Control of Oxygen Uptake during Exercise DAVID C. POOLE"'2, THOMAS J. BARSTOW', PAUL MCDONOUGH 3, and ANDREW M. JONES 2 'Departments ofKinesiology, Anatomy andPhysiology, Kansas State University,Manhattan,KS; 2School of Sport and Health Sciences, University of Exeter, St. Luke's Campits, Heavitree Road, Exeter, UNITED KINGDOM; and 3Departmentof Kinesiology, University of Texas at Arlington, Arlington, TX

ABSTRACT POOLE, D. C., T. J. BARSTOW, P. MCDbNOUGH, and A. M. JONES. Control of Oxygen Uptake during Exercise. Med. Sci. Sports Exerc., Vol. 40, No. 3, pp. 462-474, 2008. Other than during sleep and contrived laboratory testing protocols, humans rarely exist in prolonged metabolic steady states; rather, they transition among different metabolic rates (f02). The dynamic transition of V02 (402 kinetics), initiated, for example, at exercise onset, provides a unique window into understanding metabolic control. This brief review presents the state-of-the art regarding control of "02 kinetics within the context of a simple model that helps explain the work rate dependence of 'O2 kinetics as well as the effects of environmental perturbations and disease. Insights emerging from application of novel approaches and technologies. are integrated into established concepts to assess in what circumstances 02 supply might exert a commanding role over 402 kinetics, and where it probably does not. The common presumption that capillary blood flow dynamics can be extrapolated accurately from upstream arterial measurements is challenged. From this challenge, new complexities emerge with respect to the relationships between 02 supply and flux across the capillary-myocyte interface and the marked dependence of these processes on muscle fiber type. Indeed, because of interfiber type differences in 02 supply relative to V02, the presence of much lower 02 levels in the microcireulation supplying fast-twitch muscle fibers, and the demonstrated metabolic sensitivity of muscle to 02, it is possible that fiber type recruitment profiles (and changes thereof) might help explain the slowing of 41O2 kinetics at higher work rates and in chronic diseases such as heart failure and 'diabetes. Key Words: OXYGEN UPTAKE KINETICS, MUSCLE OXYGEN SUPPLY, METABOLIC CONTROL, FIBER TYPE, MICROCIRCULATION

deficit and exacerbates perturbations of the intramuscular milieu: that is, j[phosphocreatine, PCr], T[ADP]frce, Tl[Pi] (70). These changes are associated with a reduced exercise capacity, and it is possible that a greater understanding of the causes of slowed V02 kinetics in such patients will facilitate development of therapeutic strategies to reverse this problem and improve exercise tolerance and patients' quality of life. There is a substantial body of scientific literature that has examined the site of V02 kinetics limitation during moderate-intensity exercise, and the reader is referred to the excellent reviews by Whipp and Mahler (85), Hughson and colleagues (45), Hughson (40), Grassi (22,23), and Delp (16). In brief, proponents of the 0 2-delivery limitation theory point out that there is biochemical evidence for 02 adjusting the phosphorylation and redox potentials needed to drive oxidative metabolism (38,91,92). Furthermore, they cite studies demonstrating that the rate of rise to a given •02 (i.e., 4'02 kinetics) is slowed when muscle 0, delivery is impaired by 1) inspired hypoxia (i.e., 4reduced arterial 02 content (18)), 2) supine posture (41), 3) P3-adrenergic receptor blockade (39), 4) transition from prior exercise (42), and 5) diseases that impair cardiovascular dynamics and pulmonary function (70,71). In contrast, proponents of the "oxidative enzyme inertia" hypothesis base their position on the following observations: 1) most studies demonstrate that muscle 0 2 -delivery kinetics (assessed from muscle arterial inflows or cardiovascular dynamics) are appreciably faster than 402 kinetics (16), and it is difficult

s distinct from the steady state of oxygen uptake (VO2) that may be achieved during exercise, the

dynamic transition of 402 (VO2 kinetics), initiated at exercise onset, provides a unique window into under-

standing metabolic control. One major and contentious issue that has intrigued physiologists and exercise scientists for decades concerns whether, in healthy individuals, the speed of VO, kinetics at the onset of exercise is limited by

muscle 02 delivery or, rather, some rate limitation of the oxidative machinery itself (16,22,23,40,45,84). Resolution

of this issue is essential to understanding metabolic control in health, and also for defining the mechanistic bases for the

impaired (slowed) 4VO kinetics found in patient populations. Specifically, prevalent chronic diseases such as heart failure and diabetes may incur slowed V02 kinetics, which, at a given V02, mandates generation of an increased 02 Editor's Note: This paper is an Editor-in-Chief-invited contribution from ACSM's conference on Integrative Physiology of Exercise held in Indianapolis, Indiana, September 27-30, 2006. Address for correspondence: David C. Poole, Ph.D., D.Sc., Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 665065802; E-mail: [email protected]. Submitted for publication April 2007. Accepted for publication October 2007. 0195-9131/08/4003-0462/0 MEDICINE & SCIENCE IN SPORTS & EXERCISE,_ Copyright Q 2008 by the American College of Sports Medicine DOI: 10.I249/mss.0b013e31815ef29b

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to envisage a faster process limiting a slower one. 2) It is possible to alter VO2 and cardiovascular kinetics independently (95). Specifically, prior one-legged exercise speeds cardiac output and VO2 kinetics during a second bout with the same leg. In contrast, when the other leg performs the second exercise bout, V0 2 kinetics are not speeded, even though cardiac output kinetics are faster in comparison with control values. 3) For moderate-intensity exercise, neither increased arterial 02 content (62) nor muscle 02 availability (24,25) speed V02 kinetics, and even in the heavy/severeintensity domains their 02 dependence may be very modest or absent (22,86). 4) The temporal correspondence between PCr and V0 2 kinetics and their monoexponential profile support a phosphate-linked control of mitochondrial energetics (70,77). 5) Reductions in nitric oxide inhibition of mitochondrial function by L-NAME speed' V0 2 kinetics, even in the face of a potentially reduced muscle 02 delivery (50,54). 6) In muscles with a preponderance of slow-twitch fibers, microvascular oxygenation does not fall immediately or precipitously at the onset of contractions; instead, it decreases exponentially to the steady state following a 10- to 20-s delay or even exhibits a slight increase (5,6,65). Notwithstanding the positions expressed above, both camps agree that at some point altering 02 delivery will impact 402 kinetics, and this is illustrated schematically in Figure 1. Notice that, as 02 delivery is reduced moving from right to left, at some "tipping point" an 02 limitation occurs, and V0 2 kinetics (designated as the time constant, T) become progressively slowed. The dissent arises principally from consideration of where the exercising individual lies with respect to the tipping point. The 02delivery proponents would place the healthy exercising individual on the ascending limb of the response, where either an increase or decrease in 02 delivery would speed or Healthy individuals Upright cycle exercise

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FIGURE 1-Model demonstrating the effects of altering muscle O2 delivery on ''02 kinetics (i.e., increased V02 time constant (7) denotes slower kinetics). Moving from right to left, note that Tris unchanged as 02 delivery decreases (0 2 -delivery-independent V'02 kinetics) until some critical "tipping point" is reached, beyond which VO2 kinetics become progressively slowed (larger T')with further reductions in 02 delivery. The question posed in this review is, Where on this continuum are healthy individuals as they perform upright cycle or running exercise? Redrawn from Poole and Jones (70).

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slow V0 2 kinetics, respectively. In contrast, if V02 kinetics are limited by an intrinsic sluggishness of the muscle metabolic machinery, the exercising individual would lie at some point to the right of the tipping point, and thus 402 kinetics would be insensitive to either increased 02 delivery or to modest reductions in 02 delivery, provided that such reductions did not take the individual across the tipping point. In recent years, significant developments in technology and innovative experimental models and designs have ' facilitated advances in our understanding of the control of •02 kinetics in health and disease. This review uses Figure 1 as a framework within which to reexplore the limitations to 402 kinetics during exercise, .taking into account some of these latest experimental findings. As presented in indianapolis, 'IN, at the ACSM Integrative Physiology of Exercise meeting in September 2006, this paper is sequenced to demonstrate how novel experimental approaches and data help reconcile (apparently) opposed viewpoints. A. M. Jones will explore the opposing viewpoints* that V02 kinetics are or are not limited by 02 delivery. T. J. Barstow will present near-infrared spectroscopy data suggesting that capillary blood flow kinetics are considerably slower than those of muscle blood flow measured at more remote sites, and that humans therefore may exercise in the proximity of the tipping point. Finally, P. McDonough will demonstrate that the temporal relationship between 02 delivery and V02 kinetics is fiber type dependent, such that slow- and fast-twitch fibers might lie on opposite sides of the tipping point. 0 2 -DELIVERY DEPENDENCE OF V0 KINETICS (A. M. JONES)

