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POINT-COUNTERPOINT
O2 max is limited primarily by cardiac output and locomotor muscle blood flow
The Copenhagen Muscle Research Centre
Rigshospitalet
Copenhagen N, Denmark
Department of Physical Education
University of Las Palmas de Gran Canaria
Gran Canaria, Spain
e-mail: bengt.saltin{at}rh.hosp.dk
Starting in the 1950s, a number of experiments provided the experimental evidence supporting the original concept elaborated on by Hill and Lupton (12): in health, O2 max in normoxia is limited primarily by cardiac output and locomotor muscle blood flow (17). The main variable accounting for the difference in O2 max between sedentary subjects and athletes is maximal cardiac output, such that a linear relationship was observed between O2 max and maximal cardiac output, showing that 5.9–7.5 l/min of cardiac output is needed per liter of O2 max (5, 10, 17, 26). Part of the variability in the relationship between O2 max and cardiac output was attributed to the variation in hemoglobin concentration, with a smaller contribution of the systemic a-v difference (5, 10, 17, 26). It was also shown that maximal exercise stroke volume was the main factor explaining the differences between subjects in maximal cardiac output (5, 10, 17, 26). A cause and effect relationship between oxygen delivery and O2 max has been established by showing that experimental interventions increasing oxygen delivery are accompanied by an elevation of O2 max and vice versa (6, 16).
All experimental procedures causing a reduction of maximal cardiac output are associated with a lower O2 max. Reducing blood volume is associated with lower maximal cardiac output and O2 max (16). Bed rest studies showed that the main factor accounting for the reduction in O2 max was the lower maximal cardiac output attained after bed rest (27), because maximal exercise O2 fractional extraction is close to 90% after bed rest. Treatment with beta-blockers is accompanied by a reduction of maximal cardiac output and leg blood flow, which accounts for most of the reduction observed in O2 max (21). The CaO2 may be reduced by reducing hemoglobin concentration isovolemically and by carbon monoxide administration. These two interventions show a reduction in O2 max that is proportional to the magnitude of the reduction achieved in CaO2 (6, 15, 23, 30).
The influence of locomotor muscle oxygen delivery for O2 max in trained and untrained muscles was studied in the 1970s (3, 8, 28). With the use of a one-leg training model (in the cycle ergometer), Gleser (8) reported a 16% improvement of one-leg peak O2 that was accompanied by a 13% enhancement of the peak cardiac output during incremental exercise with the trained leg. However, neither O2 max nor maximal cardiac output was enhanced after one-leg training when the exercise test was performed with the two legs. Thus the study by Gleser suggests that the increase in O2 max was brought about via an enhancement of cardiac output and, likely, leg blood flow. Clausen et al. (3) reported a 10% greater peak O2 during arm cranking after a period of endurance training with the legs in the cycle ergometer. The increase in arm O2 was accompanied by 10 and 12% greater mean arterial pressure and peak cardiac output, also suggesting that O2peak during exercise with a small muscle mass is limited by locomotor muscle blood flow. In the study by Saltin et al. (28), the subjects that performed one-leg endurance training in the cycle ergometer improved their O2 max by 24% during an incremental exercise to exhaustion with the trained leg. Interestingly, the contralateral leg that was not submitted to training also improved its O2 max (6%). However, when the subjects carried out a two-legged incremental exercise the O2 max was improved only by 11%. Thus the improvement observed during two-leg exercise was a bit less than expected if the limitation to O2 max had been only of peripheral origin, suggesting that in that study part of the limitation to O2 max during two-leg exercise is due to insufficient perfusion. A subsequent one-leg training study by Klausen et al. (13) adds further evidence. Their subjects trained each leg on the cycle ergometer individually. After the training, peak leg O2 during exercise on the cycle ergometer was 16% higher during one-leg than during two-leg exercise, due to a 23% higher peak leg blood flow during one-leg maximal exercise compared with two-leg maximal exercise. In contrast, before training, peak leg O2 was the same during one-leg cycling compared with two-leg cycling, despite the fact that leg blood flow was 8% higher during one-leg exercise. This study suggests that in the trained state, the dependency of O2 max on oxygen delivery may be accentuated.
