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J Appl Physiol 86: 1101-1113, 1999;
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Vol. 86, Issue 4, 1101-1113, April 1999

INVITED REVIEW
Interaction of factors determining oxygen uptake at the onset of exercise

M. E. Tschakovsky and R. L. Hughson

Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1


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Considerable debate surrounds the issue of whether the rate of adaptation of skeletal muscle O2 consumption (QO2) at the onset of exercise is limited by 1) the inertia of intrinsic cellular metabolic signals and enzyme activation or 2) the availability of O2 to the mitochondria, as determined by an extrinsic inertia of convective and diffusive O2 transport mechanisms. This review critically examines evidence for both hypotheses and clarifies important limitations in the experimental and theoretical approaches to this issue. A review of biochemical evidence suggests that a given respiratory rate is a function of the net drive of phosphorylation potential and redox potential and cellular mitochondrial PO2 (PmitoO2). Changes in both phosphorylation and redox potential are determined by intrinsic metabolic inertia. PmitoO2 is determined by the extrinsic inertia of both convective and diffusive O2 transport mechanisms during the adaptation to exercise and the rate of mitochondrial O2 utilization. In a number of exercise conditions, PmitoO2 appears to be within a range capable of modulating muscle metabolism. Within this context, adjustments in the phosphate energy state of the cell would serve as a cytosolic "transducer," linking ATP consumption with mitochondrial ATP production and, therefore, O2 consumption. The availability of reducing equivalents and O2 would modulate the rate of adaptation of QO2.

muscle energetics; mitochondrial respiration; oxygen delivery; exercise


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THE READJUSTMENT of oxidative phosphorylation to meet the new ATP demand after a step increase in work rate is delayed and follows an approximately exponential time course. Investigations into muscle O2 uptake (QO2) kinetics have sought to confirm one of two hypotheses, namely, whether the rate of increase in oxidative phosphorylation is limited by the adaptation of O2 utilization or O2 transport mechanisms. An O2 utilization limitation reflects a metabolic inertia. This means that the rate of oxidative phosphorylation at any time point during the adaptation to steady state is determined solely by levels of cellular metabolic controllers (3, 14) and/or mitochondrial enzyme activation (44, 92). It implies that mitochondrial PO2 (PmitoO2) in all active muscle fibers at all time points during the adaptation is adequate to support the highest rate of oxidative phosphorylation possible for the current level of metabolic potential. An O2 transport limitation reflects the inertia of O2 delivery to the mitochondria. In this case, at least some of the oxidative metabolic machinery is capable of increasing its utilization of O2 more rapidly if more O2 is made available (53), inferring that PmitoO2 is not saturating in all active muscle fibers at all time points during the adaptation to a steady state.

Numerous experimental approaches have been applied to test these hypotheses in humans. These include:

1) Manipulation of the rate of increase in O2 supply.

2) Comparison of cardiac output kinetics and muscle blood flow kinetics with alveolar O2 uptake (VO2) kinetics.

3) Measurement and comparison of the time constant of changes in potential metabolic controllers with the time constant of VO2 and QO2.

Evidence for the two hypotheses is presented, and important limitations of these experimental and theoretical approaches are clarified. We then review evidence for the independent and interactive effects of cellular metabolic state (redox and phosphorylation potential), enzyme activation, and critical levels of O2 tension in determining cellular respiration. These are then put into the context of the linear, first-order model of respiratory control (41, 71, 74). This model provides a basis for testing the on-transient characteristics of respiratory control and determining the contribution of PmitoO2 as a modulator of mitochondrial respiration. It is proposed that metabolic controllers and O2 availability likely interact to determine QO2 kinetics across a wide range of exercise modalities. The adaptation of aerobic metabolism should be viewed as resulting from the integration of factors that determine the rate of adaptation of the cellular metabolic state, enzyme activation, and mitochondrial O2 supply rather than from the mutually exclusive control by O2 utilization mechanisms or modulation by O2 delivery.

Evidence for Utilization and Transport Limitations to QO2 Kinetics

Early measurements of O2 uptake by Krogh and Lindhard (65) in 1913 indicated an initial rapid adaptation, followed by a continued increase over the next 2-3 min. Berg (10), Henry (41), and Henry and De Moor (42) were among the first to provide quantitative descriptions of the response and observed that the time course of change was generally similar between the adaptation to and the recovery from exercise. Cerretelli and colleagues (16) introduced the term "early blood lactate" to denote the obligatory lactate production associated with a slow VO2 on-response. This concept supports the notion that there is a primary inadequacy of aerobic metabolism to meet the ATP demand at the onset of exercise. Either an O2 transport inertia or a metabolic inertia could account for these findings.