2

The concept of an 02 transport limitation to V02 kinetics has traditionally been championed by Dr. Richard L. Hughson of the University of Waterloo, Canada. This section therefore attempts to provide a fair synopsis of the evidence that might be harbored in favor of this concept, which implies that there is a specific "rate-limiting step" in the 02 cascade from the lungs to the mitochondria. There are certain conditions under which it might be possible to identify an 0 2-transport-related factor that results in a change in V02 kinetics-for example, breathing hypoxic gas (18,61,66), following P3-adrenergic receptor blockade (39), or (possibly) in the transition from light- to moderateintensity exercise (8,42,64). As indicated in the introduction, it is now widely accepted by researchers in this field that there are conditions under which 02 transport can impact 402 kinetics. Controversy remains, however, over the exact nature of these conditions. Arguably, this debate can be distorted by a focus on the "either/or" nature of 02transport versus 0 2-use limitations. The terms "regulation" or "modulation" of 402 kinetics by 02 transport have recently been used more widely, and these might present a more appropriate way to understand the interaction of

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factors that establish the increase in V02 during a transition to a higher work rate (40,83). One specific example of how a change in V02 kinetics might be related to a change in 02 transport is provided by the experiment conducted by Hughson and Morrissey (42) some 25 yr ago. These authors studied different exercise transitions to work rates that were strictly below the gasexchange threshold (GET). The kinetics of V0 2 were slower in the 40-80% GET transition than during the rest (or unloaded pedaling (43)) to 80% GET transition. The kinetics of heart rate showed a very similar response profile during these studies. Thus, Hughson and his associates proposed that the slower kinetics of 402 in the 40-80% GET transition were the consequence of slower 0 2-transport kinetics to the exercising muscles. Subsequently, advances in Doppler ultrasound technology enabled muscle blood flow kinetics to be examined during exercise transients, with some studies indicating a relationship between V0 2 kinetics and 0 2-transport kinetics, such as when supine exercise was compared with upright exercise (63). A recent study by McPhee et al. (64) has also indicated that muscle 02 transport is slower in the upper compared with the lower region of the moderate-intensity exercise domain. The term "regulation" rather than "limitation" of "V'02 kinetics by 02 transport is now preferred by Hughson and colleagues, because this term incorporates the obvious interaction with metabolic conditions in the determination of •02, both in the steady state and across an exercise transient (40). The rate of ATP hydrolysis is precisely matched by ATP synthesis in the steady state of exercise. As exercise intensity increases, the sum of the high-energy phosphates (ATP + PCr), which might be termed the "energetic state" of the muscle (3,14), is progressively reduced. Across the transition to exercise (i.e., in the nonsteady state), there is a progressive reduction in the energetic state until the steady-state level is finally attained. The energetic state during exercise at a constant work rate can be modified by changes in 02 supply, such as with hypoxia or hyperoxia (37,61). In vivo observations that high-energy phosphates and substrate concentrations can change at the same steady-state ATP demand might be considered to be consistent with the complex regulation of metabolism by 02, as described by Wilson and Rumsey for in vitro preparations (92). It might be further argued that this must also happen in exercise transitions when the intracellular P0 2 is changing from resting values above 30 mm Hg to those less than 5 mm Hg (75,76). Hughson (40) has recently proposed a multidimensional model to explain these complex interactions (Fig. 2). In this figure, the x-y plane represents the metabolic control where a constant rate of ATP flux can be achieved at lower mitochondrial P0 2 by reductions in the concentrations of PCr and ATP (92). With a reduction in P0 2 (as reflected by moving from point 1 to point 2 on the graph), the altered energetic state maintains the necessary balance between P0 2 and the phosphorylation and redox potentials to provide sufficient drive to keep ATP

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P0 2 , Energy Status, Enzymes and Substrates Interact at given ATP Flux

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FIGURE 2-A hypothetical scheme is presented to show how a constant rate of ATP production across the entire surface can be accomplished by the interactions of intracellular P0 2 (PI,tr3c,IularO2) on the x-axis, energetic state as indicated by the concentration of ATP + PCr on the ykaxis, and muscle enzyme or substrate concentration changes on the z-axis. Moving from point I on the graph to point 2, which would occur in hypoxia, requires reduction of the energetic state as described by Wilson and colleagues (91). Movement from point 2 to point 3 could represent exercise in the trained state, where breakdown of ATP + PCr would be less, and intracellular P0 2 could be slightly higher. Figure adapted from Hughson (40).

production at the required level (45). The third dimension in Figure 2 (in which there is constant ATP production across the full surface) allows for the effects of interventions such as prior exercise (62), drugs to inhibit nitric oxide synthase (50), or exercise training (31), to be explored. With exercise training, for example, a muscle's metabolic state might move from point 2 to 3 on the figure. Although hypothetical, this model recognizes the complex nature of metabolic control at a constant ATP flux rate. Hughson's model can be expanded to understand V0 2 kinetics by adding a fourth dimension (time) that considers the increase in oxidative production of ATP along with changes in intracellular P0 2 , the activation of enzymes, and the availability of substrate. Across the rest-to-exercise transition, metabolism is controlled by a complex series of interactions; however, one of the regulating factors is P0 2 . As described by Erecifiska and Wilson (19), "although a fall in oxygen tension does cause a decrease in the rate of ATP synthesis, it does not affect the rate of ATP utilization. However, such a situation leads to an immediate decline in the [ATP]/[ADP][Pi] which induces, through the near equilibrium relations in the first two sites of oxidative phosphorylation, an increase in reduction of cytochrome c and activation of cytochrome c oxidase. The consequent enhancement of respiration proceeds to the point at Which the rate of ATP synthesis'again matches the rate of ATP utilization." Therefore, in contrast to the concept of an "02delivery-independent zone" in Figure 1, Hughson and his

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associates would argue that 02 always regulates the kinetics of V0 2 . The model proposed in Figure 2 also highlights why researchers might have difficulty in detecting the influence of 02 transport on V0 2 kinetics (45). Under conditions of typical intracellular P0 2 the relatively flat surface on the three dimensional plot (e.g., to the right of point I on Fig. 2) will have small, but real, effects on metabolic control compared with the steeper slope (e.g., from points I to 2). On this basis, Hughson and coworkers have proposed that all exercise transitions are in the 02delivery-dependent zone depicted in Figure 1. EVIDENCE FOR AN INTRACELLULAR CONTROL OF V0

2

KINETICS (A. M. JONES)

In this section, evidence against 02 as 'a limitation to VO2 kinetics (with appropriate caveats) and evidencefor an intracellular control of 1VO 2 kinetics will be reviewed. The important influence of muscle fiber type and motor unit recruitment profiles in determining the characteristics of the7 V0 2 response to exercise will also be highlighted. There is no question that muscle 02 availability has the potential to influence metabolic control: as can be seen from equation 1, if mitochondrial 02 supply is truly insufficient, the rate of oxidative metabolism will be restricted, and this will be manifest as slower VO2 kinetics across a metabolic transient. 6ADP+6Pi+2(NADH+H

4

)+ O2---6ATP+2NAD+2H2 O l1]

While cellular metabolic adjustments can occur to maintain ATP flux rate in the face of falling P0 2 (91,92), muscle 02 supply can only be considered "limiting" if V0 2 kinetics are demonstrably impaired. There are a number of situations in which muscle 02 availability might be considered to be among the factors responsible for relatively slow v'O2 kinetics: for example, during exercise where the muscle

perfusion pressure is reduced (supine and prone leg exercise; arm exercise performed above the level of the heart (44,46)), muscle 02 supply is deliberately restricted (ischemia, hypoxia, )3-blockade (18,39)), and in older age

and a variety of disease conditions (chronic heart failure, peripheral vascular disease, diabetes (70,71)). These situations would clearly lie in the 02 delivery-dependent zone shown in Figure 1. However, the contention in this section of this review is that muscle 02 delivery does not limit V"02 kinetics during most normal forms of exercise (i.e., those in which the heart is positioned above the bulk of the working muscle mass such as in running, cycling, and rowing) in most normal healthy, physically active people below the age of approximately 50 yr, and even when the exercise intensity is high (> 80% of the V0 2 ma,). The first line of evidence against 02 as a limitation to "V10 2 kinetics under the conditions described above is that bulk muscle blood flow kinetics (and thus the kinetics of muscle 02 delivery) are almost always faster than muscle VO2 kinetics during low- as well as high-intensity exercise (4,30,63). It is difficult to envisage a situation in which the