Further evidence for a cause and effect relationship between O2 max and locomotory muscle oxygen delivery was obtained by Harms et al. (11). They showed that if the respiratory muscles are loaded, exercise capacity and locomotory muscle blood flow and O2 is reduced, suggesting that maneuvers redistributing part of the blood flow away from the locomotory muscles reduces exercise capacity and O2 max (11) and vice versa. A similar conclusion was reached by Gonzalez-Alonso and Calbet (9). In their study, subjects performed constant intensity exercise to exhaustion under normothermic and hyperthermic conditions. In both conditions, fatigue was preceded by a reduction of cardiac output and leg blood flow. Moreover, we recently showed that during whole body upright exercise the combined maximal muscular vascular conductances of the limbs outweighs the pumping capacity of the heart in humans, meaning that O2 max is limited by O2 delivery. With the use of data from the latter, we estimated that if the human with well-trained leg and arms muscles was able to use the full potential for O2 of the four limbs, then their O2 max could be about 20% higher than actually measured (2).
Although O2 max is a function of locomotor muscle blood flow, this does not exclude the possibility that other mechanisms marginally contribute to achieve O2 max in normoxia, as, for example, exercise-induced arterial hypoxemia (4, 19), a diffusional limitation between the capillaries and the mitochondria of the active muscle fibers (24), and lower O2 extraction capacity in some muscles (1). However, in all these conditions, peak O2 is increased if the limitation is somehow overcome and more O2 is made available to the mitochondria (6, 14, 22, 25). Thus the bulk of the experimental evidence accumulated during the last 80 years argues in favor of cardiac output and oxygen delivery setting the limit for maximal oxygen uptake in normoxia. All these observations also argue against theories attributing the limitation of O2 max to brain processes as the "Central Governor Model" during exercise in normoxia carried out by healthy subjects (20). This model postulates that processes arising in the brain itself, triggered or modulated by sensory feedback, inhibit somehow the central command, causing the exercise to terminate (20). This model has revitalized some ideas brought about more than a century ago, as reviewed by Gandevia (7). However, experimental evidence obtained during exercise with hyperthermia (18) and during exercise in chronic hypoxia (29) demonstrated that, at least during brief efforts aimed at producing a maximal leg or hand grip voluntary contraction, the ability to recruit the motor units is preserved even when measured close to exhaustion.
In summary, in healthy humans, O2 max at sea level is limited by systemic oxygen delivery and especially by O2 delivery to the locomotor muscles. Oxygen delivery, in turn, depends on the ability of the cardiorespiratory system (i.e., lungs, heart, and blood) to transport and distribute appropriately O2 to the active motor units, rather than on the mitochondrial oxidative capacity, which in human skeletal muscles exceeds widely maximal O2 supply in all known exercise models.
REFERENCES
O2 max in the exercise-trained human quadriceps. J Appl Physiol 86: 1048–1053, 1999.O2 max in normal humans. J Appl Physiol 67: 291–299, 1989.O2 max is not limited primarily by cardiac output and locomotor muscle blood flow
University of California, San Diego
La Jolla, California
e-mail: pdwagner{at}ucsd.edu
Let's begin this by being sure of the question we are addressing, because this topic is notorious for being easy to spin toward one's desired position by subtly changing the question. I would like to clear the deck of spin right from the start. So I will stipulate that without blood flow, O2 max would be zero: Saltin 1, Wagner 0. I will also stipulate that the venerable Fick Principle, taken at its naive simplest, would tend to support my opponent: O2 = 
x[CaO2 – CvO2], where is cardiac output, CaO2 is arterial, and CvO2 mixed venous [O2].
I will even argue for him, comparing Lance Armstrong or equivalent with a sedentary normal subject each at their maximal exercise capacities, O2 would be about twice as high in LA (
80 vs. 40 ml·kg–1·min–1). Cao2 in the absence of erythropoietin would be close to 20 ml/dl in each, maybe even lower in LA if he shows exercise-induced desaturation (1) plus the plasma volume expansion, common in trained athletes, that results in a reduced [Hb] (16). Cvo2 would be lower in LA, perhaps as low as 2 ml/dl (i.e., 90% extraction) (5), whereas in his unfit couch potato (CP) counterpart, maximal extraction might not exceed 70% (12), with Cvo2 therefore at 6 ml/dl. Thus in the Fick equation above, maximal [Cao2 – Cvo2] approximates 180 ml/l in LA and 140 ml/l in CP. This, in turn implies that LA's peak must be 32 l/min, whereas CP's is only 20 l/min (assuming both weigh 70 kg). For LA, is 60% higher but [CaO2 – CvO2] is only 30% higher. So Bengt would be justified in saying is the primary determinant of O2 max if the question is "what primarily explains the difference in O2 max between CP and LA? or [CaO2 – CvO2]?" Saltin 1.5, Wagner 0. (I will return to LA and CP later. Bengt, watch out.)
