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• W2070295938 abstract "ENVIRONMENTAL, EXERCISE AND RESPIRATORY PHYSIOLOGYCentral regulation of skeletal muscle recruitment explains the reduced maximal cardiac output during exercise in hypoxiaT. D. NoakesT. D. NoakesPublished Online:01 Oct 2004https://doi.org/10.1152/ajpregu.00608.2003MoreSectionsPDF (132 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat The following are the abstracts of the articles discussed in the subsequent letter:Calbet JAL, Boushel R, Radegran G, Sondergaard H, Wagner PD, and Saltin B. Determinants of maximal oxygen uptake in severe acute hypoxia. Am J Physiol Regul Integr Comp Physiol 284: R291 R303, 2003. —To unravel the mechanisms by which maximal oxygen uptake (V̇o2 max) is reduced with severe acute hypoxia in humans, nine Danish lowlanders performed incremental cycle ergometer exercise to exhaustion, while breathing room air (normoxia) or 10.5% O2 in N2 (hypoxia, ∼5,300 m above sea level). With hypoxia, exercise PaO2 dropped to 31–34 mmHg and arterial O2 content (CaO2) was reduced by 35% (P < 0.001). Forty-one percent of the reduction in CaO2 was explained by the lower inspired O2 pressure (PiO2) in hypoxia, whereas the rest was due to the impairment of the pulmonary gas exchange, as reflected by the higher alveolar-arterial O2 difference in hypoxia (P < 0.05). Hypoxia caused a 47% decrease in V̇o2 max (a greater fall than accountable by reduced CaO2). Peak cardiac output decreased by 17% (P < 0.01), due to equal reductions in both peak heart rate and stroke volume (P < 0.05). Peak leg blood flow was also lower (by 22%, P < 0.01). Consequently, systemic and leg O2 delivery were reduced by 43 and 47%, respectively, with hypoxia (P < 0.001) correlating closely with V̇o2 max (r = 0.98, P < 0.001). Therefore, three main mechanisms account for the reduction of V̇o2 max in severe acute hypoxia: 1) reduction of PiO2, 2) impairment of pulmonary gas exchange, and 3) reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third of the loss in V̇o2 max.Calbet JAL, Boushel R, Radegran G, Sondergaard H, Wagner PD, and Saltin B. Why is the V̇o2 max after altitude acclimatization still reduced despite normalization of arterial O2 content? Am J Physiol Regul Integr Comp Physiol 284: R304-R316, 2003.—Acute hypoxia (AH) reduces maximal O2 consumption (V̇o2 max), but after acclimatization, and despite increases in both hemoglobin concentration and arterial O2 saturation that can normalize arterial O2 concentration ([O2]), V̇o2 max remains low. To determine why, seven lowlanders were studied at V̇o2 max (cycle ergometry) at sea level (SL), after 9–10 wk at 5,260 m [chronic hypoxia (CH)], and 6 mo later at SL in AH (FiO2 = 0.105) equivalent to 5,260 m. Pulmonary and leg indexes of O2 transport were measured in each condition. Both cardiac output and leg blood flow were reduced by ∼15% in both AH and CH (P < 0.05). At maximal exercise, arterial [O2] in AH was 31% lower than at SL (P < 0.05), whereas in CH it was the same as at SL due to both polycythemia and hyperventilation. O2 extraction by the legs, however, remained at SL values in both AH and CH. Although at both SL and in AH, 76% of the cardiac output perfused the legs, in CH the legs received only 67%. Pulmonary V̇o2 max (4.1 ± 0.3 l/min at SL) fell to 2.2 ± 0.1 l/min in AH (P < 0.05) and was only 2.4 ± 0.2 l/min in CH (P < 0.05). These data suggest that the failure to recover V̇o2 max after acclimatization despite normalization of arterial [O2] is explained by two circulatory effects of altitude: 1) failure of cardiac output to normalize and 2) preferential redistribution of cardiac output to nonexercising tissues. Oxygen transport from blood to muscle mitochondria, on the other hand, appears unaffected by CH.Central regulation of skeletal muscle recruitment explains the reduced maximal cardiac output during exercise in hypoxiaTo the Editor: The findings of Calbet and colleagues in this (2, 3) and another journal (4) are more consistent with a physiological model in which the brain regulates exercise performance by altering the number of motor units that are recruited under different conditions (6, 7, 14, 15, 21), rather than with the traditional model that the authors prefer and that posits that exercise performance is determined by the rate of oxygen delivery to the exercising muscles (9–11, 18–20).The authors studied cardiovascular and respiratory function in healthy lowlanders of both genders during maximum exercise 1) in acute hypoxia at sea level (2) and 2) at altitude after a period of 9–10 wk of altitude acclimatization (3), which increased blood hemoglobin content and hence the potential oxygen delivery to both heart and skeletal muscle at any given cardiac output (4). In addition, the acute effect of increasing the inspired oxygen fraction at the point of exhaustion was also studied. Their