CONTROL OF OXYGEN UPTAKE DURING EXERCISE

kinetics of a relatively slow physiological process can be limited by a faster one, unless, of course, there are substantial 0 2 -distribution heterogeneities across the recruited muscle(s). Also, although experimental interventions that might be expected to reduce muscle 02 supply during upright exercise in healthy subjects have the potential to slow V02 kinetics, this is not consistently the case: following blood withdrawal (13), hemodilution (7), and with the application of lower-body positive pressure (90), V02 kinetics are not significantly altered. The fact that compensatory adjustments can apparently be made to maintain adequate muscle 02 supply in these circumstances indicates that the exercise must be located some distance to the right of the tipping point in Figure 1. In any case, "proof" that muscle 02 delivery is limiting in these conditions requires that V02 kinetics are speeded when 02 supply is increased-evidence that is almost completely absent. Classic studies'by Grassi and colleagues in the isolated in situ canine gastrocnemius preparation have shown that setting muscle blood flow at the required steady-state level across a metabolic transient does'not alter muscle V•O 2 kinetics at 60% V022m.,, (24) and that it only barely does so at 100% V0 2max (22,23). Moreover, enhancing the potential for muscle 02 diffusion through a combination of pump perfusion, hyperoxia, and administration of a drug to right-shift the HbO2 dissociation curve, had no further effect on V0 2 kinetics (25). Similarly, in humans, improving the potential for increased muscle 02 availability through administration of recombinant human erythropoietin (89), or having subjects inspire a hyperoxic gas mixture (62,86), does not speed phase II pulmonary V0 2 kinetics, even during high-intensity exercise. If muscle were really lacking 02 in these conditions, it is difficult to appreciate how it would not avail itself of the increased 02 afforded by these interventions. One intervention that has received considerable attention with regard to its effect on the kinetics of 'O2 is that of prior high-intensity ("priming") exercise. In situations where muscle 02 supply might be expected to be limiting in the control condition (e.g., during arm exercise or leg exercise performed in the supine position, and in senescent or sedentary/unfit subjects), there is some evidence that the performance of prior exercise, which will increase muscle vasodilatation and right-shift the HbO 2 dissociation curve, is associated with a speeding of the phase II V0 2 kinetics (21,47,58,80). During upright cycle exercise in young healthy subjects, however, the overwhelming majority of studies (21 out of 22 at the time of writing) have reported that the performance .of prior exercise does not speed the phase Bl V0 2 kinetics during subsequent high-intensity exercise (12). Rather, the principal effect of prior exercise seems to be to reduce the magnitude of the so-called ,02 slow component, which is characteristic of exercise performed above the lactate threshold (LT or GET), and thus to bring the overall V'02 response back toward a monoexponential profile (11,12) (Fig. 3). Although these data do not

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FIGURE 3-Influence of prior high-intensity (priming) cycle exercise on pulmonary V02 kinetics during subsequent high-intensity cycle exercise in a representative subject from the study of Burnley et al. (11). Closedsymbols represent responses during the first exercise bout, and open symbols represent responses during the second exercise bout. The top panel demonstrates that the kinetics of the V0 2 response were faster overall in the second (primed) bout.However, the time constant describing the adaptation of V0 2 during phase H of the response was similar in the first and second bouts (bout I T: 22 s; bout 2 r: 25 s). The facilitated 402 response in the second bout therefore resulted from an increased amplitude of the primary or fundamental component and a reduced amplitude of the slow component. The close correspondence of the VO kinetics in phase II is underlined in the middle panel, in which the VO0 responses in the two bouts are normalized to the amplitude of the primary response. The bottom panel shows the mean integrated electromyogram response of four lower-limb muscles during the first and second exercise bouts.'The proffles in the first and second bouts mirror those for VOz suggesting that (changes in) motor unit recruitment might be mechanistically associated with the (altered) V02 responses.

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rule out a possible role for (regional) muscle 02 insufficiency in the development of the V02 slow component, they do suggest that the fundamental response of 402 across a metabolic transient is principally regulated by factors more proximal to the contracting muscle. Similarly, the performance of prior exercise has not been found to alter the phase 1[ /02 -kinetics during subsequent moderateintensity exercise (12), although, interestingly, there are two recent exceptions to this finding (33,34). It should be noted, however, that any observation of a speeding of the phase HI •02 kinetics following prior exercise can never be attributed solely to enhanced muscle 02 supply, because numerous muscle metabolic and other factors will also be altered by the intervention (12,33). Mitochondrial respiration is intimately linked to the rate of muscle ATP hydrolysis, and one or more of the reactants of this process (e.g., [ADP], [Pi], phosphorylation potential, and/or [PCr] and [Cr]) is/are thought to activate oxidative phosphorylation through feedback control. Rossiter et al. (77-79) have provided evidence consistent with this theory by demonstrating close agreement between muscle [PCr] kinetics (as estimated using 3 1P-MRS techniques) and pulmonary 4102 kinetics during both moderate- and heavy-intensity exercise. Moreover, Kindig et al. (52) report that acute inhibition of creatine kinase (CK) in isolated Xenopus myocytes led to significantly faster intracellular P0 2 kinetics (equivalent to faster V02 kinetics in this model). These data indicate that the CK reaction buffers changes in [ADP] across a metabolic transient, thus attenuating one of the principal signals responsible for an acceleration of oxidative phosphorylation. The kinetics of 902 therefore seem to be principally under feedback control through the CK reaction (it is worth noting here that this will also be true even when other limitations to the V02 response, such as 02 availability, are "superimposed" (36)). However, Lit is possible that other factors also contribute to the inertia of muscle oxidative metabolism that is evident in the transition from a lower to a higher work rate. Theoretically, any rate-limiting or fluxgenerating enzyme catalyzing a nonequilibrium reaction might limit the rate of oxidative metabolism. Pharmacological activation of pyruvate dehydrogenase with dichloroacetate (DCA) reduces substrate-level phosphorylation during subsequent exercise, suggesting an enhancement of the contribution of oxidative phosphorylation to energy turnover (32). Although to date this intervention has not been shown to speed muscle or pulmonary V0 2 kinetics, there are suggestions that muscle efficiency might be improved with DCA, thus reducing the amplitudes of the fundamental and/or slow components of 402 and reducing the magnitude of the 02 deficit (26,48,79). Another possible limitation to the dynamics of V02 is the potentially pernicious influence of nitric oxide (NO) on mitochondrial function. In addition to its well-known role in the regulation of muscle vasodilatation, NO has the potential to inhibit several mitochondrial enzymes and to compete with 02 for

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the binding site at cytochrome c oxidase (9). Recent studies in horses (54) and in humans (50,87) have shown that inhibition of NO synthesis with L-NAME results in a significant speeding of phase II 402 kinetics. The effect, at least in humans, seems to be greatest at higher work rates, suggesting that it might be especially pronounced in type 1I muscle fibers (87); if so, this might also explain'why a speeding of V02 kinetics was not observed following L-NAME administration in isolated canine muscle known to have a high percentage of type I fibers (23). As mentioned earlier, NO also plays an important role in muscle vasodilatation, and thus the inhibition of NO synthesis might impair muscle blood flow. The speeding of phase HI VO2 kinetics with L-NAME therefore potentially provides simultaneous evidence for an NO-linked muscle metabolic limitation to V02 kinetics and against an important role for 02 supply, at least under the conditions of these studies. There is often a tendency for phase II V02 kinetics to' become slower at higher work rates, especially those that are above the LT (70). Although this has been attributed to an (increasing) muscle 0 2 -delivery limitation by some authors (40), another explanation is that the slower overall V02 kinetics reflect the increasing contribution of muscle fibers that are higher in the recruitment hierarchy (i.e., type TI fibers) to force production. There is evidence to suggest that these higher-order fibers -might have slower V0 2 kinetics (and also lower efficiency) relative to earlierrecruited fibers (49,59,65). Alterations in motor unit recruitment might underpin the reduced •02 slow component (and faster overall 402 kinetics) observed for the same work rate following interventions such as endurance training, hyperoxic gas breathing, and priming exercise (49) (Fig. 3), as well as the greater 402 slow component observed for the same work rate following glycogen depletion of the type I muscle fiber population (59). When exercise is initiated from a higher compared with a lower baseline metabolic rate, markedly slower phase II 402 kinetics and a higher 402 response gain are typically reported (8,43,88). Again, these observations are consistent with the metabolic responses that would be expected when a population of higher-order fibers is recruited to meet the augmented muscle force-production requirements, and they are not necessarily indicative of any impairment in muscle 02 delivery. It should be acknowledged, however, that these two effects might not be mutually exclusive (6,49,65). BALANCING 02 SUPPLY AND DEMAND AT THE CAPILLARY (T. J. BARSTOW) Insight into the factors that determine the rate of rise in muscle oxygen uptake (C'M2m) following exercise onset ultimately requires assessment of this process where it is actually occurring, that is, at the capillary/myocyte interface. However, with the exception of isolated muscle/ capillary network preparations (5), which allow for mea-

