Skip to main content
SpringerLink
Log in

RhEPO improves time to exhaustion by non-hematopoietic factors in humans

  • Original Article
  • Published:
European Journal of Applied Physiology Aims and scope Submit manuscript

Abstract

Purpose

Erythropoietin (EPO) controls red cell volume (RCV) and plasma volume (PV). Therefore, injecting recombinant human EPO (rhEPO) increases RCV and most likely reduces PV. RhEPO-induced endurance improvements are explained by an increase in blood oxygen (O2) transport capacity, which increases maximum O2 uptake (\(\dot{V}\)O2max). However, it is debatable whether increased RCV or \(\dot{V}\)O2max are the main reasons for the prolongation of the time to exhaustion (t lim) at submaximal intensity. We hypothesized that high rhEPO doses in particular contracts PV such that the improvement in t lim is not as strong as at lower doses while \(\dot{V}\)O2max increases in a dose-dependent manner.

Methods

We investigated the effects of different doses of rhEPO given during 4 weeks [placebo (P), low (L), medium (M), and high (H) dosage] on RCV, PV, \(\dot{V}\)O2max and t lim in 40 subjects.

Results

While RCV increased in a dose-dependent manner, PV decreased independent of the rhEPO dose. The improvements in t lim (P +21.4 ± 23.8 %; L +16.7 ± 29.8 %; M +44.8 ± 62.7 %; H +69.7 ± 73.4 %) depended on the applied doses (R 2 = 0.89) and clearly exceeded the dose-independent \(\dot{V}\)O2max increases (P −1.7 ± 3.2 %; L +2.6 ± 6.8 %; M +5.7 ± 5.1 %; H +5.6 ± 4.3 %) after 4 weeks of rhEPO administration. Furthermore, the absolute t lim was not related (R 2 ≈ 0) to RCV or to \(\dot{V}\)O2max.

Conclusions

We conclude that a contraction in PV does not negatively affect t lim and that rhEPO improves t lim by additional, non-hematopoietic factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ANOVA:

Analysis of variance

AWC:

Anaerobic work capacity

BL:

Baseline

CLT:

Constant-load test

CO:

Carbon monoxide

CP:

Critical power

CV:

Coefficient of variation

EP:

End point (after 4 weeks)

EPO:

Erythropoietin

f cell :

Cellular factor (HctWB/Hct)

H :

High dosage of rhEPO (10,000 IU)

Hct:

Haematocrit

HctWB :

Whole body haematocrit

i.v.:

Intra venous

ICG:

Indocyanine green

ICT:

Incremental cycling test

L :

Low dosage of rhEPO (2,500 IU)

M :

Medium dosage of rhEPO (5,000 IU)

MP:

Mid point (after 2 weeks)

NaCl:

Sodium chloride

O2 :

Oxygen

P :

Placebo (physiological NaCl solution)

P max :

Maximal power

PV:

Plasma volume

RCV:

Red cell volume

RER:

Respiratory exchange rate

rhEPO:

Recombinant human EPO

rpm:

Revolution per min

t 360 :

Time after 360 s

t lim :

Time of CLT

\(\dot{V}\)CO2 :

Carbon dioxide production

\(\dot{V}\) E :

Minute ventilation

\(\dot{V}\)O2 :

Oxygen consumption

\(\dot{V}\)O2lim :

Mean \(\dot{V}\)O2 during the last 30 s before t lim

\(\dot{V}\)O2max :

Maximum oxygen consumption

References

  • Arcasoy MO (2008) The non-haematopoietic biological effects of erythropoietin. Br J Haematol 141:14–31

    Article  CAS  PubMed  Google Scholar 

  • Berglund B, Ekblom B (1991) Effect of recombinant human erythropoietin treatment on blood pressure and some haematological parameters in healthy men. J Int Med 229:125–130

    Article  CAS  Google Scholar 

  • Böning D, Maassen N, Pries A (2011) The hematocrit paradox—how does blood doping really work? Int J Sports Med 32:242–246

    Article  PubMed  Google Scholar 

  • Breymann C, Rohling R, Huch A, Huch R (2000) Intraoperative endogenous erythropoietin levels and changes in intravascular blood volume in healthy humans. Ann Hematol 79:183–186

    Article  CAS  PubMed  Google Scholar 

  • Brines M, Cerami A (2006) Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int 70:246–250

    Article  CAS  PubMed  Google Scholar 

  • Brun JF, Bouchahda C, Chaze D, Benhaddad AA, Micallef JP, Mercier J (2000) The paradox of hematocrit in exercise physiology: which is the “normal” range from an hemorheologist’s viewpoint? Clin Hemorheol Microcirc 22:287–303

    CAS  PubMed  Google Scholar 

  • Burge CM, Skinner SL (1995) Determination of hemoglobin mass and blood volume with CO: evaluation and application of a method. J Appl Physiol 79:623–631

