Human aerobic performance: too much ado about limits to V̇_O2

There has been a long history of papers devoted to examining the factor or factors that conspire to limit maximum oxygen uptake. These usually focus on single species in an attempt to ascertain which functional ‘bottleneck’ is likely to set the upper limit to oxygen flow. In general, these fall into two categories, both of which have greatly increased our understanding of the mammalian respiratory system. First, because oxygen flows through structures in series (Fig.1), (1) O₂ uptake by the mitochondria, (2) O₂ delivery by the circulation or (3) O₂ uptake by the lungs, the relative resistance (conductance) of each of these can be estimated and its contribution to the overall ‘limit’ approximated (di Prampero, 1985; di Prampero and Ferretti, 1990; Ferretti and di Prampero, 1995). However, this approach is complicated by the fact that some resistances are fixed and others variable, for example in response to training, and remain ‘tuned’ to demand (Lindstedt et al., 1988). In contrast, another approach has been to focus on one step and detail how this single step may be rate-limiting (Saltin and Strange, 1992; Wagner, 1992). One problem with this view is that this single-step ‘limitation’ has been ascribed to a number of different components in the cascade (Rowell, 1993; Wagner, 2000). The absence of consensus on where the ‘limitation’ lies may indicate that no single ‘limitation’ exists. Both these approaches have usually focused on relatively small changes (10–15%) in the maximum rate of oxygen uptake, and usually in humans.

Our intention here is to take a slightly different approach, one that is also intended to provide insight into the design of the respiratory system. Rather than focus on small increases or decreases in rates of oxygen uptake, we hope to demonstrate that a broadly comparative picture yields distinct insights. We analyze this problem in three steps. First, we ask how the mammalian respiratory system is designed to match O₂ delivery to O₂ demand over a 5000-fold range of V̇_O2max. Second, we ask how the human system is designed to meet the twofold range of V̇_O2max found among individuals. Third, we evaluate adjustments of steps in the O₂ cascade (such as blood doping, supplemental O₂, etc.) to evaluate whether a single ‘limitation’ dominates maximal O₂ flux. Through these comparisons, we seek to identify how the respiratory system is designed to match oxygen supply with oxygen demand. This comparative approach gives new insights and may change the nature of the question asked concerning how the respiratory system is designed to deliver O₂ to meet demand.

Underlying this approach is our belief that no single step in the O₂ delivery cascade dictates total flux but rather that each step contributes to flux. This notion of shared flux control is common to current thinking in biochemical pathways (Fell and Thomas, 1995; Kascar and Burns, 1973), the concept of symmorphosis (Weibel and Taylor, 1981; Weibel et al., 1991) and a recent physical analysis of the cardiovascular system (West et al., 1999).

The quantitative analysis accomplished on the mammalian respiratory system may offer insight into the design of the human system. Our first question is how the range of V̇_O2max of over 5000-fold (0.03 versus 169mls⁻¹)(Seeherman et al., 1981) is achieved among all mammals. Let us start at the muscle, where the energy cost of locomotion determines the maximum O₂ demand. The two structures key to O₂ delivery and uptake are the mitochondria using O₂ and the capillaries delivering O₂. Fig.2 shows that the volume of capillaries that deliver blood and the volume of mitochondria that use O₂ are directly proportional to V̇_O2max. The result is that the higher V̇_O2max of larger animals corresponds with proportional increases in the muscle capillary capacity for O₂ delivery and the muscle mitochondrial capacity for O₂ uptake. The proportionality between structure and flux is demonstrated by the constancy of V̇_O2max per mitochondrial volume despite a 5000-fold range in total flux between mouse and steer (Hoppeler, 1990).