CONTROL OF OXYGEN UPTAKE DURING EXERCISE

surements of intracapillary oxygen tension profiles and time course of r6d blood cell flux, observations have been limited to those made distant from the capillary bed (e.g., blood flow and oxygen extraction measured across an exercising muscle or limb (4,24,25)). The first two sections of this review elegantly summarized our understanding of the controlling features of V0 2m based primarily on findings from distant sites (conduit artery, lungs, etc.). However, we sought a methodology that would allow us to "observe" capillary gas exchange noninvasively in human skeletal muscle during exercise, in a somewhat analogous manner to the direct observations of microvascular P0% (PmvO2) in isolated muscles (5). Near-infrared spectroscopy (NIRS) noninvasively measures oxygenated and deoxygenated (HI-Ib) forms of hemol globin + myoglobin (Hb + Mb) in the microcirculation and myocytes of muscle tissue. As such, HHb has been used to estimate fractional 02 extraction within the microcirculation (15,20,29). Using technology that provides either an approximation (15,29) or an absolute concentration (20), the response of HHb demonstrates a similar pattern following exercise onset: there is a period of 5-10 s of no change, followed by a second phase of rapid increase (average time constants ranged from 6-10 s) to a third, relatively constant plateau (Fig. 4 middle panel). The initial period of relatively constant HHb, similar to that observed in microvascular P0 2 in isolated muscle (5), coupled with the observation that •0 2m begins to rise immediately with exercise onset with no apparent time delay (53,70), implies that during the first few seconds after exercise onset, oxygen delivery (QO2) is precisely matched to the rising V0 2m, such that fractional 02 extraction remains constant (dashed arrows in Fig. 4). Whether this matching is fortuitous or the result of the integration of muscle pump and/or rapid vasodilatory mechanisms (16,83,84) remains to be elucidated. The rapid increase in HHb during the second phase (Fig. 4, solid arrows) reflects a transient imbalance between VO 2m and Q02, which seems to be restored during the third, plateau; phase (Fig. 4, dotted arrows). The kinetics of adjustment of HHb during this second phase, whether expressed as a tim6 constant or as an MRT (time constant + time delay) are consistently found to be faster than those of phase II pulmonary V02 (15,20,29,33,34), suggesting that HHb per se is not a good surrogate for V0 2m kinetics. The likely reason for this lack of agreement between HHb and V02 kinetics, and the implications for the plateau phase, are discussed below. As noted in the previous sections, the kinetics of adjustment of conduit artery blood flow are either faster than (24,57,63,70) or similar to (27,30) those of V%2 m. Although these data have been used to speak against 02 flow limitation to V0 2 (m) kinetics (i.e., points to the right of the tipping point in Fig. 1), they do not necessarily provide evidence for the lack of an 02 delivery limitation at the level of the microcirculation. Further insights into the underlying integrated responses implied by the HHb

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dynamics have been attained by the development of the ability to estimate the kinetics of capillary blood flow (QCcap) (20). By rearranging the Fick equation, Qcap can be estimated noninvasively as QCcp = V0 2m/(CaO2 - CvO 2 ), assuming that the phase II kinetics of pulmonary 1T0 2 are a good surrogate for V0 2m (30,77) and that the deoxy (Hb + Mb) signal (HHb) from NIRS is proportional to (CaO 2 - CvO 2) (15,20,29,35). Based on these assumptions, the following results have been observed: 1) for both cycling (20) and knee extension exercise (35), the estimated Ocar kinetics are biphasic, reflecting an initial rapid rise to plateau during the first 10-15 s, followed by a slower exponential rise to a steady-state level for moderate exercise

(Fig. 4, lower panel). This biphasic nature of the Q-p kinetics is similar to that observed in capillaries of isolated rat spinotrapezius muscle (55) and in conduit arteries (74,81), which reinforces the appropriateness of the NIRS approach to estimate QLIp. 2) The kinetics of conduit (femoral) artery blood flow are significantly faster than those of Qc,p (35). This finding has significant implications for both the control, and initial distribution, of limb/muscle blood flow following exercise onset. First, they suggest that measurement of blood flow kinetics in the conduit artery upstream of the contracting muscle(s) may not reflect the kinetics of red blood cell flux in the microcirculation where gas exchange is occurring. Second, the apparent disparity between conduit artery kinetics (faster) and capillary kinetics (relatively slower) suggests that control of the distribution of flow within the contracting limb/muscle is an important factor in determining the kinetics of capillary RBC flux. 3) The overall kinetics of Q).p were either similar to (cycling (20)) or slower than (knee extension (35)) those of •V02m. These latter two findings suggest the following scenario: immediately on initiation of muscle contractions, conduit artery and capillary blood flow increase in concert with the rising 4 0 2 m. At the level of the capillaries, this increased flow matches VO 2m, such that HHb changes little. Within a few seconds, this initial blood flow response begins to plateau, necessitating an increase in 02 extraction to sustain the rising V0 2m. Within a few more seconds, the blood flow response is again coupled to the V0 2 m, and HIHb becomes relatively constant. The overall kinetics (as mean response time MRT) of QCp are similar to those of VO,2m (20,35) and imply that there may not be as much of a reserve of 02 delivery as has been intuited by the generally faster kinetics observed in conduit arteries (i.e., even in healthy subjects performing moderate exercise, the relationship is closer to the tipping point in Figure 1 than previously thought). Further, this implies that disease processes such as diabetes or peripheral arterial disease might not need to dramatically slow 02 delivery in order to have a pernicious effect on VO 2m kinetics. This coupling of blood flow to the rising'v10 2m is impressive, and it suggests a heretofore unappreciated dynamic integration between •10 2m and blood flow. While the precise mechanism(s) remain to be elucidated, one likely candidate is some form of oxygen sensing within the microcirculation (10), which could be effected through the release of nitric oxide (NO) from S-nitrosohemoglobin as oxygen partial pressure falls in the capillaries (1). It should be noted here that the increase in HHb (as fractional 02 extraction, or the fall in microvascular P0 2) with exercise, either transiently or in the steady state, is not an obligatory sign of an inadequate blood flow response (15,51). Rather, the increase in HHb with increasing metabolic rate is predicted by the positive intercept of the blood flow/V0 2 relationship, as observed across the entire body (as cardiac output and pulmonary VTO 2), exercising

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FIGURE 4-Data showing both the derivation of capillary blood flow (Qc,p) and the underlying phenomena for the response of deoxy (Bb + Mb) (HHb) for the transition from light to moderate exercise. "The upper panel is estimated muscle VO2 (VO 2 m), derived from the phase II kinetics of pulmonary 1i'O2. The middle panel shows the measured response of HHb, and the bottom panel is the resulting calculated 0Q,p (as VO2 m/HHb). Following exercise onset, there is a period of 5-10 s, during which time HHb remains relatively constant (dashedarrows). Given that ,'Oý 2 m is rising exponentially with little or no delay, this implies that Q.p rises in proportion to IO 2 m. The rapid increase in HHb during the second phase of the response (solid arrows) suggests that the increase in Q,.p slows down, such that O2 extraction has to increase to facilitate the continued rise in VO 2m. However, in another few seconds, HHb plateaus. Given that this occurs sooner than the steady state for 'O 2 m is attained, this implies that Q..,, continues to increase in a fashion again tightly coupled to the rising VO 2 m. The suggestion is offered that at least during this region, the increase in blood flow may be integrated with the rise in metabolic rate through an oxygen-sensing mechanism, such as the release of NO from hemoglobin as P0 2 falls along the capillary.