key findings were the following.Key finding 1.Peak cardiac output was reduced in subjects exposed either acutely or chronically to hypoxia, as previously shown (23–25, 27, 28). This reduction was due to decreases in both heart rate and stroke volume.Key finding 2.However, under all conditions of hypoxia, cardiac output (2, 3, Fig. 3A), heart rate (2, Fig. 3E; 3, Fig. 3C), and stroke volume (2, Fig. 3C; 3, Fig. 3E) were entirely appropriate for the work rates at which they were measured.Key finding 3.Cardiac output increased marginally with acclimatization to chronic hypoxia (3, Fig. 3A) but was still substantially below the maximum value achieved in normoxia.Key finding 4.The increase in cardiac output during maximum exercise in hypoxia after altitude acclimatization was due to an increase in stroke volume, whereas heart rate was reduced (3, Fig. 3, E and C).Key finding 5.Peak work rate did not increase significantly after altitude acclimatization (Ref. 3, Table 1), although measured O2 delivery to the exercising muscles increased by 40% (∼800 ml O2/min) (3, Fig. 4C), two-leg oxygen consumption (V̇o2) by ∼550 ml/min (3, Fig. 4E), whereas pulmonary V̇o2 appears to have increased by only ∼280 ml/min (3, Fig. 2D).Key finding 6.The substantially reduced exercise performance and the low “maximal” cardiac output measured in hypoxia were instantly reversed when the inspired O2 concentration was increased from 10.5% to either 21% (2, see R298) or to 55% (3, Fig. 3A).The authors explained these six findings accordingly.Conclusion 1.Hypoxia limits the intrinsic pumping capacity of the heart, causing a “downregulation of maximal cardiac output” (2, see R299) perhaps as a consequence of an altered “output drive from cardiovascular nuclei in the CNS” (2, see R299).Conclusion 2.Alternatively, the hypoxia may act peripherally to “curtail increases in (skeletal muscle) power output, which, in turn, would limit the action of the (skeletal) muscle pump and ventricular filling” (2, see R300) by reducing venous return (conclusion 2a). However the authors ultimately reject this conclusion: “ … it is more likely that hypoxia first attenuates increases in cardiac output that limits muscle oxygen delivery and power output and, in turn, the muscle pump and ventricular filling,” thereby confirming the “importance of O2 delivery as a limiting factor for V̇o2 max both in normoxia and hypoxia” (2, see R302, conclusion 2b).Conclusion 3.The finding that acute exposure to normoxia (2) or hyperoxia (3) immediately normalized exercise performance supported a central (cardiovascular or neural) mechanism for the action of hypoxia since “the fact that it was possible to continue the incremental exercise test with reoxygenation argues against a peripheral (muscular or metabolic) mechanism as the main cause of fatigue in severe acute hypoxia” (2, see R300).Conclusion 4.The authors recognize that “an alternative explanation is that severe hypoxemia may have altered the capacity to fully activate motor units and thus caused a decrease in maximal exercise performance” (3, see R312) so that the “reduction in cardiac output… could be envisaged as a regulatory mechanism aimed at protecting either the heart itself or more importantly the CNS from hypoxic damage” (2, R299). My contention is that the authors' data do not support conclusions 1–3, which they in fact acknowledge, whereas conclusion 4 is more probably correct.To arrive at conclusions 1–3, the authors interpret their findings according to the popular model of exercise physiology that has been termed the A. V. Hill Cardiovascular/Anaerobic model (20) after its first proponent and Nobel Laureate. Hill's model, as originally described (11) but not as currently taught (19, 20), is that the development of a progressive myocardial ischemia during maximum exercise limits the maximum cardiac output. This myocardial ischemia establishes the upper limit of oxygen delivery to and use by the exercising muscles—the concept of the maximum oxygen consumption (V̇o2 max) (18). Above this limit and as a consequence of this ischemia, both the heart and the exercising muscles must contract anerobically, producing lactic acid according to the theory first proposed by Fletcher and Hopkins in 1907 (5). Accumulation of the lactic acid then prevents muscle relaxation because Hill believed that 1) lactic acid was the chemical that initiated muscle contraction and 2) its oxidative removal was necessary for complete muscle relaxation to occur (9). Anerobiosis, because it prevented the oxidative removal of lactic acid, then terminated exercising by interfering with skeletal muscle relaxation. Hence, according to this Hill model, oxygen delivery to muscle determines its function (Fig. 1). The assumption is that the two variables are causally linked; that is, that A (skeletal muscle blood flow/oxygen delivery) determines or causes