Commentary on Point-Counterpoint

Abstract

POINT-COUNTERPOINT COMMENTSCommentary on Point-CounterpointStefan KeslacyStefan KeslacyPublished Online:01 Jan 2006https://doi.org/10.1152/japplphysiol.01156.2005MoreSectionsPDF (78 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat This letter is in response to the Point:Counterpoint series “Positive effects of intermittent hypoxia (live high:train low) on exercise performance are/are not mediated primarily by augmented red cell volume that appeared in the November issue (vol. 99: 2053–2058, 2005; doi: 10.1152/japplphysiol.00877.2005; http://jap.physiol.org/content/vol99/issue5/2005).To the Editor: The increased-performance after hypoxic training is a real challenge for researchers. A lot of studies tried to explore the implied physiological mechanisms, but the results are contradictory. The increased red cell volume (RCV) response due to altitude training represents one of these mechanisms. The protagonists of this discussion (3) seem to agree on the fact that several studies have shown a remarkable interindividual variability in RCV response. Thus, to better understand these variations, one should focus on the mechanisms that promote RCV. A potential mechanism is an increase in erythropoietic response. Evidence suggests that both stem cell factors signaling pathways and c-Kit receptors are essential in erythropoiesis (2). Thus it would be indispensable to evaluate the erythropoietin level and activity before and after hypoxic exposure, especially the signaling events initiated by the binding of erythropoietin to the Epo receptor. Variations of RCV could therefore be explained by a different contribution of erythropoietin in the improvement in sea level performance after altitude training/living. Mutant mice should be useful, in particular with phenotypic abnormalities affecting the Dominant White Spotting and Steel loci (1). The use of this animal model will provide a more precise evaluation of hypoxia-induced erythrocyte volume to minimize (but not cancel) considerations about performance economy, level of altitude, placebo effect, and artifacts of measurement. This should be taken into account for future studies by 3-D analysis (4), double-blind designs, and better knowledge of hypoxia-induced erythropoiesis.REFERENCES1 Broudy VC. Stem cell factor and hematopoiesis. Blood 90: 1345-1364, 1997.Crossref | PubMed | ISI | Google Scholar2 Munugalavadla V and Kapur R. Role of c-Kit and erythropoietin receptor in erythropoiesis. Crit Rev Oncol Hematol 54: 63–75, 2005.Crossref | ISI | Google Scholar3 Levine BD and Stray-Gundersen J; Gore CJ and Hopkins WG. Point:Counterpoint: Positive effects of intermittent hypoxia (live high:train low) on exercise are/are not mediated primarily by augmented red cell volume. J Appl Physiol 99: 2053–2058, 2005.Link | ISI | Google Scholar4 Slawinski JS and Billat VL. Changes in internal mechanical cost during overground running to exhaustion. Med Sci Sports Exerc 37: 1180–1186, 2005.Crossref | ISI | Google ScholarjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyjapJ Appl PhysiolJournal of Applied PhysiologyJ Appl Physiol8750-75871522-1601American Physiological SocietyRobert S. MazzeoDepartment of Integrative Physiology University of Colorado Boulder, Colorado e-mail: [email protected]January2006D. A. Giussani, and A. S. ThakorDepartment of Physiology University of Cambridge Cambridge, United Kingdom e-mail: [email protected]January2006Giuseppe Insalaco, and Institute of Biomedicine and Molecular Immunology “A. Monroy” (IBIM) Italian National Research Council (CNR) e-mail: [email protected]Maria Rosaria BonsignoreInstitute of Medicine and Pneumology University of Palermo Palermo, ItalyJanuary2006Fernando A. RodríguezInstitut Nacional d'Educació Física de Catalunya Department of Biomedical Sciences Universitat de Barcelona Barcelona, Spain e-mail: [email protected]January2006Karen S. MarkDepartment of Pharmacology University of Missouri-Kansas City Kansas City, Missouri e-mail: [email protected]January2006C. Reboul, and S. TanguyFaculty of Sciences Avignon, France e-mail: [email protected]January2006Leonhard Schaffer, and Hugo H. Marti1Department of Obstetrics Division of Perinatal Physiology University of Zurich 2Institute of Physioloy University of Zurich Zurich, Switzerland 3Institute of Physiology and Pathophysiology University of Heidelberg Heidelberg, Germanye-mail: [email protected] e-mail: [email protected]January2006Alfredo Gamboa, and 1Vanderbilt University Nashville, Tennessee e-mail: [email protected]Jorge L. Gamboa2Department of Physiology University of Kentucky Lexington, KentuckyJanuary2006Jon Peter WehrlinSection for Elite Sport Swiss Federal Institute of