Altered O2 transport. In humans, alterations in the content and PO2 of the arterial blood or the blood flow adaptation have been used to test the hypothesis of an O2 transport limitation to QO2 kinetics. Obviously, to support an O2 transport limitation it would be necessary to show that increased O2 delivery accelerated QO2 kinetics, compared with the "normal" condition. However, it must be recognized that what constitutes the control or "normal" exercise condition is open to debate. Whether QO2 kinetics are accelerated with increases in O2 transport depends on the exercise condition chosen as the control condition. When sea-level (~21% inspired O2), upright cycling exercise is defined as the normal exercising condition, then hypoxia (10-14% inspired O2 is commonly used) slows the VO2 kinetic response (an estimate of QO2) during cycling exercise (68, 77), whereas hyperoxia (>= 60% inspired O2) accelerates the VO2 kinetic response during cycling exercise only at work rates above the ventilatory threshold (Tvent) but not below (57, 68, 69). Similarly, impairment of cardiac output adaptation via beta -blockade (52, 56) and light-to-moderate exercise transition vs. rest-to-light or -moderate exercise transition (24, 58), or reduction of the local arterial perfusion pressure via supine exercise (54, 70) have all resulted in slower VO2 kinetics. In contrast, attempted impairment of muscle blood flow with lower body positive pressure during semi-upright cycling failed to slow VO2 kinetics (99), whereas slightly faster cardiac output kinetics in heart-transplant patients obtained by a preceding exercise bout did not speed up the VO2 kinetics (37). Although this evidence suggests that the adjustment of QO2 can often be impaired with reductions in O2 transport, there is little evidence to suggest that QO2 kinetics can be accelerated, except perhaps at work rates above Tvent. This evidence might lead to the conclusion that O2 transport is not limiting under normal exercise conditions (99). However, this does not preclude a role for an O2 transport limitation under a number of common exercise conditions such as exercise at altitude, athletic activities in which the exercising muscles are not well below heart level, and activities in which the duration of contractions significantly reduced the time allowed for muscle perfusion to occur (e.g., rowing, downhill skiing). If a different exercise mode is used as the control condition, then acceleration of QO2 kinetics relative to the normal condition can be achieved by improving O2 delivery. Lower body negative pressure applied during supine cycling accelerates VO2 kinetics (54), as does leg occlusion added during arm exercise (55), prior heavy exercise (upright cycling exercise is the normal condition here) (34), and improvement of the rate of blood flow adaptation in exercising forearm muscles by positioning the arm below heart level compared with above (60).

All of these studies have inherent limitations in their measurement of actual QO2 uptake kinetics. Typically, cycling exercise QO2 kinetics are estimated from VO2 (i.e., alveolar O2 uptake). The VO2 response is biphasic, with an early increase influenced predominantly by increased pulmonary blood flow and a second phase to steady-state levels additionally influenced by O2-depleted venous blood from the exercising muscle [see Whipp and Ward (98) for review]. Modeling of VO2 and QO2 kinetics during exercise transients (7, 8) and observations of equivalence between phosphocreatine (PCr) kinetics and the time constant of the phase-two VO2 response (4, 13) suggest that this second phase closely represents the dynamics of QO2 across a variety of exercise intensities. Because the second phase is thought to represent the arrival of the O2-depleted blood from the exercising muscle (98), these lines of evidence support the use of the phase-two time constant when evaluating effects on QO2 kinetics under different O2 delivery conditions via measurements of VO2. However, Essfeld et al. (28) have shown that the relationship between VO2 and QO2 kinetics is sensitive to differences between muscle blood flow and QO2 kinetics. Their modeling suggests that VO2 and QO2 kinetics are similar when there is a small difference between the time constants of muscle perfusion and QO2 kinetics, but VO2 estimates of QO2 should be viewed with caution when the adaptation of muscle perfusion differs from QO2.

When QO2 is estimated by using the Fick principle across the vascular bed of a muscle during voluntary exercise, certain limitations must also be recognized. With in situ animal preparations (46), it is possible to isolate the vascular supply and return of the exercising muscle and to ensure activation of all muscle fibers by electrical stimulation. In contrast, for studies of voluntary submaximal exercise in humans, the venous effluent at in vivo venous sampling sites will invariably be a mixture of blood from both exercising and nonexercising tissues because of the heterogeneous nature of motor unit recruitment (95) and vascular supply (10, 87). Therefore, any differences in the relative contribution of nonworking and working muscle venous effluent during different phases of the dynamic adaptation to exercise could introduce error in the estimate of exercising muscle fiber arteriovenous O2 difference [(a-v)DO2].