B (exercise performance).Fig. 1.Model 1 of factors determining maximal exercise performance.Download figureDownload PowerPointThe forgotten component of this theory was Hill's belief that the heart is the organ at greatest risk of ischemic injury during maximum exercise (10, 11). But Hill surmised that myocardial ischemia could not proceed unchecked without a fatal consequence. Hence he postulated the existence of a “governor” either in the heart or the brain that would limit the pumping capacity of the heart, thereby limiting the extent of the myocardial ischemia that would develop during maximal exercise (11, p. 161–163).Calbet et al. (2, 3) invoke this model to conclude that because hypoxia impairs exercise performance, it must act by limiting oxygen delivery to the active skeletal muscles. This effect must therefore be due to a direct effect of hypoxia on the heart, thereby limiting the maximum cardiac output that can be achieved in hypoxia (conclusions 1, 2b, and 3).But conclusion 4 is derived from an opposing model, which posits that exercise performance is determined by a third factor, C (Fig. 2), which then explains an apparently causal, but spurious, relationship between A and B. Thus, in this opposing model, the arrow of causality between A and B is reversed, because it predicts that oxygen use does not determine skeletal muscle function during exercise, but is simply the inevitable consequence of the increased skeletal muscle contractile activity during exercise (Fig. 2). This has been termed the Central Governor Model (21, 24).Fig. 2.Model 2 of factors determining maximal exercise performance.Download figureDownload PowerPointOf central relevance to this debate is that models 1 and 2 predict exactly opposite responses of the cardiac output to exercise in hypoxia. Model 1 predicts that the cardiac output and hence muscle O2 delivery will always be maximal in hypoxia to fully deliver all available O2 to the “anaerobic” muscles and therefore to maximize the exercise performance (21, 23, 24). This is because in this model, the heart acts simply as the slave to the (voracious) oxygen requirements of the exercising muscles. Recall Hill's belief that such is the muscles' greed for oxygen that myocardial ischemia will develop during maximum exercise. Indeed I would argue that model 1 is entirely incompatible with the finding of a low and submaximal cardiac output at exhaustion in persons with an intact nervous system, in any intervention that reduces the oxygen carrying capacity of the blood, be it hypoxia or anemia (4).In contrast, model 2 predicts that the cardiac output will be dictated purely by the work of the muscles (the exercising work rate) and that there will be no evidence for impaired cardiac function in hypoxia, because the CNS regulates the exercise performance specifically to ensure that cardiac or other damage does not occur during exercise, regardless of the environmental conditions (19–21). Thus, according to this model, any intervention that increases or decreases the work rate will cause a matching response in the cardiac output but without producing cardiac dysfunction as a result of hypoxia or ischemia. I argue that all the findings of Calbet et al. (2, 3) support this latter interpretation, disproving model 1.Thus, although the cardiac output is reduced in hypoxia, the cardiac output, heart rate, and stroke volume were entirely appropriate for the work rate under all conditions (key finding 2). But if the cardiac output is appropriate for the lower maximal work rate achieved in hypoxia and if it is achieved at submaximal heart rates and stroke volumes and without any evidence for cardiac dysfunction, then the cardiac output cannot determine the work rate. Rather it must be the reverse; namely that the work rate determines the cardiac output as it must if model 2 is correct. Hence the authors' postulate that myocardial dysfunction limits the cardiac output and exercise performance in hypoxia (conclusions 1 and 2b) is their attempt to fit the data to the model. Indeed their data show that cardiac function was not impaired in hypoxia.Thus their findings (key finding 4) that stroke volume was increased and heart rate reduced at maximal exercise in hypoxia after altitude acclimatization is the opposite of that caused by increasing myocardial hypoxia or ischemia (13, 22) and shows that cardiac functional reserve was increased at exhaustion after altitude adaptation. Thus neither myocardial ischemia nor hypoxia could have determined the exercise performance, as is required by model 1. Indeed the authors ultimately admit the implausibility of these two conclusions: “The possibility of an insufficient myocardial O2 delivery in chronic hypoxia is even less plausible” (3, R311). Hence the authors do not really believe conclusions 1 and 2b.This interpretation is supported by other studies showing that