Sports Magglingen, Switzerland e-mail: [email protected]January2006Robert F. Grovere-mail: [email protected]January2006Birgit FriedmannUniversity Hospital Sports Medicine Heidelberg, Germany e-mail: [email protected]January2006David T. Martin, and Allan G. HahnAustralian Institute of Sport Belconnen, Australia e-mail: [email protected]January2006George A. BrooksUniversity of California-Berkeley Berkeley, California e-mail: [email protected]January2006Walter SchmidtSports Medicine/Sports Physiology University of Bayreuth Bayreuth, Germany e-mail: [email protected]January2006Bernd WolfarthDepartment of Preventive and Rehabilitative Sports Medicine Technical University Munich Munich, Germany e-mail: [email protected]January2006To the Editor: There are a number of points worth noting regarding the Point:Counterpoint on positive effects of intermittent hypoxia on exercise performance (2). Studies at the summit of Pikes Peak (4,300 m) have consistently demonstrated that, for a given absolute and/or relative exercise intensity, o2 of the exercising legs is unchanged after acclimatization when compared with initial exposure (1, 4, 5). These findings are observed during both submaximal steady-state as well as during graded exercise. This indicates that no changes in economy of O2 utilization had occurred. This was confirmed by a subsequent study showing that although β-adrenergic blockade resulted in a reduction of O2 delivery to working muscle, leg o2 was unaltered as a result of an increase in O2 extraction. This occurred both pre- and postacclimatization to 4,300 m, suggesting no change in economy.However, as in any altitude study, both the degree of hypoxia (altitude elevation) and duration of stay are factors that dictate the extent of physiological and metabolic adaptations associated with exposure. Additionally, it is clear that, for a given altitude, there is interindividual variability regarding the extent of these adaptations (e.g., red cell volume, EPO, altitude sickness) as well as how the hypoxic stress is perceived by the body (differences in sympathoadrenal responses; Ref. 3). Finally, the potential benefits from the live high:train low paradigm are going to be event and training specific and will not necessarily result in improved performance for all athletes. Where it is found to improve performance, the effect that live high:train low has on the lactate threshold and performance velocity at this workload needs to be more rigorously investigated. To the Editor: Athletes can increase their performance by altitude training; however, the physiological mechanism conveying this benefit remains unclear. Levine and Stray-Gundersen (2) put forward a convincing argument stating that improved performance and o2 max can be attributed to erythropoiesis, increased red cell volume, and, thereby, increased oxygen carrying capacity. Conversely, Gore and Hopkins (2) support that other mechanisms, such as an improvement in exercise economy, fractional oxygen utilization, and/or changes in cardiovascular regulation that result in increased muscle blood flow, are just as likely to mediate the increased performance. On balance, these arguments need not be necessarily antagonistic. It is likely that the mechanism underlying the beneficial effects of altitude training on exercise performance is multifactorial in nature and that the relative contribution of various mechanisms providing the benefit will depend on the severity and duration of the hypoxic challenge, i.e., the duration of training at altitudes ranging from 2,000 to 5,000 m. A recent study by Calbet and colleagues (1) seems to illustrate the point. The study determined the influence of blood hemoglobin concentration ([Hb]) on maximal exercise capacity, o2 max, and muscular blood flow (LBF) in subjects acclimatized to high altitude in Bolivia. The data show that the increased [Hb] with altitude acclimatization did not improve maximal exercise capacity or o2 max. However, LBF and vascular conductance were higher at altitude. Calbet and colleagues suggest that the lack of an effect of [Hb] on o2 max in this particular instance was compensated for by reciprocal changes in LBF via local metabolic control of the muscle vasculature.To the Editor: Whether augmented red cell volume by intermittent hypoxia improves exercise performance is still controversial (4). Erythropoietin (Epo) synthesis is stimulated by hypoxia, and Epo is released during exercise-induced hypoxemia or when exercise is carried out under hypoxic conditions. Epo increases only temporarily at altitude, and aspartate aminotransferase activity in erythrocytes is augmented, indicating reduced mean cell age (1).Information on the effects of hypoxia on the