A similar proportionality between O₂ delivery capacity and V̇_O2max is found at the next step of the cascade, the cardiovascular system. Cardiac output and O₂ delivery both increase in proportion to maximal flux (Kayar et al., 1994). The structures of the pulmonary system also vary directly with V̇_O2max, but there is an apparent excess of O₂-diffusing capacity in all mammals (Weibel and Taylor, 1981). The end result is (i) that the structures of each step of the respiratory system scale in proportion to or in excess of V̇_O2max (Weibel and Taylor, 1981), (ii) that each step in the system appears to operate at or near its maximum at V̇_O2max and, as a result, (iii) that the O₂ flux per mitochondrial volume is nearly constant (Hoppeler, 1990). Clearly, a single step does not determine flux, but rather the structural and functional capacities of each step of the cascade increase almost in proportion to achieve the extraordinary range of V̇_O2max found with body size in mammals.

Humans differ from most mammals in one important respect relevant to V̇_O2max: exercise involves bipedal rather than quadrupedal locomotion. This use of two rather than four limbs means that the whole musculature is not used to achieve V̇_O2max. Thus, defining the active muscle mass in humans is a critical problem, with differences in V̇_O2max occurring between exercise modes such as running and cycling. For this analysis, we focus on cycling exercise, which evokes a nearly twofold range in V̇_O2max between sedentary and well-trained athletes (Hoppeler et al., 1973) or between young and old subjects (Conley et al., 2000). Is this range of V̇_O2max in humans accompanied by a proportional range in the capacities for O₂ uptake, delivery and use or does a single step dictate flux?

An early study of muscle properties and V̇_O2max showed that mitochondrial volume density, Vv(mt,f), was proportional to V̇_O2max from sedentary humans to athletes (Hoppeler et al., 1973). Exercise training studies seemed to contradict this proportionality by showing a 40% increase in quadriceps Vv(mt,f) but only a 15% increase in whole-body V̇_O2max (Hoppeler et al., 1985). However, a quantitative comparison of the expected change in muscle versus whole-organism V̇_O2max revealed the problem with this comparison of relative changes at the whole-body and muscle levels. The first step was to compare the changes that occurred at the level of the leg. This comparison showed that the increase in muscle power output agreed closely with the increase in muscle Vv(mt,f) with training. Thus, ATP use, as measured by leg power output, increased in proportion to the mitochondrial capacity for O₂ uptake and ATP supply. The mitochondrial volume in the muscle increased as would be expected on the basis of the increased O₂ demand for muscle power output. The second step was to compare O₂ uptake estimated for the leg with whole-body V̇_O2. This comparison revealed that the V̇_O2 needed for this increase in power was close to the whole-body increase in V̇_O2max that occurred with training. Thus, no discrepancy existed between changes at the level of the leg or between the leg and whole-body levels when the estimated change in V̇_O2 at the leg was compared directly with the whole-body V̇_O2 changes after training. This quantitative approach revealed that muscle mitochondrial volume, the estimated rate of O₂ consumption and the actual rate of O₂ uptake all increased proportionately with training. These results, and recent studies of sedentary subjects showing no increase in V̇_O2max after breathing supplemental O₂ (Cardus et al., 1998), suggest that V̇_O2max reflects the muscle oxidative capacity recruited during exercise, as it does in quadrupedal mammals.

A quantitative approach also helps us understand the factors responsible for the decline in V̇_O2max with age. Elderly subjects show a large decline in V̇_O2max relative to the young. A recent study showed that this decline in V̇_O2max was accompanied by parallel changes in the oxidative capacity of the quadriceps muscle group with age (Conley et al., 2000). The end result was that a significant fraction of the decline in V̇_O2max could be accounted for by the age-related change in the oxidative capacity of the quadriceps. In both adult and elderly subjects, the oxidative capacity of the quadriceps accounted for 30% of the whole-body rate of O₂ uptake in accord with the fraction of quadriceps versus whole-limb power output during cycling. The implication of this study is clear: the drop in V̇_O2max with age reflects the loss of O₂-consuming muscle. This study demonstrates that the kind of quantitative O₂ balance studies that have been accomplished in quadrupedal animals are also possible in humans even with the limitations of the bipedal gait. The result of this analysis in humans is the same as in quadrupeds: the range of V̇_O2max corresponds quantitatively with the range of the oxidative capacity of muscle involved in exercise.