But, this is not the question that we are being asked to address. The question is: "Is cardiac output (or muscle blood flow) the primary determinant of O2 max or not?" Stated in other words, if a normal subject is exercising at O2 max and you were somehow able to augment any single part of the O2 transport and use chain, what effect would this have on O2 max? And, would cardiac output, as one part of that chain, have the largest effect, as Bengt will argue? I hope he will not try and argue is the sole limiting factor, or I will blow him out of the water in rebuttal.
There is undeniable evidence that O2 max can be acutely altered at will in normal humans by any one of a number of interventions (8, 10, 14, 17, 21), of which altering is but one. Let's step down the O2 transport pathway, examining each step in turn.
Changing FIO2 changes O2 max in the same direction (5, 6). Ventilation at O2 max is very hard to alter in normal subjects, but published theoretical models demonstrate that maximal O2 transport and thus O2 max would be affected by changes in ventilation (20). A/ inequality (2), alveolar-capillary diffusion limitation (18), and (post) pulmonary shunts (2) can and do play a small but demonstrable role in reducing arterial oxygenation and thus O2 max, as our own editor showed many years ago (9). Cardiac output (or muscle blood flow) clearly affects O2 max, although direct interventions to test this have been done only in animals such as dogs, for example, by pericardiectomy (3), which allows a higher cardiac output and O2 max. Changes in [Hb] (15) and in the P50 of Hb (4, 11) both alter convective O2 transport to the muscles and have been shown to affect O2 max in controlled studies. Skeletal muscle O2 transport conductance (between capillaries and mitochondria), which relates closely to capillarity, has also been shown to play a significant role in setting O2 max (13). Finally, maximal mitochondrial rate of O2 consumption has the power to affect O2 max (7).
Although the above demonstrates, beyond argument even by Bengt, that is by no means the only factor contributing to O2 max, I have not yet provided the key arguments that must address the core question of sensitivity of O2 max to a given percent change in each of the above steps. Saltin still 1.5, Wagner still 0. Answering that question will put the nail in the /Saltin coffin, as follows.
First, suppose maximal mitochondrial O2 consumption is less than maximal O2 available by transport from the air to the mitochondria. Further raising O2 transport by increasing cardiac output (or for that matter any of the other above O2 pathway steps) will have no effect on O2 max because it is by definition O2 supply independent. Saltin 1.5, Wagner 1.0.
But suppose things are turned the other way around: maximal mitochondrial O2 use potential now exceeds O2 availability. Then, according to the evidence presented above, augmenting each and every step in O2 transport should have a positive effect on O2 max, and it does. Suppose each component is augmented by 20% of its value, one at a time. Integrated physiological models incorporating all pathway steps (20) and Fig. 1 show that a 20% increase in FIO2 raises O2 max by only 5.0%, due to the flat O2-Hb dissociation curve in the normal range. Increasing ventilation 20% will also lead to a small (1.3%) increase, again because PO2 is on the flat part of the curve, and raising PO2 has little effect on CaO2. Increase lung diffusing capacity 20% in an athlete who has mild hypoxemia due to diffusion limitation and O2 max will increase by 2.9%. Increasing diffusing capacity in a subject without diffusion limitation obviously cannot improve O2 max. If skeletal muscle O2 diffusional conductance is increased by 20%, O2 max will be 5.0% higher. Increase [Hb] by 20% and O2 max increases by only 3.9%. Finally, increase by 20%, and O2 max increases by only 2.6%, half that when muscle O2 conductance is raised equally. Why? Because muscle O2 conductance has only one significant effect—to increase O2 flux from blood to cells. But raising has opposing effects (19). First, it increases convective O2 transport by the circulation as predicted by both Bengt and the Fick principle. But the higher simultaneously reduces transit time in both lung and muscle capillaries and this worsens diffusion limitation, significantly opposing this convective gain.
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would simply limit O2 extraction due to rapid red cell transit. The only way LA can get to 80 ml/min O2 max is by having both an exceptional and a matching, exceptional muscle capillary-to-mitochondrion O2 transport system to permit almost full O2 extraction from the rapidly flowing blood. Thus, even if Bengt argues from the Fick Principle, as in my opening paragraph, the untold story is that muscle O2 conductance must also be extraordinary, every bit as important as , or O2 extraction could not possible reach 90%. I rest my case, Bengt: Saltin 1.5, Wagner 10.