myocardial function is preserved during “maximal” exercise even in more severe hypoxia (25, 27, 28) and is achieved with an increased coronary blood flow (8, 12), indicating the presence of coronary reserve in maximal exercise in normoxia (further proving that ischemic myocardial dysfunction does not limit maximal exercise in normoxia as is required by Hill's original model 1).Their alternate conclusion (conclusion 2a) that skeletal muscle hypoxia determines performance in hypoxia is disproved, as they also admit (conclusion 2b) by key finding 6 that acute exposure to hyperoxia instantly improved the exercise performance, proving that a peripheral regulator such as lactic acid could not have limited exercise in hypoxia as is required by model 1 (20). Indeed blood lactate concentrations at termination of exercise in hyperoxia were significantly higher than values measured at exercise termination in both normoxia and hypoxia (3, Table 1). This is further evidence that the (lower) venous and arterial lactate concentrations at fatigue in normoxia and hypoxia could not have limited exercise under those conditions, as is required by model 1.Indeed the evidence that exercise performance in more severe hypoxia always terminates at low blood lactate concentrations, the lactate paradox, as does exercise in most disease states, provides some of the strongest evidence against model 1 (18–20). Furthermore, after chronic adaptation to altitude, leg oxygen consumption was the same at the peak work rate in hypoxia as it was at the same work rate (∼255 W) in normoxia (3, Fig. 4E), proving that skeletal muscle hypoxia could not have been present at exercise termination before altitude acclimatization. Indeed hypoxia has yet to be found in the exercising skeletal muscles during progressive maximum exercise to exhaustion in either normoxia (17, 26) or hypoxia (16).Their alternate conclusion (conclusion 2a) that impaired venous return limits maximum exercise performance in hypoxia (as a consequence of impaired functioning of the skeletal muscle pump that assists venous return) is also disproved by the findings that stroke volume was the same (and not lower) at all work rates in hypoxia and in normoxia (3, Fig. 3E) and that stroke volume increased with altitude adaptation and reached the highest values in altitude-adapted subjects at exercise termination in hypoxia (3, Fig. 3E). This could not have occurred if venous return was impaired by hypoxia. Nor is there any other evidence that hypoxia necessarily impairs skeletal muscle function in vivo in persons exercising with an intact CNS (17).But the most compelling evidence disproving model 1 was their finding (key finding 6) that exercise performance in hypoxia did not increase after altitude acclimatization that increased blood hemoglobin concentrations, blood oxygen carrying capacity (4), and hence increased potential O2 delivery to the heart and exercising skeletal muscles. On the basis of the slope of the V̇o2/work rate relationship for altitude-adapted subjects exercising in hypoxia (3, Fig. 2D), an increase in skeletal muscle O2 delivery of ∼800 ml O2/min should have increased the peak achieved work rate by ∼120 W, which did not occur.This summarily disproves any causal relationship between oxygen delivery and muscle function under these conditions (Fig. 1). But if these findings disprove model 1, do they support the theoretical basis of model 2, which holds that the CNS regulates exercise performance in hypoxia (conclusion 4)?A fundamental teaching in muscle physiology, but which seems to have escaped the attention of many exercise physiologists, is that an increased recruitment of motor units in the active muscles is the principal mechanism by which skeletal muscle force production is modified (7, 13). Hill did not know this, explaining why his model 1 excludes any contribution by the CNS. His presumption must have been that all the motor units in the exercising limbs are active during maximal exercise, for his model can only work if all the motor units in the active limbs are active at exhaustion so that their force production can be regulated by the action of inhibitory metabolites, principally lactic acid. Otherwise, recruitment of any quiescent motor units would allow the exercise to continue. Yet there is no evidence that all available motor units are ever recruited during any form of voluntary exercise in humans (6).The proposal of Bigland-Ritchie and Vollestadt (1) that skeletal muscle motor unit recruitment may be reduced in hypoxia has been proven by Kayser and colleagues (14, 15). Hence skeletal muscle motor unit recruitment is submaximal in hypoxia indicating that model 1 cannot explain why fatigue develops in hypoxia. Furthermore, if altitude adaptation fails to alter the physiological variable(s) that determine this reduced skeletal muscle motor unit recruitment in hypoxia