    CAS  PubMed  Google Scholar 

  • Burgomaster KA, Hughes SC, Heigenhauser GJF, Bradwell SN, Gibala MJ (2005) Six sessions of sprint interval training increases muscle oxidative potential and cycle endurance capacity in humans. J Appl Physiol 98:1985–1990

    Article  PubMed  Google Scholar 

  • Cayla JL, Maire P, Duvallet A, Wahrmann JP (2008) Erythropoietin induces a shift of muscle phenotype from fast glycolytic to slow oxidative. Int J Sports Med 29:460–465

    Article  CAS  PubMed  Google Scholar 

  • Coyle EF, Hopper MK, Coggan AR (1990) Maximal oxygen uptake relative to plasma volume expansion. Int J Sports Med 11:116–119

    Article  CAS  PubMed  Google Scholar 

  • Heuberger JAAC, Tervaert JMC, Schepers FML, Vliegenthart ADB, Rotmans JI, Daniels JMA, Burggraaf J, Cohen AF (2013) Erythropoietin doping in cycling: lack of evidence for efficacy and a negative riskbenefit. Br J Clin Pharmacol 75:1406–1421

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hilty L, Langer N, Pascual-Marqui R, Boutellier U, Lutz K (2011) Fatigue-induced increase in intracortical communication between mid/anterior insular and motor cortex during cycling exercise. Eur J Neurosci 34:2035–2042

    Article  PubMed  Google Scholar 

  • Hojman P, Brolin C, Gissel H, Brandt C, Zerahn B, Pedersen BK, Gehl J (2009) Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles. PLoS One 4:e5894

    Article  PubMed Central  PubMed  Google Scholar 

  • Holloszy JO, Coyle EF (1984) Adaptations of skeletal muscle of endurance exercise and their metabolic consequences. J Appl Physiol 56:831–838

    CAS  PubMed  Google Scholar 

  • Hopkins WG (2000) Measures of reliability in sports medicine and science. Sports Med 30:1–15

    Article  CAS  PubMed  Google Scholar 

  • Hopkins WG (2006) Estimating sample size for magnitude-based inferences. Sportscience 10:63–70

    Google Scholar 

  • Jacob M, Conzen P, Finsterer U, Krafft A, Becker BF, Rehm M (2007) Technical and physiological background of plasma volume measurement with indocyanine green: a clarification of misunderstandings. J Appl Physiol 102:1235–1242

    Article  CAS  PubMed  Google Scholar 

  • Jeukendrup A, Saris WHM, Brouns F, Kester ADM (1996) A new validated endurance performance test. Med Sci Sports Exerc 28:266–270

    Article  CAS  PubMed  Google Scholar 

  • Kanstrup IL, Ekblom B (1984) Blood volume and hemoglobin concentration as determinants of maximal aerobic power. Med Sci Sports Exerc 16:256–262

    Article  CAS  PubMed  Google Scholar 

  • Lavoie C, Diguet A, Milot M, Gareau R (1998) Erythropoietin (rHuEPO) doping: effects of exercise on anaerobic metabolism in rats. Int J Sports Med 19:281–286

    Article  CAS  PubMed  Google Scholar 

  • Lundby C, Thomsen JJ, Boushel R, Koskolou M, Warberg J, Calbet JAL, Robach P (2007) Erythropoietin treatment elevates haemoglobin concentration by increasing red cell volume and depressing plasma volume. J Physiol 578:309–314

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lundby C, Hellsten Y, Jensen MBF, Munch AS, Pilegaard H (2008) Erythropoietin receptor in human skeletal muscle and the effects of acute and long-term injections with recombinant human erythropoietin on the skeletal muscle. J Appl Physiol 104:1154–1160

    Article  CAS  PubMed  Google Scholar 

  • Miura A, Endo M, Sato H, Barstow TJ, Fukuba Y (2002) Relationship between the curvature constant parameter of the power-duration curve and muscle cross-sectional area of the thigh for cycle ergometry in humans. Eur J Appl Physiol 87:238–244

    Article  PubMed  Google Scholar 

  • Mortensen SP, Dawson EA, Yoshiga CC, Dalsgaard MK, Damsgaard R, Secher NH, Gonzalez-Alonso J (2005) Limitations to systemic and locomotor limb muscle oxygen delivery and uptake during maximal exercise in humans. J Physiol 566:273–285

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Morton RH (2006) The critical power and related whole-body bioenergetic models. Eur J Appl Physiol 96:339–354

    Article  PubMed  Google Scholar 

  • Noakes TD (2008) Testing for maximum oxygen consumption has produced a brainless model of human exercise performance. Br J Sports Med 42:551–555