bone marrow could be obtained by issues recently addressed in exercise physiology. Supramaximal exercise is a physiological stimulus for erythrocyte progenitor release in athletes; in addition, endothelial precursors are mobilized after exercise, and angiogenetic factors modulated by hypoxia, such as VEGF, are released (5). Circulating hematopoietic progenitors are increased in peripheral blood of runners and likely reflect an adaptation to recurrent, exercise-associated release of bone marrow cells (2). We believe that the effects of training under hypoxic conditions on the bone marrow may be more complex than simply activating erythropoiesis. That this may indeed be the case is suggested by the release of immature reticulocytes after supramaximal exercise in rowers, associated with an acute decrease of plasma erythropoietin concentration. Thus it is possible that release of reticulocytes and proangiogenetic cells and mediators are induced by acute hypoxemia even in the absence of clear erythropoietic stimulation (5). Conversely, reticulocyte parameters were found to be steady during a 6-day endurance competition at sea level in runners (3). Further studies on bone marrow-derived cells are needed to understand the effects of live high:train low in athletes.To the Editor: The fulfillment of the postulates adapted by Levine and Stray-Gundersen (1) reasonably proves the cause-and-effect relationship between enhanced erythropoiesis and aerobic performance. The improvement in economy as primary mechanism contended by Gore and Hopkins (1) seems to be less compelling and the adaptive physiological mechanisms more speculative.However, the approach used for the discussion could be viewed as somewhat reductionistic. The ubiquitous, complex adaptive responses to intermittent hypoxia (IH) suggest several other physiologically plausible mechanisms and potentially synergistic and/or regulatory interactions. For illustration: 1) IH has shown to elicit long-term facilitation in respiratory neurons (4); 2) increased lung diffusion capacity, tidal volume and alveolar blood flow during exercise, and improved matching of ventilation to perfusion have been described after IH in training athletes (3); and 3) LHTL is able to improve systolic function (2).Thus a fourth postulate could logically be proposed in adjunction to those enunciated by Levine and Stray-Gundersen (1) for the sake of this discussion: the correlation between cause and effect (improvement in exercise performance) cannot be explained by another physiological mechanism, factor, or interaction. In our opinion, this postulate is far from being fulfilled by either of the contending parts.Considering the complex nature of physiological adaptations to IH, it seems reasonable that other mechanisms and, even more likely, a complex, nonlinear interaction of physiological factors may as well contribute to the positive effects of IH and certainly warrant further investigation using conventional and new models and paradigms (e.g., nonlinear analysis of complex, dynamic systems).To the Editor: These Point:Counterpoint articles discuss whether hematological changes, i.e., red cell volume (RCV) underlie improved performance of athletes after high-altitude exposure (4). Although the focus was to understand the physiological changes in response to hypoxia associated with high altitude, clearly their approaches and analytical tools differ. Levine and Stray-Gundersen use a more realistic terrestrial LHTL model but Evans Blue technique to indirectly measure RCV. In contrast, Gore and Hopkins use the artificial LHTL model but an appropriate CO-Hb rebreathing technique to assess total Hb mass. Many discrepancies stem from differences in experimental design and outcomes assessment, which require further studies including addressing methodological issues and double-blind designs, as stated in the counterpoint (4).The hypothesis that increased RCV is related to improved performance is indirectly supported by the correlation between Δ5 K time and o2 max (3). Although Ashenden et al. (1) reported elevated reticulocyte Hb levels in simulated high-altitude athletes with no change in Hb mass, they did not report any correlation to performance or o2 max (1).Clearly both sides have valid points to their argument, which lead them to propose additional studies including HIF-1α, lactate threshold, and buffering capacity. There remains the underlying problems of subject variability and blinded subjects that are likely to contribute to result error. The level of endurance, subject's physical and mental fitness due to stress, depression, or overtraining can alter physiological parameters (2). What ramifications will LHTL have on release of