Did you know—why does maximal oxygen uptake increase in humans following endurance exercise training?

It has been appreciated for more than a century that maximal oxygen uptake (VO2max) increases with endurance training (ET). A question that has emerged in our community is why that is so? More specifically, what is the main target of biological signals induced by endurance exercise? It must be assumed that mechanical and chemical signals leading to VO2max improvement do not “realize” that the ultimate purpose of ET is to increase the aerobic capacity to move faster for prolonged time! Here we propose that the main signals facilitating adaptations are related to maintaining resting homeostasis rather than improving on O2 delivery limiting steps. One deep-rooted axiom in biology asserts that the rate limiting step(s) of a physiological function adapts when stressed. Considering the transport of oxygen (O2) from air into mitochondria as a definite function, it can be inferred that the commonly observed increases in red blood cell volume (RBCV), maximal cardiac output and skeletal muscle capillarization in response to ET occur to overcome limitations to their essential task of conveying O2 to the exercising muscle fibre, which as a matter of fact determines the upper limit of O2 uptake (VO2max) in healthy humans.1 In line with this reasoning but on the evolutionary timescale, Ewald Weibel and co-workers applied the hypothesis of symmorphosis to VO2max.2 Symmorphosis postulates that maximal O2 transport capacities of sequential steps in the O2 cascade are quantitatively matched in such manner that no step is overbuilt in relation to O2 demand at VO2max, concurring with the notion of economical “design”.3 Symmorphosis has obtained partial support from comparative analyses of O2 transport between different species of mammals, including humans.4 Yet, certain steps in the human O2 cascade are manifestly unmatched regarding their potential for O2 transport, eg, the lung versus circulatory capacities.5 Accordingly, ET-induced adaptations associated with increases in VO2max must be present in the circulatory “bottlenecks”6 but not necessarily in the respiratory system, which indeed demonstrates little phenotypic modifications with ET.7 At this point, we have obliviously returned to the aforementioned and omnipresent axiom as opportunely applied in exercise physiology: regular endurance exercise challenges and thereby specifically prompt alterations in the weakest steps of the O2 cascade, ultimately resulting in adaptations that improve upon their limitation to O2 transport. Before endorsing our own argumentation, we have to trace the entity of and primary causality between key ET-induced adaptations and VO2max improvement. The total blood volume (BV) of elite endurance athletes, reaching up to ~110 mL per kg of body mass or 9 L for a male weighting 80 kg, is almost twice that of healthy untrained individuals.8 Less salient, albeit fundamental adaptations, ~10% increments in BV, are observed after several weeks to months of ET in previously untrained individuals.6, 9-11 Once BV becomes stabilized for a given dose of ET, the two major blood volumetric components, ie, plasma volume (PV) and RBCV, are proportionally augmented thus leaving haematocrit (Htc) roughly unaltered.9, 12 The crucial role of BV expansion in VO2max responses to ET is evidenced when post-training PV and RBCV are restored to pre-training levels via phlebotomy, a procedure that abolishes increases in maximal cardiac output (Qmax) and VO2max, notwithstanding the presence of enhanced skeletal muscle capillarization and mitochondrial biogenesis.6, 13 RBCV expansion augments the capacity to deliver O2, and thereby VO2max, via two mechanisms: (i) larger total BV facilitates venous return and cardiac filling, which by means of the Frank-Starling mechanism leads to increased stroke volume and Qmax, and (ii) higher number of circulating red blood cells and specifically, the haemoglobin inside them, preserves blood O2 carrying capacity, which would be otherwise reduced because of PV expansion.1 While the fact that VO2max is mainly determined by RBCV and haemoglobin mass (Hbmass) is generally accepted, little attention has been devoted to the mechanisms that regulate erythropoiesis with ET.12 Specifically, the question arises as to whether erythropoiesis is optimally stimulated by ET. Surprising as it may seem, the initial increase in BV is solely attributed to PV expansion, which occurs after a few ET sessions. From the point of view of O2 transport and VO2max improvement, this early adaptation can hardly be seen as favourable since on the one hand cardiac function is enhanced via the Frank-Starling mechanism, but on the other hand, Htc and blood O2 carrying capacity are reduced.14 In order to definitely increase VO2max, the target should be erythropoiesis. In this regard, the main hormone stimulating red blood cell production, erythropoietin (Epo), is only slightly and transiently augmented after acute endurance exercise coinciding with the fall in Htc in untrained individuals, an effect that becomes imperceptible with the progression of ET and gradual RBCV expansion approaching Htc normalization.9 It should be noted that Epo is mostly produced by kidney peritubular fibroblast-like cells and regulated by O2-dependent pathways,15 whose activities are ultimately contingent upon arterial O2 content.16 The increase of circulating Epo with ET may essentially be triggered by post-exercise PV expansion and the resultant decrease in arterial O2 content in a negative feedback loop attempting to maintain normal Htc and O2 carrying capacity.12 Haematological adaptations to ET may thus aim for homeostasis rather than to increase O2 transport capacity and VO2max. Indeed, Htc levels rarely exceed normal untrained values, 42-46 % (♂) in elite endurance athletes. If VO2max improvement were a priority response to ET, the homeostatic mechanisms that preclude increases in Htc above normal values would be reset to yield a higher, optimal level for O2 transport and endurance performance17 similar to that of superb athletic mammals, around 60 % Htc at rest, further increased during exercise.18 When the effect of Epo is genetically altered in humans, as in the presence of rare genetic variants associated with hypersensitivity of the Epo receptor, blood O2 carrying capacity “escapes” from homoestasis and Htc levels ~60 % are the norm in these individuals, including a multiple gold medalist in endurance events.19 Of note, not only genetic alterations of key regulatory pathways or massive blood transfusions overcome haematological limitations and facilitate extraordinary endurance achievements.20, 21 Twice per week injection of microdoses of Epo (10-40 IU/kg) steadily augmented Hbmass throughout a 12-week regimen in regularly endurance-trained individuals.20 The overall gain in Hbmass induced by this mild pharmacological intervention exceeded 100 g, equivalent to the haemoglobin contained in two 450 mL bags of liquid-stored red blood cells.22 Such accretion of Hbmass entails an impact on VO2max barely achieved by years of ET in trained individuals.23, 24 Collectively considered, erythropoiesis is far from being effectively spurred by endurance exercise in humans. Hence, ET does not optimally target the main haematological “bottleneck” in the O2 transport chain, which therefore limits major improvements in VO2max. In the pursuit of understanding physiology there is a natural propensity to envisage purposes. The complexity of several mechanisms of biological adaptation appear very unlikely to be just a matter of chance, a collateral consequence. This inclination is reinforced by the predominant influence of an all-pervading but utterly scientific theory such as natural selection. Insofar as certain physiological functions have been plausibly modelled by selection pressures,25, 26 not every body function and its adaptability has been subjected to the same degree of unidirectional evolutionary pressure. From a physiological standpoint, the fact that endurance exercise does not primarily target the major limiting step for O2 transport in humans denotes that our species did not evolve with the urgency to excel at endurance events, in striking contrast with other non-primate mammals.27, 28 The Homo sapiens VO2max response to ET may be most accurately interpreted as one of manifold sequels of our obstinate attempt to maintain homeostasis, one that aims for a fixed level of blood O2 carrying capacity incompatible with outstanding O2 uptake. The authors do not have any conflicts of interests to declare.

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