Meeting the muscle O₂ demand is the cardiovascular capacity for O₂ delivery, which is determined by the product of cardiac output and O₂ extraction. Both normally active and athletic subjects have similar and high (up to 90%) O₂ extractions at V̇_O2max, and the increase in O₂ delivery that underlies the twofold increase in V̇_O2max results from an increase in cardiac output (see Fig.5.2)(Rowell, 1993). This difference in cardiac output is due to a higher stroke volume in athletes in accord with the larger heart of endurance-trained athletes. These findings indicate that a twofold difference in cardiovascular O₂ delivery capacity underlies the twofold difference in V̇_O2max between sedentary and athletic subjects.

Finally, sufficient oxygen must be provided to the lungs, via ventilation, and to the blood, via diffusion through the lungs, to satisfy the demand of exercising muscles. There is no evidence for these structures being able to adapt, during an animal’s lifetime. Lacking the plasticity that characterizes the other structures of the respiratory system, it is not surprising that the capacity of the lung for oxygen uptake exceeds the normal demand, suggesting to some that the lung may be ‘built in excess’ (Weibel et al., 1991). However, when we examine these structures across the full range of V̇_O2max from a 5g mouse to a 500kg horse, we see that all structures vary proportionately (Weibel et al., 1991). For example, the cross-sectional area of the trachea varies directly with V̇_O2max among mammals. Hence, it would appear that all mammals have a ‘reserve capacity’ to accommodate to, for example, high-altitude hypoxia or use or training-induced increases in the aerobic capacity of the muscles. Thus, the maximum ventilatory capacity may be fully exploited in humans only in the most elite endurance athletes (Lindstedt et al., 1994); for all others, capacity is excessive.

What determines V̇_O2max, the capacities for O₂ delivery and uptake or the limitations to O₂ flux? To answer this question, let us examine the effect of varying single steps in the O₂ delivery cascade.

Cardiovascular O₂ delivery is the single identifiable factor most often implicated as the limit to oxygen uptake. Consequently, most of the recent drug scandals in endurance sports, starting with blood doping in the 1984 US Olympic cycling team, are designed to increase oxygen delivery. The current drug of choice, erythropoietin, can boost hematocrit dramatically and, until only recently, exogenous erythropoietin has been undetectable. This focus on boosting O₂ delivery seems to assume that humans do not conform to the general pattern of balance among respiratory system capacities. It also begs the question of what is responsible for the remaining respiratory structures being over-built (i.e. possessing capacity in excess of need or demand) if cardiovascular O₂ delivery is a single rate-limiting step.

One explanation for why cardiovascular O₂ delivery is thought to limit V̇_O2max is that this step is the simplest to manipulate experimentally. Resultant correlations between rates of O₂ delivery and V̇_O2max have been interpreted as demonstrating a rate-limiting role of oxygen delivery. On the surface, the evidence supports this concept. For example, when O₂ delivery is diminished, either by the withdrawal of erythrocytes or by the imposition of hypoxia, the rate of oxygen uptake is nearly always reduced in direct proportion. However, these results do not exclude the alternative interpretation that delivery is merely adequate (rather than limiting). How strong is the evidence supporting this single-step limitation to V̇_O2max?

Arterial oxygen content can be easily manipulated by changing the concentration of inspired oxygen or by the withdrawal or addition of red blood cells to alter hematocrit. In all cases, oxygen delivery varies with arterial oxygen content. In fact, when delivery is reduced by anemia or hypoxia, the oxygen extraction remains high (90%) and V̇_O2max declines in direct proportion to O₂ delivery (Lindstedt et al., 1988). However, when delivery is enhanced rather than reduced, a very different pattern emerges. A meticulous study (Spriet et al., 1986) measured arterial oxygen content, cardiac output and V̇_O2max in very highly trained endurance runners (mean V̇_O2max 77.5mlO₂kg⁻¹min⁻¹) given up to three units (500ml each) of additional blood. They reported that a large increase in O₂ delivery (up to 30%) was accompanied by a slight increase (<7%) in V̇_O2max. As a consequence, O₂ extraction dropped from over 90% to under 75% (Fig.3). The simple interpretation of these data is that oxygen delivery exceeded the capacity of the oxygen sink (mitochondria) in the exercising muscles and, hence, that muscle power output was unable to profit from the available oxygen.