proinflammatory cytokines, activation of transcription factors (5) that may impact erythropoiesis, anaerobic threshold, endorphin release, and ultimately exercise performance?To the Editor: I read with interest the Point:Counterpoint about the effects of “living high:training low” (LHTL) on aerobic performances. The authors focused on the association between aerobic performances and red cell volume consecutive to LHTL (2). This question is prone to controversy, probably because focusing the debate only on red cell volume augmentation is reductive. It is partly true that, when the LHTL is compared with common sea level training, the augmentation of red cell volume seems to play a major role. However, in another context, when LHTL is compared with the classical used altitude training [living high:training high (LHTH)], other factors, including cardiovascular adaptations, could play a major role. Indeed, in the literature, increased total blood hemoglobin resulting from LHTH was not classically related to improvement of aerobic performances (1). As we recently proposed in a rodent model (4, 5), this phenomenon could be explained by specific cardiovascular adjustments associated with chronic hypoxia induced by altitude acclimatization. This may offset the positive effects of polycythemia on exercise performance by limiting blood delivery to exercising muscles. Therefore, we could consider that the positive effects of LHTL on exercise performance could be mediated by the preventive role played by low-altitude training sessions on deleterious hypoxia-induced cardiovascular adaptations. Moreover, it is of note to highlight that Liu et al. (3) reported an improvement of left ventricular function consecutive to LHTL. Thus additional studies about blood hemoglobin and cardiovascular, but also peripheral, adaptations consecutive to LHTL will be needed to investigate these hypotheses.To the Editor: No doubt, altitude exposure stimulates erythropoiesis, resulting in improved aerobic capacity (3). It is also evident that this response is elicited by increased erythropoietin expression, which in turn is activated by the hypoxia-inducible factor-1 (HIF-1). Because the degree of HIF-1 activation is strictly dependent on the actual Po2 (2), it appears very likely that the increase in red cell volume (RCV) is dependent on duration and severity of tissue hypoxia. However, there are a number of additional adaptive changes occurring during hypoxic exposure. First, increased RCV expands total plasma volume (PV) and total blood volume after return to sea level (5), which itself can contribute to an improved oxygen transport by increasing cardiac output through better filling pressures and the Frank-Starling mechanism. Higher cardiac output would optimize oxygen consumption due to an increase in mass oxygen transport. Second, hypoxic induction of HIF-1 in skeletal muscle will activate the vascular endothelial growth factor (VEGF) pathway, which in turn can stimulate angiogenesis, resulting in increased capillary density, improved tissue oxygenation, and thus likely in enhanced performance (4). No sound data concerning this aspect seem available yet, although angiogenic growth factors have been shown to respond to acute exercise in human skeletal muscle (1). Third, as many glycolytic enzymes are HIF-1 targets, increased glycolytic activity after hypoxic exposure could contribute to better performance as well.In summary, hypoxic adaptation can occur on the systemic (RCV, cardiac output), local (angiogenesis), and cellular (glycolysis) level, and each mechanism may contribute to enhanced performance when “living high and training low.”To the Editor: There is enough evidence to support that short-term exposure to high altitude or induced hypoxia is erythropoietic. It also depends on the altitude and the time of exposure. There is also evidence that blood volumes change rapidly after descending to sea level (1). The mechanisms involved in these changes and the posterior neocytolysis are less understood than the ones involved in acclimatization. Intermittent hypoxia (living high:training low) enhances exercise performance at sea level. However, it is still controversial if augmented red cell volume is responsible for the enhanced exercise performance (2). In 1959, Richardson and Guyton (3) showed in dogs that cardiac output increased with anemia and fell with rises in hematocrit and that blood O2 availability was maximal at an hematocrit of 40% and decreased above and below this value. Using a mathematical model, based on a significant amount of data, Villafuerte et al. (4) suggested that the increase in red cell volume that allows an increase and maintenance of venous Po2, with minimal decline