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limbs (e.g., femoral artery blood flow and leg V02 (69)), and even individual muscles. BALANCING 02 SUPPLY AND DEMAND ACROSS DIFFERENT FIBER TYPES (P. MCDONOUGH) Up to this point in the review, the methodologies used have not facilitated differentiating, with certainty, the dynamic responses among different fiber types. Thus, when the linear relationship between blood flow (Q) and metabolic rate (VO2) is described for the exercising legs as 0 = (S x V02) + /, where S represents the slope (i.e., 5.3; data from ref. (56)) and I the intercept (i.e., 2.8 L.min- 1 ; data from Knight et al. (56)), the tacit presumption is made that all fibers and microvascular units operate in close proximity to these mean values (69). Moreover, inter-fibertype differences in the dynamics of the increased Q immediately following exercise onset, particularly as this relates to that of V02, have not been explored. It is well established, however, that human leg muscles constitute a mosaic of slow-twitch (type I) and fast-twitch (type II) fibers, which are discriminated by very different vascular (Q) and metabolic (Vf 2) control processes. Understanding the net effect of these control processes is crucial, in part, because it is the instantaneous balance between 02 delivery (QO2) and 402 that determines the microvascular 02 pressure (PmvO2), which, in turn, drives blood-myocyte 02 flux and (via its effect on intracellular P0 2) modulates the intracellular energy state (3,38,65,91,92). Investigations in animals at rest and during exercise indicate that there is a pronounced heterogeneity of Q among different muscles and fiber types (2,68,72). This spatial stratification of Q is likely attributable to those mechanisms that control arteriolar vasodilation across the different fiber types. Specifically, endothelial nitric oxide synthase mRNA expression, as well as sensitivity and maximal responsiveness to endothelium-dependent vasodilation, is far greater in arterioles from slow- compared with fast-twitch muscles (17,93,94). Moreover, first-order arterioles from fast-twitch muscles elicit a higher sensitivitythat is, a greater vasoconstriction to noradrenaline (16). From these observations, it wouild be predicted that contraction-induced hyperemia would be exacerbated in muscles comprising slow-twitch, highly oxidative fibers. Whether this impacts the PmvO 2 depends, of course, on the relationship between any augmentation of the Q response with that of 4fO2.. For example, if Q dynamics are speeded equivalently with those of V02, the PmvO 2 profile would remain unchanged. The same could be said for the steadystate response if the contracting absolute 0 and 402 are not different. Based on the above considerations, Behnke et al. (6) and McDonough et al. (65) judiciously selected rat hindlimb muscles for their fiber-type content to test the hypothesis that, following the onset of contractions, the exercising 9 response would be faster and more robust

CONTROL OF OXYGEN UPTAKE DURING EXERCISE

(i.e., quantitatively greater), compared with that of V02, in slow- compared with fast-twitch muscles. The prediction, therefore, was that following the onset of contractions, PmvO 2 would fall faster and farther (i.e., to lower steadystate contracting values) in the fast-twitch gastrocnemius (65) and peroneal (6) muscles than the slow-twitch soleus. As clearly depicted in Figure 5 for the soleus and mixed and white portions of the gastrocnemius, these predictions were borne out. In the soleus muscle, the Q response was sufficiently vigorous that PmvO2 remained close to resting values for approximately 15-30 s before falling exponentially with a time constant of 25-30 s to steady state at 20 mm Hg. In contrast, PmvO 2 in the fast-twitch mixed and white gastrocnemius plummeted immediately (time delay, 5-9 s; time constant, 6-11 s) following the onset of contractions to steady state at approximately 10 mm Jig, which was only half that found in the soleus. In addition, in the nonsteady state, gastrocnemius PmvO2 actually fell ,below that seen in the subsequent steady state. These responses are symptomatic of a relatively parsimonious Q0 2-to-,O 2 in fast-twitch compared with slow-twitch muscles. An additional interesting feature of the slow- versus fasttwitch fiber dichotomy was evidenced when these same muscles were compared during the steady state of low- and high-intensity contractions. Moving from the lower to higher intensity, the soleus increased its V02 predominantly by increasing !, whereas thegastrocnemius, in the face of a relatively small increase of Q at the higher intensity, increased fractional 02 extraction through an elevation of its diffusional 02 conductance (D0 2). Thus, while transitioning from contractions of low to higher intensity, when 30 25 E 20

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Time (s) FIGURE 5--Microvascular O partial pressure (PmvO 2) response for rat soleus (sol, slow twitch), as well as mixed (MG, fast twitch) and white gastrocnemius (WG, fast twitch) following the onset of 1-Hz contractions. Thin lines, real data; thick lines, model fits. Note the longer time delay, slower subsequent fall, and higher steady-state PmvO for sol than for MG or WG. Also note the biphasic response of PmvO2 in MG and WG that temporarily reaches PmvO2 values below the subsequent steady state. This figure supports the contention that 02 delivery may he limiting 02 kinetics in fast-twitch (MG, WG) but not slow-twitch (sol) muscles. Reproduced from McDonough et,al. (65), with permission.

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the soleus increased DO 2 by only 30%, the gastrocnemius increased it by 60% (white) to 120% (mixed), and this accounted for a further fall in steady-state PmvO2 in the mixed gastrocnemius (65). The first time that PmvO2 was measured in muscle following the onset of contractions, Behnke and colleagues (5) hypothesized that, if 02 delivery (Q02) were limiting, PmvO2 would be expected to fall precipitously at exercise onset. Furthermore, PmvO 2 should fall transiently below steady-state levels reflecting the lag in the hyperemic response prior to achieving steady-state values commensurate with the exercise intensity. These features of the response were not found in the spinotrapezius, which is a specialized postural muscle of mixed fiber type (5). However, they are clearly evident in the mixed and white gastrocnemius shown in Figure 5, but not in the slow-twitch soleus. These observations suggest that, if the exercise bout is sufficiently intense that it recruits a mosaic of slow-and fast-twitch fibers, the latter may be 0 2-delivery limited (ascending limb of Fig. 1). Moreover, for those fast-twitch fibers or muscle portions in which PmvO 2 has reached very low levels, blood-myocyte 02 diffusion may be compromised, and thus 4V02 kinetics may be slowed. This increasing recruitment of fast-twitch fibers likely explains the reduced gain of the primary component ofV4O2 kinetics as well as the overall slowing (i.e., presence of a slow component that prolongs the MRT) observed at higher exercise intensities (70). Moreover, it may also help explain how different interventions such as hyperoxia (62) and priming exercise (11,12) (as discussed above in Evidence for an intracellulaicontrol of A'02 kinetics) may modulate V02 kinetics if they either reduce the proportional recruitment of fast-twitch fibers or, alternatively, improve 02 delivery to those fibers at the onset of exercise. Accepting that lower PnivO2 is indicative of a reduced intracellular P0 2 (65), one fascinating consideration that arises from the differential PmvO 2 profiles observed between fiber types is that one locus of control for the energetic response of the myocyte is moved further upstream from the myocytes themselves-at least for fast-twitch fibers. Historically, the metabolic potentials of the different fiber types have not only helped categorize them into oxidative and glycolytic subpopulations, but their metabolic' potentials also have been invoked to explain their reliance on oxidative versus substrate-level phosphorylation when activated. Given the recent findings presented herein, the possibility must be acknowledged that arteriolar vasodilation as it affects the Q0 2-to-VO2 balance dictates the PmvO 2 and, hence, directly influences the intracellular P0 2 (65). In turn, that intracellular P0 2 dictates the energy charge and modulates the degree of metabolic perturbation (A[ADP]free, A[PCr], A[Pi]) necessary to generate the required ATP (3,38,91,92). In addition to the implications for understanding exercise and muscle energetics in health, these findings may explain some of the perturbations characteristic of major diseases.

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For example, type II diabetes slows V0 2 kinetics following the onset of exercise and compromises exercise tolerance (67,71). There are at least two plausible mechanistic bases for these effects based on the differential regulation of PmvO 2 demonstrated herein: 1) the diabetes-induced lowering of slow-twitch fiber oxidative capacity will force recruitment of a greater population of fast-twitch fibers with their lower PmvO 2 and the energetic consequences of such (i.e., IA[ADP]free, IA[PCr], TA[Pil), and 2) impaired arteriolar vasodilation consequent to decreased bioavailability of nitric oxide and elevated plasma endothelin-1 concentrations, for example, will reduce Pmv0 2 in slowtwitch muscles, thereby modulating their cellular energetics toward those of their fast-twitch counterparts. Both these mechanisms would be expected to slow V02 kinetics, increase the 02 deficit incurred, and exacerbate substratelevel phosphorylation. From the above, it may not be sufficient to characterize a given bout of "exercise" as simply lying to the left or right of the tipping point (i.e., Q02 limited, or not; Fig. 1). Rather, unless the exercise is of a type and intensity that solely recruits slow-twitch fibers (e.g., in the moderateintensity domain), there may be discrete populations of fibers operating concomitantly on the right (slow-twitch, non-0 2-delivery limited) and left (fast-twitch, Q02 limited) of the tipping point. Exercise conditions (e.g., inspired hypoxia/hyperoxia) or diseases (e.g., diabetes, heart failure) that either change the Q02 (and PmvO 2) of a muscle fiber(s) or the fiber type recruitment profile will modify the balance of that exercise with respect to the tipping point. OVERALL CONCLUSIONS Although 02 has the potential to "regulate" metabolic control, it is clear from the above that agreement is still lacking regarding the role of, and conditions under which, muscle 02 delivery "limits" V02 kinetics. Hughson (40) proposes that V02 kinetics is always dependent on 02 delivery--that is, that P0 2 interacts with the cellular redox and phosphorylation potentials to ensure an appropriate ATP flux rate-but that the resolution of available experimental techniques is not always sufficient to enable alterations in VO2 response profiles to be detected. The work of Hughson (40) (Fig. 2) therefore rejects the notion, implicit in Figure 1, that there are both 0 2-deliverydependent and 0 2-delivery-independent zones. The counterpoint position championed by A. M. Jones in the Evidence for an intracellular control of 1ý0 2 section espouses the view that muscle 02 delivery cannot be considered to be definitively "limiting" unless V02 kinetics can be measurably speeded following removal of the putative restriction. Specifically, there is compelling evidence that 02 delivery does not limit the speed of 02 kinetics during rhythmic leg exercise such as cycling or running in young healthy individuals: experimental

