: hematological parameters wt+tg21 tg6 plasma Epo U/l 22 260 red blood cells 1012 / l 6.2 13.8 hemoglobin g/l 140 235 hematocrit % 40 79 ( 90) reticulocyte counts % 1.7 3.4 blood volume ml 2.2 5.5 arterial pO2 mmHg 125 133 arterial oxygen content ml / dl 17 31Institute of Veterinary Physiology Chart 5
  • 6. The higher the hematocrit the higher the performance?
  • 7. Reduced exercise performance in Epo-overexpressing tg6 mice with a hematocrit of exercise performance in Reduced ~80 % EPO- overexpressing mice with a hematocrit of ~80 % swimming running 0.22 100 exercise time (min) swim speed (m/s) 0.20 wt 75 0.18 50 0.16 25 0.14 tg6 0.12 0 20 40 60 80 100 120 wt tg6 secondsInstitute of Veterinary Physiology Chart 7
  • 8. An endurance athlete copes with achronically elevated hematocrit Eero Mäntyranta (born 1937) hematocrit: 68% won 6 gold medals between 1960-1966
  • 9. An optimal hematocrit for maximal performance? wt tg6 Hematocrit: 0.4 Hematocrit: 0.8-0.9   Hematocrit Hematocrit NESP (“Epo”) Phenylhydrazine (PHZ) leads to hemolysis acute Treadmill chronicInstitute of Veterinary Physiology Chart 9
  • 10. Maximal performance is reached at hematocrit levels 0.57-0.68 · VO2max Time to exhaustion .Schuler et al., PNAS 2010
  • 11. What is the limiting factor? Viscosity! ∙ VO2max vs. blood viscosity
  • 12. ConclusionsThe present study confirms our hypothesis thatoptimal hematocrit during systemic exercise inmice exists.Maximal working capacity of the heart was notreached at the optimal hematocrit for maximalendurance performance.Blood viscosity is the most likely candidate to limitexercise performance.
  • 13. Mäntyranta expresses a truncated formof the Epo receptorTruncated Epo receptor causes dominantly inherited benignhuman erythrocytosis byde la Chapelle et al., PNAS 1993
  • 14. Complications in mice suffering from Epo-induced excessive erythrocytosisInstitute of Veterinary Physiology Chart 14
  • 15. Degenerative process in the liver of 5 month-old tg6 mice wt tg6 tg6 ->: hemosiderin 50µm  : inflammationInstitute of Veterinary Physiology Chart 15
  • 16. Degenerative processes in the sciatic nerve of 5 month-old tg6 mice 20µm 2µm A: Axoplasma SC: Schwam cells  axonal swelling ML: Myelin lamellae Co: Collagen fibres  deformed fibresInstitute of Veterinary Physiology Chart 16
  • 17. Hindlimb paralysis and neuromuscular degeneration in tg6 mice Motor disorders characterized by bi- or unilateral spastic contraction and paralysis of the hindlimbsInstitute of Veterinary Physiology Chart 17
  • 18. Degenerated skeletal muscle fibres in tg6 mice wt tg6 = muscle capillariesInstitute of Veterinary Physiology Chart 18
  • 19. circulation reduced oxygen Epo Epo anti-apoptotic effect bone on erythroid oxygen marrow precursor cells sensing: HIF-2 + neg.Feedback - Epo-synthesis Hb-O2 erythrocytes O2 oxygen uptake + hematocrit +Institute of Veterinary Physiology Chart 19
  • 20. Repoxygen® was intended for gene therapy Recombinant epo oxygen HIF gene therapy HRE hEpo DNA - HIF is present in all cells of the human body - Thus oxygen-regulated Epo synthesis should be possible in muscle, too - Introduction into muscle by: - viral vectors - direct muscular injection - hEpo expression is expected to be oxygen-regulatedInstitute of Veterinary Physiology Chart 20
  • 21. Repoxygen®: no further development HIF - Is not in clinical trials HRE hEpo DNA - Economics: Repoxygen vs. classical project is stopped rhEpo - Additional problems: - normal Epo expression: kidney (fetal liver) but not muscle - HRE is variable - oxygen-regulated Repoxygen expression in humans: unknown - Introduction into human body: - viral vectors - direct muscular injection - CAVE: uncontrolled Epo expression polycythemia serious risks including deathInstitute of Veterinary Physiology Chart 21
  • 22. oxygen low normal blood loss (normoxia) anemia altitude Hypoxia-Inducible Factor Hypoxia-Inducible Factor (HIF): stabilized (HIF): degraded by PHD‘s HIF HIF PHD„s + O2 induce HRE HIF target genes DNA Hypoxia - Erythropoietin (Epo) Response - Vascular Endothelial Growth Factor Element - etc.Institute of Veterinary Physiology Chart 22
  • 23. Acknowledgement s B. Schuler E. Vannoni J. Vogel D. Wolfer A. Bogdanova C. Lundby L. Ogunshola F. Ruschitzka J. Soliz Th. Lüscher B. Grenacher M. Maggiorini M. Alvarez R. Jacobs V. DiazInstitute of Veterinary Physiology Chart 23
  • 24. Institute of Veterinary Physiology Chart 24
  • 25. Institute of Veterinary Physiology Chart 26
  • 26. Epo-overexpressing tg6 mouse: resting hemodynamic parameters wt tg6 heart rate beats/min 569 ± 18 605 ± 9 systolic blood pressure mmHg 119 ± 5 120 ± 5 cardiac output ml/min 6.4 ± 1.7 6.7 ± 1.7 Ruschitzka et al., PNAS 2000Institute of Veterinary Physiology Chart 27
  • 27. How do tg6 mice adapt to excessive erythrocytosis? by NO-mediated vasodilation by regulating blood viscosityInstitute of Veterinary Physiology Chart 28
  • 28. Elevated eNOS synthesis in Epo- overexpressing tg6 mice control wt tg6 eNOS (140 kDa) control wt tg6 tg6Institute of Veterinary Physiology Chart 29
  • 29. Regulated elevation of bloodviscosity in tg6 mice Hct blood 0.43 wt 80 0.89 wt, hemoconc. 0.88 tg . apparent blood viscocity (mPa.s) 60 40 Note: tg plasma viscosity is not altered 20 0 Vogel et al. Blood 2001 11 23 90 shear rate s-1
  • 30. Enhanced elongation of tg6 erythrocytes (ektacytometry) tg6 elongation of erythrocytes (%) wt 10 * * * 5 * * * 0 12 25 90 shear rate (s-1) **=p<0.01 Vogel et al., Blood 2003Institute of Veterinary Physiology Chart 31
  • 31. Erythrocytes of camillidae are elliptical 100x The erythrocytes of llamas, alpacas and camels are small, flat and oval-shaped. The lifespan of the llama„s erythrocyte is 60 days.

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