in arterial Po2, reaches an optimal peak at an Hb value of 14.7 g/dl. It seems that there is an optimal range of hemoglobin concentration for oxygen transport and tissue oxygenation. High or low red blood cell concentrations are not optimal, and it needs to be a component of this debate to establish optimal values for this range. However, other mechanisms involved in hypoxia adaptation and enhanced exercise performance should also be considered.To the Editor: Both the point and the counterpoint side (3) cited our congress abstract (4), which reported increased hemoglobin mass (Hbmass), red cell volume (RCV), o2 max, and a correlation coefficient (r) of ∼0.7 between ΔHbmass and Δo2 max for female and male athletes. Yet this correlation has to be put into perspective by the limited number of athletes (5 females and 5 males). When females and males were taken together, r was reduced to 0.35. However, our experiences (including actual unpublished data) with national team (4) and world class athletes (5) support the findings of Levine and Stray-Gundersen (2), namely that an adequate hypoxic dose increases Hbmass and RCV, and this may positively affect aerobic performance. This coherence may be diminished by a series of confounding factors such as an inadequate hypoxic dose, an inadequate training stimulus, measurement error of RCV and Hbmass determination (1), different individual responses to altitude, medical problems, and difficulties of timing the performance after the LHTL training camp. However, we agree with Dr. Gore that one of the most important aspects in this debate is measurement error of RCV and Hbmass(1, 3) and that further studies in this field are needed. To our knowledge, there has been no controlled LHTL study with elite endurance athletes that used an estimated high enough natural hypoxic dose, measured Hbmass with the carbon monoxide rebreathing method, controlled for blood doping, and related the changes of Hbmass in relation to measured error of Hbmass measurement.To the Editor: The arguments presented for and against the potential influence of augmented red cell volume on exercise performance (2) are based primarily on the classic dimensions of “exercise performance,” namely maximum oxygen uptake in the laboratory and running time for endurance events on the track (3). The underlying hypothesis is that a major determinant of “performance” is oxygen transport. Hence augmenting red cell volume should increase oxygen transport by increasing the oxygen carrying capacity of the arterial blood and/or increasing maximum cardiac output by increasing blood volume. However, data on these basic parameters of oxygen transport are conspicuously absent. For example, during performance at low altitude, is oxygen carrying capacity (hemoglobin concentration) actually higher after altitude exposure? Hemoglobin concentration is highly dependent on changes in plasma volume, and just as hemoconcentration follows ascent to altitude, so hemodilution promptly follows descent; hemoglobin concentration has been shown to fall >1 g/100 ml I within 24 h. Is maximum cardiac output significantly altered after altitude exposure? Hemodilution (plasma volume expansion) should increase blood volume and, when added to augmented red cell volume, ventricular filling pressures should be higher, enhancing stroke volume. Are stroke volumes larger at sea level after altitude exposure? Is there any change in the fraction of the cardiac output distributed to the exercising muscles? Pulmonary diffusing capacity has been reported to increase during a sojourn at altitude (1). Is there any measurable improvement in arterial blood oxygenation (oxygen content) during maximal exertion at low altitude after exposure to moderate altitude?To the Editor: There is common agreement that erythropoiesis is stimulated during altitude exposure and that an increase in red cell volume (RCV) causes improved aerobic capacity (5). However, Gore and Hopkins suggest that the 5-8% increase in RCV described by Levine and Stray-Gundersen (4) after 4 wk of live high:train low-altitude training (LHTL) might to a major extent be explained by measurement error. Furthermore, they doubt all studies in which augmented RCV or total hemoglobin mass (tHbmass) after altitude training was reported. It is hard to believe that different research groups who used different methods for RCV [Evans blue dye (4)] or tHbmass determination [CO rebreathing (2, 3)] all produced erroneous measurements with the result of increased RCV/tHbmass after altitude acclimatization. It seems more likely that effective stimulation of erythropoiesis indeed is dependent on the duration and grade of the hypoxic exposure and that there is a wide