Aerobic performance is limited at high altitude by the low O₂ partial pressure and resultant hypoxia. However, when exercising at high altitude, it is possible to supplement O₂ in the inspired air to return the subject functionally to ‘sea-level’ values of V̇_O2max (hypobaric normoxia). Thus, when sojourners go to high altitude and are provided with additional oxygen, the consequence is an increase in the rate of oxygen consumption in direct proportion to the increase in arterial oxygen content and, hence, oxygen delivery. On the surface, these results seem to support a single cardiovascular limitation to V̇_O2. However, once again, a different pattern emerges when high-altitude natives, rather than sojourners, perform the same experiment. Comparing individuals from two different studies, at nearly the same altitude (3600m altitude residents, 3790m altitude sojourners), the two groups have a similar peak V̇_O2 (Cymerman et al., 1989; Favier et al., 1995). However, in contrast to the sojourners, when the high-altitude natives are given the sea-level-equivalent inspired oxygen partial pressure, the increase in V̇_O2max (8%) is much smaller than that of the sea-level sojourners (38%) (Fig.4). It seems that living at high altitude, where chronic hypoxia necessarily limits one’s aerobic activity, the muscles collectively have a much lower aerobic capacity. Apparently, there is no stimulus to maintain the aerobic capacity of the muscles at a level beyond that which can be supplied via cardiovascular delivery. Thus, when the muscles are flooded with the equivalent of sea-level oxygen delivery, they simply have no aerobic machinery to utilize all that oxygen.

Finally, Richardson et al. (Richardson et al., 1999) have elegantly shown that intracellular (myoglobin-associated) P_O2 can also be manipulated by changing the fractional O₂ content of the inspired air (Fi_O2) from 0.12 (hypoxia) to 0.21 (normoxia) and 1.0 (hyperoxia). The drop in the mitochondrial rate of O₂ uptake in hypoxia (30%) is identical to the drop in intracellular P_O2 (30%). In contrast, a 65% increase in intracellular P_O2 yields only an 11% increase in mitochondrial V̇_O2. Once again, we see that, when delivery is reduced, V̇_O2 drops accordingly. However, when delivery is increased, more oxygen is apparently available to the mitochondria than can be utilized (Fig.5).

Taken together, these data demonstrate using three different model systems that V̇_O2 does track O₂ delivery, but only when delivery is reduced not when delivery is supplemented. This suggests to us that delivery is apparently rarely excessive. However, the fact that V̇_O2 does increase somewhat in response to increased O₂ delivery also argues against some other single rate-limiting step in the cascade. In other words, just as we see a structural balance accompanying the greatly varying V̇_O2 among mammals, so too within humans there is more evidence for a balance of structures and shared limitation than there is for a single-step limitation. When delivery is enhanced, unless there is a concomitant increase in the aerobic capacity of the muscles, little gain in V̇_O2max is realized.

By expanding our comparisons from within humans to among all mammals, there is a huge ratio of signal to noise such that V̇_O2max varies by many orders of magnitude, not just a few per cent. What emerges is a consistent pattern of oxygen balance – structures ensuring supply are adequate to supply and utilize the oxygen required to meet the locomotor costs. Furthermore, those structures with the greatest plasticity will vary in proportion to oxygen uptake. These structures seem to be muscle mitochondrial volume and capillary density, cardiac output and hemoglobin concentration. In contrast, structures lacking plasticity (trachea, lungs) must be built with sufficient capacity to accommodate use-induced increases in oxygen demand during an animal’s lifetime. There is no consistent evidence for a single rate-limiting step across the 5000-fold range of V̇_O2 among mammals, including humans. Finally, V̇_O2max is just one of many interacting factors that collectively conspire to set the upper limits of human endurance performance.

The authors are funded by NIH grants AR45184, AR41928 (to K.E.C.) and AG18701 (to S.L.L.).