    Article  CAS  PubMed  Google Scholar 

  • Orth VH, Rehm M, Thiel M, Kreimeier U, Haller M, Brechtelsbauer H, Finsterer U (1998) First clinical implications of perioperative red cell volume measurement with a nonradioactive marker (sodium fluorescein). Anesth Analg 87:1234–1238

    CAS  PubMed  Google Scholar 

  • Plenge U, Belhage B, Guadaloupe-Grau A, Andersen PR, Lundby C, Dela F, Stride N, Pott FC, Helge JW, Boushel R (2012) Erythropoietin treatment enhances muscle mitochondrial capacity in humans. Front Physiol 3:50

    Article  PubMed Central  PubMed  Google Scholar 

  • Prommer N, Sottas PE, Schoch C, Schumacher YO, Schmidt W (2008) Total hemoglobin mass—new parameter to detect blood doping? Med Sci Sports Exerc 40:2112–2118

    Article  CAS  PubMed  Google Scholar 

  • Ross R, Gray CM, Gill JMR (2015) Effects of an injected placebo on endurance running performance. Med Sci Sports Exerc 47:1672–1681

    Article  PubMed  Google Scholar 

  • Rundqvist H, Rullman E, Sundberg CJ, Fischer H, Eisleitner K, Stahlberg M, Sundblad P, Jansson E, Gustafsson T (2009) Activation of the erythropoietin receptor in human skeletal muscle. Eur J Endocrinol 161:427–434

    Article  CAS  PubMed  Google Scholar 

  • Russell G, Gore CJ, Ashenden MJ, Parisotto R, Hahn AG (2002) Effects of prolonged low doses of recombinant human erythropoietin during submaximal and maximal exercise. Eur J Appl Physiol 86:442–449

    Article  CAS  PubMed  Google Scholar 

  • Sawka MN, Convertino VA, Eichner ER, Schnieder SM, Young AJ (2000) Blood volume: importance and adaptations to exercise training, environmental stresses, and trauma/sickness. Med Sci Sports Exerc 32:332–348

    Article  CAS  PubMed  Google Scholar 

  • Schmidt W, Prommer N (2010) Impact of alterations in total hemoglobin mass on VO2max. Exerc Sport Sci Rev 38:68–75

    Article  PubMed  Google Scholar 

  • Schuler B, Vogel J, Grenacher B, Jacobs RA, Arras M, Gassmann M (2012) Acute and chronic elevation of erythropoietin in the brain improves exercise performance in mice without inducing erythropoiesis. FASEB J 26:3884–3890

    Article  CAS  PubMed  Google Scholar 

  • Stallknecht B, Vissing J, Galbo H (1998) Lactate production and clearance in exercise: effects of training. A mini-review. Scand J Med Sci Sports 8:127–131

    Article  CAS  PubMed  Google Scholar 

  • Thomsen JJ, Rentsch RL, Robach P, Calbet JAL, Boushel R, Rasmussen P, Juel C, Lundby C (2007) Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity. Eur J Appl Physiol 101:481–486

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to the participants for their voluntarily contribution. We also thank Renate Huch, Christian Bauer, Marco Toigo and René Rossi for scientific assistance. The study was financially supported by the Eidgenössische Sportkommission, Magglingen (to UB).

Author information

Author notes

    Authors and Affiliations

    1. Exercise Physiology, Institute of Human Movement Sciences, ETH Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

      Simon Annaheim & Urs Boutellier

    2. Laboratory for Protection and Physiology, EMPA, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, 9014, St. Gallen, Switzerland

      Simon Annaheim

    3. Exercise Physiology, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

      Simon Annaheim & Urs Boutellier

    4. Department of Anaesthesiology, University Hospital, Nussbaumstrasse 20, 80336, Munich, Germany

      Matthias Jacob & Markus Rehm

    5. Division of Obstetrics, Department of Obstetrics and Gynaecology, University Hospital, 8000, Zurich, Switzerland

      Alexander Krafft & Christian Breymann

    6. Exercise Physiology, ETH Zurich, Rychenbergstr. 49a, 8400, Winterthur, Switzerland

      Urs Boutellier

    Authors
    1. Simon Annaheim
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Matthias Jacob
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Alexander Krafft
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Christian Breymann
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Markus Rehm
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Urs Boutellier
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Urs Boutellier.

    Ethics declarations

    Conflict of interest

    The authors have no conflicts of interest.

    Additional information

    Communicated by Michael Lindinger.

    S. Annaheim and M. Jacob contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Annaheim, S., Jacob, M., Krafft, A. et al. RhEPO improves time to exhaustion by non-hematopoietic factors in humans. Eur J Appl Physiol 116, 623–633 (2016). https://doi.org/10.1007/s00421-015-3322-6

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00421-015-3322-6

    Keywords

    Search

    Navigation