individual variation in physiological responses to altitude exposure (1, 2).Gore and Hopkins argue that the most likely mechanism to explain increased performance after LHTL is an improvement in exercise economy because reduced o2 during submaximal exercise after intermittent hypoxic exposure has been described in several studies. These results cannot easily be explained because the findings for RER, ventilation, lactate concentration, and muscle buffer capacity are inconsistent in the cited studies. In addition, evidence is lacking that a slightly reduced submaximal o2 after LHTL really indicates improved exercise economy during high exercise intensities or improved maximum steady-state intensity, which are relevant for competitive endurance exercise.To the Editor: In his 1959 text book entitled, “Physiology of Muscular Activity,” Dr. Karpovich asks the question “Will a man trained at a high altitude do better at sea level?”(2). Karpovich suggests there should be “improvements in endurance events.” Research over the last 46 years has revealed that improvements in sea level performance after altitude training can occur but are not always associated with increases in red cell volume (RCV; Ref. 1). Despite this observation, Levine and Stray-Gundersen (4) argue that changes in performance post-altitude training are primarily mediated by changes in RCV, a view that is becoming increasingly popular with coaches and athletes. Similar to others, our laboratory has repeatedly observed an increase in performance (∼1-2%) after altitude training in internationally competitive athletes who demonstrate no measurable increase in RCV (1). Conversely, Drs. Levine and Stray-Gundersen (3) observed increases in RCV with no improvements in running performance. Although Drs. Levine and Stray-Gundersen have provided the scientific community with only preliminary evidence suggesting that the live high:train low approach may be superior to traditional altitude training, they promote LHTL as unequivocally advantageous. Similarly, the data supporting RCV as the primary mechanism driving improvements in performance post altitude are strongly promoted but poorly supported, and the potential roles of other reported adaptations such as improvements in muscle buffering capacity and economy are not given due credence. As suggested by Karpovich years ago, it appears that additional research is required to understand the effects of “training at altitude and blood addition on all-out performance at high and low altitude” (2).To the Editor: Kevin Costner made it big in “Dances With Wolves,” and now others achieve stardom in “Dances With Pins”! In debating living high and training low (LHTL) for sea level (SL) exercise performance, Ben Levine and Jim Stray-Gunderson (aka, the Angels) and Chris Gore and Will Hopkins (aka, the Pins) starred in a 21st Century remake of the medieval classic “how many angels can dance on the head of a pin” (3).The Angels pinned their hopes on stimulating the erythropoietic pathway by LHTL. But they were unmasked as their script devolved to reveal the classical plot that o2 max determines exercise endurance. In their roles, the Angels were superb for they are among our most accomplished cardiovascular physiologists. Still, the Pins and I are skeptical: o2 max is not the sole determinant of SL exercise performance (2).So far as the Pins are concerned, they acted well in the cardiovascular arena, and their dialogue was more expansive as they addressed issues such as biomechanics and “lactate anaerobic threshold” after LHTL. But, heavens, where have they been?! It is known that lactate flux is affected by altitude (1), but regrettably we know little about lactate kinetics after LHTL.Seemingly, both teams were rather closed in their thinking. Arguments were confined to peripheral factors (erythropoiesis, biomechanics, lactate, etc), and neither team mentioned that neuromuscular recruitment is centrally driven. Noakes and colleagues (4) have been rather adamant on the role of CNS control over neuromuscular function, and previously Reeves and colleagues (5) concluded that the CNS plays a role in determining muscle function at altitude.So, applause for Angels and Pins; Oscar Mayers all around.To the Editor: To judge the debate between Levine/Stray-Gundersen and Gore/Hopkins (4) regarding the effectiveness of intermittent hypoxia (IH) on erythropoiesis both methodological and physiological aspects have to be combined.1. On the assumption that IH has a similar effect on erythropoiesis as a continuous stay at altitude, the maximum increase in red cell volume can be assumed to be 6–8%. This exceeds the confidence limits of the CO-rebreathing technique (2) and should be det