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interventions designed to either reduce or enhance muscle 02 delivery have no discernible effect on the time constant of the phase 1I VO2 response, even during high-intensity exercise (70-100% V02max (7,11,13,86,89)), suggesting that exercise of this type lies some distance to the right of the tipping point portrayed in Figure 1. With respect to this issue, heavy priming exercise is an intervention that may facilitate both intracellular metabolic processes. and enhanced muscle 02 delivery. And, whereas the overwhelming majority of evidence demonstrates that priming exercise does not speed the primary component of the •02 kinetics (12), two recent studies have shown a positive, result, particularly in subjects with lower fitness levels (33,34). This priming exercise-induced speeding of the •02 kinetics occurred concomitantly with an elevated pyruvate dehydrogenase activation (33), suggesting a role for reduced "metabolic inertia" in this response. In other populations (the elderly, diseased, or unfit), and in exercise modes in which muscle perfusion pressure is compromised, V02 kinetics might indeed be limited, in part, by an 02supply limitation, because, in these conditions, interventions that would be expected to alter muscle 02 delivery very often also alter the 402 kinetics (70). Although these viewpoints might seem polarized, they are not necessarily irreconcilable. T. J. Barstow's novel application of near-infrared spectroscopy technology yields the surprising conclusion that whereas the dynamics of muscle or limb blood flow may be much faster than 02 kinetics (15,16,57,84), those of capillary blood flow may not be. The logical interpretation of this finding is that even at moderate exercise intensities, muscles may operate precariously close to the tipping point. Hence, the pemicious effects of disease on '02 kinetics may arise from only a minor impediment to the normal hyperemic control processes, or, possibly, from a pathologically induced shift in fiber type recruitment toward more fast-twitch fibers. In this latter regard, P. McDonough's demonstration of different 02 supply-to-V0 2 relationships in muscles predominantly comprising fast-twitch or slow-twitch fibers leads to the conclusion that the operating position on Figure 1 is governed by the relative recruitment of these different fiber types. Moreover, the finding of extremely low 02 levels in microvessels supplying fast-twitch fibers suggests that their metabolic behavior may be dictated by upstream

hyperemic control processes to a heretofore unappreciated degree. Both A. M. Jones and P. McDonough suggest that the slower 402 kinetics that are sometimes observed at higher exercise intensities might relate to the recruitment of higherorder (fast-twitch) muscle fibers. These fibers have 02 supply-to-Vi 2 relationships which make it more likely that at least some fibers will be operating to the left Of the tipping point, where increased or decreased muscle 02 delivery would serve to speed or slow the overall V02 kinetics, respectively. Moreover, the often-profound slowing of V0 2 kinetics observed in various disease conditions, and the effects observed with, interventions such as endurance training, priming exercise, and hyperoxia, might be related, at least in part, to effects on muscle fiber type and/or fiber recruitment profiles and the associated alteration to the 02 supply-to-VO 2 relationships. Interestingly, this hypothesis is in keeping with Figure 1, and yet it does not conflict with the predictions of the model proposed by Hughson (40) (Fig. 2) or with the data presented by T. J. Barstow. Taking endurance training as an example, the increased mitochondrial density in all fiber types might be expected to delay and/or reduce the recruitment of type H muscle fibers (A.M.J. and P.M.), to maintain P0 2 at a higher level and thus reduce the fall in cell energy state (40) (Fig. 2), and, perhaps, to enhance the distribution of blood flow to cells with higher metabolic activity, such that capillary blood flow kinetics are less likely to limit muscle •02 kinetics (T.J.B.). Therefore, although the role of 02 as a limitation to 402 kinetics remains controversial and certainly complex, the application of new technologies and experimental techniques is already beginning to reconcile apparently disparate positions and is helping to unravel the secrets of metabolic control in health and disease. The authors gratefully acknowledge the role of the National Institutes of Health (HL-50306), the American, Heart Association, Heartland Affiliate, and the American College of Sports Medicine, without whose generous support this work would not have been

possible. Special thanks are accorded Professors Scott K. Powers, George A. Brooks, and Timothy I. Musch for their encouraging and facilitating the presentation of this symposium at the ACSM Integrative Physiology of Exercise meeting held in Indianapolis, IN,

in September 2006. Professor Richard L. Hughson presented in the Indianapolis symposium and was an integral part of the preliminary

drafts of this paper. Unfortunately, he chose to withdraw from authorship before publication.

REFERENCES 1. Allen BW, Piantadosi CA. How do red blood cells cause hypoxic

Muscle oxygen kinetics at onset of intense dynamic exercise in

vasodilation? The SNO-hemoglobin paradigm. Am J Physiol Heart Circ PhysioL 2006;291 :H 1507-12. 2. Armstrong RB, Laughlin MH. Blood flows within and among rat muscles as a function of time during high speed treadmill exercise. J PhysioL 1983;344:189-208. 31 Arthur PG, Hogan MC, Bebout DE, Wagner PD, Hochachka PW. Modeling the effects of hypoxia on ATP turnover in exercising

humans. Am J Physiol Regul lntegr Comp PhysioL 2000;279:

muscle. J Appl PhysioL 1992;73:737-42.

4. Bangsbo J, Krustrup P, Gonzalez-Alonso J, Boushel R, Saltin B.

CONTROL OF OXYGEN UPTAKE DURING EXERCISE

R899-906. 5. Behnke BJ, Kindig CA, Musch TI, Koga S, Poole DC. Dynamics

of muscle microvascular oxygen pressure across the rest-exeicise transition. Respir PhysioL 2001;126:53-63. 6. Behnke BJ, McDonough P, Padilla DJ, Musch TI, Poole DC. Oxygen exchange profile in muscles of contrasting fibre types. JPhysiol (Lond) 2003;549:597-605. 7. Berger NJ, Campbell IT, Wilkerson DP, Jones AM. Influence of

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IN

acute plasma volume expansion onw02 kinetics, VO 2peak, and performance during high-intensity cycle exercise. JAppl PhysioL 2006;101:707-14. 8. Brittain CJ, Rossiter HB, Kowalchuk JM, Whipp BJ. Effect of prior metabolic rate on the kinetics of oxygen uptake during moderate-intensity exercise. Eur JAppl PhysioL 2001 ;86:125-34. 9. Brown GC. Nitric oxide and mitochondria. FrontBiosci.2007;12: 1024-33. 10. Buehler PW, Alayash Al. Oxygen sensing in the circulation: "cross talk" between red blood cells and the vasculature. Antioxid Redox Signal 2004;6:1000-10. 11. Burnley M, Doust JH, Ball D, Jones AM. Effects of prior heavy exercise on 402 kinetics during heavy exercise are related to changes in muscle activity. J Appl PhysioL 2002;93:167-74. 12. Bumley M, Koppo K, Jones AM. 'Priming exercise' and 402 kinetics. In: Jones AM, Poole DC, editors. Oxygen Uptake Kinetics in Sport, Exercise andMedicine. London (UK): Routledge; 2005. p. 230-60. 13. Burnley M, Roberts CL, Thatcher R, Doust JH, Jones AM. Influence of blood donation on 02 uptake on-kinetics, peak 02 uptake and time to exhaustion during severe-intensity cycle exercise in humans. Exp PhysioL 2006;91:499-509. 14. Connett RI, Honig CR, Gayeski TEJ, Brooks GA. Defining hypoxia: a systems view of 402, glycolysis, energetics, and intracellular P0 2 .JAppl PhysioL 1990;68:833-42. 15. DeLorey DS, Kowalchuk JM, Paterson DH. Relationship between pulmonary 02 uptake kinetics and muscle deoxygenation during moderate-intensity exercise. JAppi Physiol. 2003;95:113-20. 16. Delp MD. Control of skeletal muscle perfusion at the onset of dynamic exercise. Med Sci Sports Exerc. 1999;31(7):1011-8. 17. Delp MD, Colleran PN, Wilkerson MK, McCurdy MR., MullerDelp J. Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity. Am JPhysiol. 2000;278-H1866-73. 18. Engelen M, Porszasz J, Riley M, Wasserman K, Maehara K, Barstow TJ. Effects of hypoxia on 02 uptake and heart rate kinetics during heavy exercise. JAppl Physiol. 1996;81:2500-8. 19. Erecifiska M, Wilson DF. Regulation of cellular energy metabolism. JMembrane Biol. 1982;70:1-14. 20. Ferreira LF, Townsend DK, Lutjemeier BJ, Barstow TJ. Muscle capillary blood flow kinetics estimated from pulmonary 02 uptake and near-infrared spectroscopy. JAppi PhysioL 2005;98: 1820-8. 21. Fukuba Y, Ohe Y, Miura A, et al. Dissociation between the time courses of femoral artery blood flow and pulmonary V02 during repeated bouts of heavy knee extension exercise in humans. Exp PhysioL 2004;89:243-53. 22. Grassi B. Skeletal muscle 402 on-kinetics: set by 02 delivery or by 02 utilization? New insights into an old issue. Med Sci Sports Exerc. 2000;32(l):108-16. 23. Grassi B. Limitation of skeletal muscle 402 kinetics by inertia of cellular respiration. In: Jones AM, Poole DC, editors. Oxygen Uptake Kinetics in Sport, Exercise and Medicine. London (UK): Routledge; 2005. p. 212-29. 24. Grassi B, Gladden LB, Samaja M, Stary CM, Hogan MC. Faster adjustment of 02 delivery does not affect V02 on-kinetics in isolated in situ canine muscle. JApplPhysioL 1998;85:1394-403. 25. Grassi B, Gladden LB, Stary CM, Wagner PD, Hogan MC. Peripheral 02 diffusion does not affect V0 2 on-kinetics in isolated in situ canine muscle. JAppl PhysioL 1998;85:1404-12. 26. Grassi B, Hogan MC, Greenhaff PL, et al. Oxygen uptake onkinetics in dog gastrocnemius in situ following activation of pyruvate dehydrogenase by dichloroacetate. J PhysioL 2002;538: 195-207. 27. Grassi B, Hogan MC, Kelley KM, et al. Role of convective 02 delivery in determining 402 on-kinetics in' canine muscle contracting at peak 402. JApp1 Physiol. 2000;89:1293-301.