REFERENCES
O2 max at constant O2 delivery in dog muscle in situ. J Appl Physiol 70: 2656–2662, 1991.O2 during maximal cycle ergometry. J Appl Physiol 73: 1114–1121, 1992.O2 max. J Appl Physiol 66: 2491–2495, 1989.O2 max with a right shifted Hb-O2 dissociation curve at a constant O2 delivery in dog muscle in situ. J Appl Physiol 84: 995–1002, 1998.O2 max. J Appl Physiol 73: 1067–1076, 1992.O2 max in normal humans. J Appl Physiol 67: 291–299, 1989.O2 max. Respir Physiol 93: 221–237, 1993.[CrossRef][Web of Science][Medline]O2 max at sea level and altitude. Respir Physiol 106: 329–343, 1996.[CrossRef][Web of Science][Medline]O2peak (39%) and whole body (WB) O2 max (35%) was observed after 6 wk of training (Ref. 8, p. 1070), whereas maximal exercise intensity was only enhanced by 9%. Leg O2 only accounted for 53–55% of WB O2 at maximal exercise (before-after training), i.e., far below the normal 75–85% (5). These low leg peak O2 values were likely caused by underestimation of peak leg blood flow (BF; which was only 5–6 l/min). Because during WB exercise, systemic a-v difference is never higher than leg a-v difference, peak cardiac output should have been >19 l/min before training and >23 l/min after training (+20%), leaving 9–10 l/min of BF for the rest of the body, which is too high a figure (5). Because DO2 (oxygen conductance) is calculated as peak leg O2/mean capillary PO2 (PmcO2) (10), it is likely that DO2 was also underestimated (8).
Could a "couch potato" (CP) enhance his O2 max by increasing his cardiac output and BF? CP should be able to achieve an arm BF of 2.5–3 l/min with an O2 extraction a bit lower in the arms than the legs during maximal exercise (1–3, 7). This means that the O2peak of CP arms could reach 0.6–0.7 l/min. To perform maximal exercise with the four extremities, CP will need to increase his maximal cardiac output from 20 to 24 l/min. With the extra perfusion, CP could achieve a O2 max 20% greater, even when assuming a lower muscle diffusing capacity in the arms than in the legs (2). CP could also increase his O2 max after blood transfusion or treatment with EPO. After this intervention, PmcO2 will be similar or a bit higher (6), meaning that the increase of O2 max requires an increase of DO2 after transfusion or EPO. If for a given PmcO2, DO2 is enhanced when [Hb] is increased, it implies that O2 max is not limited by a structural resistance to diffusion in the skeletal muscle of healthy humans, i.e., what Roughton and Forster called membrane component of the oxygen conductance (9). Thus, for DO2 to be the key limiting factor for O2 max, first the evidence that DO2 actually represents the maximal attainable oxygen diffusing capacity in skeletal muscles should be provided. However, we agree that a diffusion limitation theoretically is a possibility but functionally it is a very minor player in healthy humans (4).
REFERENCES
O2 during maximal cycle ergometry. J Appl Physiol 73: 1114–1121, 1992.O2 max. J Appl Physiol 73: 1067–1076, 1992.O2 max. Respir Physiol 93: 221–237, 1993.[CrossRef][Web of Science][Medline]O2. We agree that one major difference between an athlete and a couch potato is in maximal cardiac output. However, we surprisingly agree that other factors contribute substantially to maximal O2. Bengt and Jose say this in paragraph 2 referring to the role of CaO2, which is not blood flow and restate this in their concluding paragraph, agreeing that lungs, heart, and blood are all important, just as I have argued. But they cannot use this to advance their own argument because the topic was not about O2 delivery, it was about blood flow.
I must also remind my friends that the topic includes the word primarily. They provided no evidence that per unit of change in the responsible variable, blood flow is the primary factor, more important than any other conductances in the O2 transport chain. They have failed to realize that for a high cardiac output to allow a high O2 max, the diffusing capacities in both the lungs and muscles must be correspondingly high, or pulmonary O2 loading and tissue unloading must be compromised, as pointed out many years ago by Piiper et al. (1, 2). They have assigned primary importance to one variable (flow) without assessing all other pertinent variables. How can you compare the roles of each variable when not all are addressed? Suppose you ask which is the fastest way to get from point A to B? By car, bicycle, or plane, and don't even study other alternatives such as by train or on foot. You simply cannot conclude that by train or on foot are not faster ways to get there. By looking at only part of the story, they have presented only part of the answer.
REFERENCES
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