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INVITED EDITORIALS
Department of Sport and Exercise Science, Aberystwyth University, Ceredigion, United Kingdom
THAT THE RATE of pulmonary oxygen uptake (
O2) does not immediately increase in response to a step increase in work rate, resulting in the so-called "oxygen deficit," is one of the oldest and most controversial observations in exercise physiology. Relatively little controversy emanates from the description of the O2 kinetics: that the "fast" or "primary" component is exponential in character, that a "slow component" emerges at work rates above the lactate threshold, and that the origin of both components resides within the exercising muscle is not disputed (11). However, the mechanisms underpinning these transient O2 responses are subject to considerable and often heated debate. Part of the reason this debate persists is that it has until recently been difficult to directly associate measurements made at the mouth with mechanisms within the muscle. As a result, the fundamental challenge that the field of O2 kinetics presents will be familiar to all exercise physiologists: to what extent do physiological inferences derived from whole body measurements (at the mouth and/or in the systemic circulation) translate to (and from) physiological processes occurring within the myocytes and microcirculation?
It is first important to note that, when narrow limits of statistical confidence are provided by the appropriate sampling and averaging of O2 kinetics data, the transient pulmonary O2 signal during whole body exercise in healthy participants reflects the muscle O2 kinetics (11). The muscle O2 kinetics, in turn, is coupled by mitochondrial creatine kinase to the dynamics of high-energy phosphate metabolism in the cell (10): the time course of phosphocreatine (PCr) degradation has been shown to be functionally identical to the simultaneously measured O2 response (6). In addition, a slow component in pulmonary O2 is mirrored by a slow component in PCr degradation (7). Broadly speaking, therefore, what is measured at the mouth (taking account of appropriate transport delays) closely reflects energetic events occurring within the exercising muscle. However, the extent to which the kinetics of O2 is determined by O2 delivery to the cell, or by a lag in O2 utilization by the cell, remains the principal issue of debate. As might be expected, the problems associated with the translation of experimental findings from the cell and adjacent capillaries to the muscle and further to the whole body provide a major source of controversy. In addition, the degree to which O2 delivery influences the O2 response is crucially dependent on the experimental design. Factors such as body orientation, exercise intensity, exercise mode, and contractile regime may shift the locus of control toward or away from O2 dependence (5).
Recently, the view has been expressed that the O2 delivery/utilization debate is a false dichotomy. A more realistic view of this issue is that there is a "tipping point" in the relationship between the speed of the O2 kinetics (expressed using the primary O2 time constant) and muscle O2 delivery (Fig. 1; Ref. 5). To the left of this tipping point, the kinetics is undeniably O2 delivery dependent, whereas to the right of the tipping point, the kinetics is determined by O2 utilization. In this context, specific human populations and/or experimental conditions may occupy distinct and predictable positions on the continuum. For example, the kinetics of well-conditioned young subjects performing upright cycle exercise might not become O2 delivery dependent even at work rates that elicit the maximum O2 (5). Crucially, attempting to increase O2 delivery by breathing hyperoxic inspirates does not discernibly speed the O2 kinetics (e.g., 12), which seems to provide compelling evidence in favor of an intracellular locus of control. In contrast, older humans, particularly those possessing chronic cardiovascular, respiratory, and/or muscular pathologies, may be consistently positioned to the left of the tipping point (i.e., O2 delivery dependent; 5), and hence therapeutic strategies to improve muscle O2 delivery may enhance exercise tolerance by speeding O2 kinetics.
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O2 kinetics, as also reported by Schneider et al. (8). These findings are surprising, since it has been demonstrated that such damage also severely disrupts the microvasculature and thus compromises the matching of O2 delivery to O2 demand [in effect, left-shifting (reducing) O2 delivery; Fig. 1], which would be expected to result in the O2 kinetics being slowed (3). A possible conclusion, therefore, is that the O2 time course is independent of O2 delivery. However, Davies et al. (1) also provide novel evidence that the kinetics of near-infrared spectroscopy (NIRS)-derived deoxygenated hemoglobin (HHb) was slowed at the onset of exercise with muscle damage. This could occur if muscle blood flow had been increased in an attempt to increase microvascular PO2 to maintain O2 flux to the active myocytes. Thus the work of Davies et al. (1) suggests that to preserve O2 kinetics during severe-intensity exercise following muscle damage, compensatory cardiovascular adjustments must occur. This work provides an excellent example of the power of integrative and translational physiology: taking measurements at the whole body and muscle levels simultaneously and paying heed to known physiology from other experimental models, Davies et al. (1) have reconciled previously disparate findings and suggested new avenues of inquiry.
In measuring variables related to the matching of O2 delivery and O2 utilization, Davies et al. (1) raise important physiological questions and suggest how answers might be sought. One avenue of investigation concerns whether muscle blood flow kinetics is altered by prior muscle damage as would be predicted from their results. Interestingly, recent calculations based on measurements of HHb and O2 kinetics suggest that capillary blood flow dynamics may be considerably slower than those measured in the conduit artery (2), and the effect of muscle damage on capillary blood flow kinetics in humans is also unknown. Thus, where the preservation of O2 kinetics by cardiovascular adjustments occurs begs the question, at which functional level(s) might these adjustments occur?
Returning to the tipping point concept, the data presented by Davies et al. (1) suggest that their subjects’ O2 kinetics may have been positioned close to the tipping point itself. However, the "position" of a subject in relation to the tipping point is, in itself, a simplified view of the physiology. Heterogeneities in perfusion and metabolism, accentuated by inter- and intraindividual variations in fiber type and capillary distribution, imply that the position is perhaps better expressed not as a point but as a distribution. But how wide should this distribution be to reflect these heterogeneities? Perhaps most importantly, how should the relationship between O2 kinetics and O2 delivery be presented to most accurately reflect the underlying physiology? At present, the tipping point concept is intended only to illustrate the dependence or independence of the primary O2 time constant on O2 delivery. Yet it is known that muscles containing predominantly type II fibers evidence slower kinetics of PCr degradation than those containing predominantly type I fibers (4). These fiber-specific responses may influence the O2 kinetics at high work rates even if O2 delivery is adequate. If we are to generate hypotheses using the tipping point concept, then the model should take account of these findings also. Perhaps what is needed is a diagram analogous to that presented by Wagner (9) to describe the interplay between convective and diffusive O2 delivery in determining the maximal O2 (9).
In summary, the study of Davies et al. (1) highlights the benefits of adopting integrative and translational approaches to investigate the energetics of whole body exercise. This investigation also significantly strengthens the rationale for considering the contributions of O2 delivery and O2 utilization to the control of O2 kinetics in light of the tipping point concept.
FOOTNOTES
Address for reprint requests and other correspondence: M. Burnley, Dept. of Sport and Exercise Science, Carwyn James Bldg., Aberystwyth Univ., Aberystwyth, Ceredigion SY23 3FD, United Kingdom (e-mail: mhb{at}aber.ac.uk)
REFERENCES
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  H. J. Green, M. E. Burnett, I. C. Smith, S. M. Tupling, and D. A. Ranney Failure of hypoxia to exaggerate the metabolic stress in working muscle following short-term training Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R593 - R604. [Abstract] [Full Text] [PDF]
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T. Saitoh, L. F. Ferreira, T. J. Barstow, D. C. Poole, A. Ooue, N. Kondo, and S. Koga Effects of prior heavy exercise on heterogeneity of muscle deoxygenation kinetics during subsequent heavy exercise Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R615 - R621. [Abstract] [Full Text] [PDF]
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