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Official Joumal of the American College of Sports Medicine

28. Grassi B, Hogan MC, Kelley KM, Howlett RA, Gladden LB. Effects of nitric oxide synthase inhibition by L-NAME on oxygen uptake kinetics in isolated canine muscle in situ. JPhysioL 2005; 568:1021-33. 29. Grassi B, Pogliaghi S, Rampichini S, et al. Muscle oxygenation and pulmonary gas exchange kinetics during cycling exercise ontransitions in humans. JAppl PhysioL 2003;95:149-58. 30. Grassi B, Poole DC, Richardson RS, Knight DR, Erickson BK, Wagner D. Muscle 02 uptake kinetics in humans: implications for metabolic control. JAppl Physiol. 1996;80:988-98. 31. Green HJ, Jones S, Ball-Bumett M, Farrance B, Ranney D. Adaptations in muscle metabolism to prolonged voluntary exercise and training. JAppl PhysioL 1995;78:138-45. 32. Greenhaff PL, Campbell-O'Sullivan SP, Constantin-Teodosiu D, Poucher SM, Roberts PA, Timmons JA. An acetyl group deficit limits mitochondrial ATP production at the onset of exercise. Biochem Soc Trans. 2002;30:275-80. 33. Gurd BJ, Peters SJ, Heigenhauser GJ, et al. Prior heavy exercise elevates pyruvate dehydrogenase activity and speeds 02 uptake kinetics during subsequent moderate-intensity exercise in healthy young adults. JPhysioL 2006;577:985-96. 34. Gurd BJ, Sheuermann BW, Paterson DH, Kowalehuk JM. Prior heavy-intensity exercise speeds 402 kinetics during moderateintensity exercise in young adults. J Appi PhysioL 2005;98: 1371-8. 35. Harper AJ, Ferreira LF, -Lutjemeier BJ, Townsend DK, Barstow TJ. Human femoral artery and estimated muscle capillary blood flow kinetics following the onset of exercise. Exp PhysioL 2006; 91:661-71. 36. Haseler LJ, Kindig CA, Richardson RS, Hogan MC. The role of oxygen in determining phosphocreatine onset kinetics in exercising humans. J Physiol. 2004;558:985-92. 37. Haseler LJ, Richardson RS, Videen JS, Hogan MC. Phosphocreatine hydrolysis during submaximal exercise: the effect of F10 2. JAppl PhystoL 1998;85:1457-63. 38. Hogan MC, Arthur PG, Bebout DE, Hochachka PW, Wagner PD. Role of Oz in regulating tissue respiration in dog muscle working in situ. JAppi PhysioL 1992;73:728-36. 39. Hughson RL. Alterations in the oxygen deficit-oxygen debt relationships with beta adrenergic receptor blockade in man. JPhysioL 1984;349:375-87. 40. Hughson RL. Regulation of 402 on-kinetics by 02 delivery. In: Jones AM, Poole DC, editors. Oxygen Uptake Kinetics in Sport, Exercise andMedicine. London (UK): Routledge; 2005. p. 185-211. 41. Hughson RL, Cochrane JE, Butler GC. Faster 02 uptake kinetics at onset of supine exercise with than without lower body negative pressure. J Appl PhysioL 1993;75:1962-7. 42. Hughson RL, Morrissey MA. Delayed kinetics of respiratory gas exchange in the transition from prior exercise. J Appl PhysioL 1982;52:921-9. 43. Hughson RL, Morrisey MA. Delayed kinetics of 402 in the transition from prior exercise. Evidence for 02 transport limitation of 402 kinetics. A review. Int J Sports Med. 1983;4:31-9. 44. Hughson RL, Shoemaker JK, Tschakovsky ME, Kowalchuk JM. Dependence of muscle 402 on blood flow dynamics at onset of forearm exercise. JAppl Physiol. 1996;81:1619-26. 45. Hughson RL, Tschakovsky ME, Houston ME. Regulation of oxygen consumption at the onset of exercise. Exerc Sport Sci Rev. 2001 ;29(3): 129-33. 46. Hughson RL, Xing HC, Borkhoff C, Butler GC. Kinetics of ventilation and gas exchange during supine and upright cycle exercise. Eur JApplPhysiol Occup PhysioL 1991;63:300-7. 47. Jones AM, Berger NJ, Wilkerson DP, Roberts CL. Effects of "priming" exercise on pulmonary 02 uptake and muscle deoxygenation kinetics during heavy-intensity cycle exercise in the supine and upright positions. JAppi PhysioL 2006;101:1432-41. 48. Jones AM, Koppo K, Wilkerson DP, Wilmshurst S, Campbell IT.