according to model 2 (21), then exercise performance and cardiac output will not increase, although the potential for oxygen delivery to the exercising muscles may increase substantially so that, according to model 1, exercise performance must increase.Indeed, the finding that the exercise performance improves immediately the oxygen concentration in the inspired air is increased (key finding 6) is the single best evidence proving that the CNS regulates performance in hypoxia. For only the CNS can instantly increase the exercise performance by increasing the number of motor units that it will allow to be recruited, thereby increasing muscle force production according to the traditional teaching in muscle physiology (7, 13).In summary, I argue that the six findings of Calbet et al. (2, 3) cannot be explained according to the traditional Hill model; in fact, they disprove that model. Rather they are entirely compatible with the Central Governor model (19–21, 23, 24). This model postulates that the extent of skeletal muscle recruitment by the CNS is the regulated variable and is determined by the need of the brain to protect itself and the body from harm (6, 18) by ensuring the maintenance of homeostasis in all bodily systems even during maximal exercise. The clear danger in hypoxia is a reduction in the arterial Po2 (29). Exercise of increasing intensity in hypoxia produces a progressive reduction in arterial Po2 (3, Table 1; 29). Thus it makes absolute sense that the brain should protect itself from hypoxic insult by allowing only those exercise work rates that do not reduce arterial Po2 below a critical value.The CNS ensures that this critically low arterial Po2 is never reached during maximal exercise specifically by limiting the number of motor units that are recruited. The overt physiological markers of this control mechanism are the submaximal cardiac output, stroke volume, heart rate, and blood lactate concentration at peak exercise in hypoxia. The failure of altitude adaptation to normalize the arterial Po2 (3; Table 1) explains why this intervention fails to enhance exercise performance, although it increases potential oxygen delivery to the exercising muscles. In contrast, inhaling oxygen-enriched air that instantly increases the arterial Po2 (3; Table 1) immediately releases the brake—the “governor”—on skeletal muscle recruitment, allowing work rate and cardiac output to increase to appropriate, near maximum values (3; Table 1).Indeed the authors correctly interpret this crucial regulatory function of the arterial Po2 because they acknowledge that “the mechanism causing the reduction in the maximal cardiac output is directly related to the PaO2 and relatively independent of CaO2” (3, R311). Yet, by interpreting their other findings according to the traditional model 1, they arrive at an incorrect conclusion: “The reason why the cardiovascular system does not substantially increase O2 delivery to the exercising muscles after altitude acclimatization despite apparent function reserve remains unknown” (3, R315).REFERENCES1 Bigland-Ritchie R, and Vollestadt N. Hypoxia and fatigue: how are they related? 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Wagner, and Bengt SaltinDepartment of Physical Education University of Las Palmas de Gran Canaria, Spain The Copenhagen Muscle Research Centre Rigshospitalet, 2200 Copenhagen N, DenmarkThe Copenhagen Muscle Research Centre Rigshospitalet, 2200 Copenhagen N, Denmark Department of Exercise Science Concordia University Montreal, Quebec, CanadaThe Copenhagen Muscle Research Centre Rigshospitalet, 2200 Copenhagen N, DenmarkThe Copenhagen Muscle Research Centre Rigshospitalet, 2200 Copenhagen N, DenmarkThe Copenhagen Muscle Research Centre Rigshospitalet, 2200 Copenhagen N, DenmarkDepartment of Medicine Section of Physiology University of California-San Diego La Jolla, California102004To the Editor: We appreciate Dr. Noakes' interest in our papers (4, 5, 7) on cardiovascular responses to exercise in hypoxia. In his letter to the Editor, Dr. Noakes carefully selects text and data from a series of our papers to support a unifying regulatory paradigm (“Central Governor Model”) for limits to exercise. Fatigue is set by what he calls “Central Governor,” presumably located in the central nervous system (CNS). Although we agree in some aspects, we think that Dr. Noakes' model cannot be generalized. The contradictions suggested by Dr. Noakes simply do not exist; they are the outcome of a biased interpretation of our data and selective quoting of pieces of the discussion, which, used out of context, can mislead the reader to the wrong conclusion. We wish to respond to his letter by focusing on the data and to clarify several points that appear to be misinterpreted. There are a number of points to be made that we will s" @default.
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