http://www.acsm-msse.org

Dichloroacetate does not speed phase-II pulmonary ý10 2 kinetics following the onset of heavy intensity cycle exercise. Pflugers Arch. 2004;447:867-74. 49. Jones A, Pringle JS, Carter H. Influence of muscle fibre type and motor unit recruitment on V0 2 kinetics. In: Jones AM, Poole DC, editors. Oxygen Uptake Kinetics in Sport, Exercise andMedicine. London (UK): Routledge; 2005. p. 261-93. 50. Jones AM, Wilkerson DP, Koppo K, Wilmshurst S, Campbell IT. Inhibition of nitric oxide synthase by L-NAME speeds phase II pulmonary V0O2 kinetics in the transition to moderate-intensity exercise in man. JPhysiol.2003;552:265-72. 51. Kemp G. Kinetics of muscle oxygen use, oxygen content, and blood flow during exercise. JApp1 PhysioL 2005;99:2463-9. 52. 'Kindig CA, Howlett RA, Stary CM, Walsh B, Hogan MC. Effects of acute creatine kinase inhibition on metabolism and tension development in isolated single myocytes. JAppl Physiol.2005;98: 541-9. 53. Kindig CA, Kelley KM, Howlett RA, Stary CM, Hogan MC. Assessment of 02 uptake dynamics in isolated single skeletal myocytes. JAppl PhysioL 2003;94:353-7. 54. Kindig CA, McDonough P, Erickson HH, Poole DC. Nitric oxide synthase inhibition speeds oxygen uptake kinetics in horses during moderate domain running. Respir Physiol NeurobioL 2002;132: 169-78. 55. Kindig CA, Richardson TE, Poole DC. Skeletal muscle capillary hemodynamics from rest to contractions: implications for oxygen transfer. JAppl Physiol. 2002;92:2513-20. 56. Knight- DR, Poole DC, Schaffartzik W, et al. Relationship between body and leg 90 2 during maximal cycle ergometry. JAppl PhysioL 1992;73:1114-21. 57. Koga S, Poole DC, Shiojiri T, et al. Comparison of oxygen uptake kinetics during knee extension and cycle exercise. Am J Physiol Regul Integr Comp PhysioL 2005;288:R212-20. 58. Koppo K, Bouckaert J. Prior arm exercise speeds the V'O2 kinetics during arm exercise above the heart level. Med Sci Sports Exerc. 2005;37(4):613-9. 59. Krustrup P, Soderlund K, Mohr M, Bangsbo J. Slow-twitch fiber glycogen depletion elevates moderate-exercise fast-twitch fiber activity and 02 uptake. Med Sci Sports Exerc. 2004;36(6): 973-82. 60. Linnarsson D. Dynamics of pulmonary gas exchange and heart rate changes at start and end of exercise. Acta Physiol Scand SuppL 1974;415:1-68. 61. Linnarsson D, Karlsson J, Fagraeus L, Saltin B. Muscle metabolites and oxygen deficit with exercise in hypoxia and hyperoxia. J Appl PhysioL 1974;36:399-402. 62. MacDonald M, Pedersen PK, Hughson RL. Acceleration'of-V02 kinetics in heavy submaximal exercise by hyperoxia and prior high-intensity exercise. J Appl Physiol. 1997;83:1318-25. 63. MacDonald MJ, Shoemaker 3K, Tschakovsky ME, Huglhson RIL. Alveolar oxygen uptake and femoral artery blood flow dynamics in upright and supine leg exercise in humans. J Appl PhysioL 1998;85:1622-8. 64. MacPhee SL, Shoemaker JK, Paterson DH, Kowalehuk JM. Kinetics of 02 uptake, leg blood flow, and muscle deoxygenation are slowed in the upper compared with lower region of the moderate-intensity exercise domain. J Appl Physiol. 2005;99: 1822-34. 65. McDonough P, Behnke BJ, Padilla DJ, Musch TI, Poole DC. Control of microvascular oxygen pressures in muscles comprised of different fibre types. J PhysioL 2005;563:903-13. 66. Murphy PC, Cuervo LA, Hughson RL. Comparison of ramp and step exercise protocols during hypoxic exercise in man. Cardiovasc Res. 1989;23:825-32. 67. Padilla DJ, McDonough P, Behnke BJ, et al. Effects of type II diabetes on muscle microvascular oxygen pressures. Respir Physiol Neurobiol. 2007;156:187-95.

CONTROL OF OXYGEN UPTAKE DURING EXERCISE

68. Piiper J, Pendergast DR, Marconi C, Meyer M, Heisler N, Ceretelli P. Blood flow distribution in dog gastrocnemius muscle at rest and during ýtimulation. J App! PhysioL 1985;58: 2068-74. 69. Poole DC. Influence of exercise training on skeletal muscle oxygen delivery and utilization. In: Crystal RG, West JB, Weibel ER, Barnes PJ, editors. The Lung: Scientific Foundations. New York (NY): Raven Press; 1997. p. 1957-67. 70. Poole DC, Jones AM. Towards an understanding of the mechanistic bases of VO2 kinetics. In: Jones AM, Poole DC, editors. Oxygen Uptake Kinetics in Sport, Exercise and Medicine. London (UK): Routledge; 2005. p. 294-328. 71. Poole DC, Kindig CA, Behnke BJ. V02 kinetics in different disease states. In: Jones AM, Poole DC, editors. Oxygen Uptake Kinetics in Sport, Exercise and Medicine. London: Routledge; 2005. p. 353-72. 72. Poole DC, Sexton WL, Behnke BJ, Ferguson CS, Hageman KS, Musch TI. Respiratory muscle blood flows during physiological and chemical hyperpnea in the rat. J Appl Physiol. 2000;88: 186-94. 73. Pringle JS, Doust JH, Carter H, et al. Oxygen uptake kinetics during moderate, heavy and severe intensity "submaximal" exercise in lhumans: the influence of muscle fibre type and capillarisation. Eur J Appl Physiol. 2003;89:289-300. 74. Radegran G, Saltin B. Muscle blood flow' at onset of dynamic exercise in humans. Am JIPhysiol. 1998;274:H314-22. 75. Richardson RS, Duteil S, Wary C, Wray DW, Hoff J, Carlier PG. Human skeletal muscle intracellular oxygenation: the impact of ambient oxygen availability. J Physiol. 2006;571:415-24. 76. Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, Wagner PD. Myoglobin 02 desaturation during exerciseevidence of limited 02, transport. J Clin Invest. 1995;96:1916-26. 77. Rossiter HB, Ward A, Doyle VL, Howe FA, Griffiths JR, Whipp BJ. Inferences from pulmonary 02 uptake with respect to intramuscular [phosphocreatine] kinetics during moderate exercise in humans. J Physiol. 1999;5 18:921-32. 78. Rossiter HB, Ward SA, Kowalchuk JM, Howe FA, Griffiths JR, Whipp BJ. Dynamic asymmetry of phosphocreatine concentration and 02 uptake between the on- and off-transients of moderate- and high-intensity exercise in humans. J Physiol. 2002;541:991-1002. 79. Rossiter HB, Ward SA, Howe FA, et al. Effects of dichloroacetate on •'02 and intramuscular 31P metabolite kinetics during highintensity exercise in humans'. JApp[PhysioL 2003;95:1105-15. 80. Scheuermann BW, Bell C, Paterson DH, Barstow TJ, Kowalchuk JM. Oxygen uptake kinetics for moderate exercise are speeded in older humans by prior heavy exercise. J Appl Physiol. 2002;92: 609-16. 81. Shoemaker JK, Hughson RL. Adaptation of blood flow during the rest to work transition in humans. Med Sci Sports Exerc. 1999;31(7): 1019-26. 82. Tordi N, Perrey S, Harvey A, Hughson RIL. Oxygen uptake kinetics during two bouts of heavy cycling separated by fatiguing sprint exercise in humans. JAppl Physio!. 2003;94: 533-41. 83. Tschakovsky ME, Hughson RIL. Interaction of factors determining oxygen uptake at the onset of exercise. J-Appl PhysioL 1999;86: 1101-13. 84. Tschakovsky ME, Sheriff DD. Immediate exercise hyperemia: contributions of the muscle pump vs. rapid vasodilation. J Appl Physiol. 2004;97:739-47. 85. Whipp BJ, Mahler M. Dynamics of pulmonary gas exchange during exercise. In: West JB, editor. Pulnonary Gas Exchange, VooL IL New York (NY): Academic Press; 1980. p. 33-96. 86. Wilkerson DP, Berger NJ, Jones AM. Influence of hyperoxia on pulmonary 02 uptake kinetics following the onset of exercise in humans. Respir Physiol NeurobioL 2006; 153:92-1 06. 87. Wilkerson DP, Campbell IT, Jones AM. Influence of nitric oxide

,Medicine & Science in Sports & Exercisev '473

88.

89.

90.

91.

synthase inhibition on pulmonary 02 uptake kinetics during supramaximal exercise in humans. J Physiol. 2004;561:623-35. Wilkerson DP, Jones AM. Influence of initial metabolic rate on pulmonary 02 uptake on-kinetics during severe intensity exercise. Respir PhysiolNeurobiol. 2006;152:204-19. Wilkerson DP, Rittweger J, Berger -NJ, -Naish PF, Jones AM. Influence of recombinant human erythropoietin treatment on pulmonary 02 uptake kinetics during exercise in humans. J Physiol. 2005;568:639-52. Williamson JW, Raven PB, Whipp BJ. Unaltered oxygen uptake kinetics at exercise onset with lower-body positive pressure in humans. Exp PhysioL 1996;81:695-705. Wilson DF, Ericinska M, Drown C, Silver IA. Effect of oxygen tension on cellular energetics. Am JPhysioL 1977;233:C135-40.

474

Official Journal of the American College of Sports Medicine

92. Wilson DF, Rumsey WL. Factors modulating the oxygen dependence of mitochondrial oxidative phosphorylation. Adv Exp Biol Med. 1988;222:121-31. 93. Woodman CR, Shrage WG, Rush JWE, Ray CA, Price EM. Hindlimb unweighting decreases endothelium-dependent dilation and eNOS expression in soleus not gastrocnemius. JAppi PhysioL 2001;91:1091-8. 94. Wunsch SA, Muller-Delp J, Delp MD. Time course of vasodilatory responses in skeletal muscle arteri6les at onset of exercise. Am J Physiol. 2000;279:H1715-23. 95. Yoshida T, Kamiya J, Hishimoto K. Are oxygen uptake kinetics at the onset of exercise speeded up by local metabolic status in active muscle? Eur J Appi Physiol Occup Physiol. 1995;70: 482-6.

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TITLE: Control of Oxygen Uptake during Exercise SOURCE: Med Sci Sports Exercise 40 no3 Mr 2008 The magazine publisher is the copyright holder of this article and it is reproduced with permission. Further reproduction of this article in violation of the copyright is prohibited.