In their study of blood flow and leg O2 uptake kinetics with upright cycling exercise, Grassi et al. (38) interpreted the transient increase in venous O2 content in the first 0-15 s and the subsequent minimal change in calculated leg VO2 to indicate that O2 delivery was in excess of O2 demand in the initial 15 s of exercise. However, they also acknowledged the potential effect of blood flow heterogeneity in determining the mixed venous O2 content. One contributor to such an effect might be the potentially disproportionate effect of the muscle pump on blood flow distribution initially vs. later in exercise, which may have been a factor in their results. Activation of the muscle pump at exercise onset would serve to increase flow through capillaries adjacent to both active and inactive fibers. Depending on the amount of active muscle mass and the effect on intramuscular pressure of the contractions, early venous effluent may, to a large degree, come from elevated flow past nonactive fibers and, therefore, result in the observation of a transient reduction or lack of increase in (a-v)DO2 measured at a site draining the exercising limb. As exercise progresses, an increase in metabolic vasodilation occurs, effectively "stealing" flow from adjacent capillary modules that are not dilated (10, 87) as part of a feedback regulation. The contribution of venous effluent from venules draining active fibers would be expected to predominate as exercise continues and the measured components of the Fick principle (total limb blood flow and venous effluent O2 content) would be more accurately related to muscle O2 consumption. Indeed, examination of the data from the study of Grassi et al. (38) and Hughson et al. (60) suggests that such an effect is likely. During upright cycling (38) or forearm exercise below heart level (60), where a hydrostatic column on the venous side exists and a muscle pump effect can be observed (29, 93), there is virtually no increase in (a-v)DO2 in the initial 10-15 s of exercise. However, when forearm exercise is performed above heart level, where no muscle pump effect occurs (93), (a-v)DO2 is elevated by 10 s of exercise (60).

An additional concern might be the time delay between the site of O2 extraction and the venous sample site. This delay will vary with blood flow (28, 38) and might pose a problem in determining the temporally appropriate flow for a given measure of O2 extraction. This problem has been partially addressed by Grassi et al. (38), who estimated the venous volume between active muscle and venous sample site and determined that the transit delay in their experiments would be <2.5 s. Hughson et al. (60) performed Fick principle calculations of estimated QO2 kinetics using a 10-s delay between the time of measured arterial inflow and venous blood sampling and found no effect on the estimated time constant of the forearm QO2 kinetics under different rates of flow adaptation. Transit delay should, therefore, account for only a minor portion of the observed delay in O2 consumption.

Cardiac output kinetics and muscle blood flow kinetics vs. estimates of QO2 kinetics. Typically, VO2 time constant (corresponds to the time taken to reach 63% of the amplitude of the response when the latter is monoexponential) estimates of QO2 kinetics during whole body or cycling exercise are in the range of 30-40 s (77, 97-99, 105). The first combined measurements of cardiac output and VO2 kinetics indicated that cardiac output adapted more rapidly (17, 22). Subsequent estimates of cardiac output kinetics in similar exercise conditions confirmed this (23, 27, 105). The kinetics of bulk muscle blood flow are often (27, 70, 79, 90) faster. However, it has been observed by some that blood flow during the second phase of adjustment closely matches the metabolic adaptation (38). These results have been interpreted to indicate that bulk O2 delivery to the exercising muscle is adequate at the onset of exercise to meet the O2 demands of the muscle, since O2 transport appears to reach a steady state before O2 consumption.

However, results obtained when the rate of adaptation of bulk muscle blood flow was altered suggest that bulk O2 transport may not properly represent O2 transport to active muscle fiber mitochondria. When the forearm was being exercised above heart level (60) or leg-kicking exercise was performed with the subjects in the supine position (70), blood flow kinetics were consistently faster than VO2 kinetics. When the arm (moved from above to below heart) or the legs (moved from supine to upright posture) were then provided with a larger local pressure gradient, which accelerated blood flow kinetics, there was an accompanying acceleration of VO2 kinetics (Fig. 1). Similarly, a faster increase in leg blood flow after 9 days of exercise training was associated with faster VO2 kinetics (90). In each case, the blood flow response was faster than the accompanying VO2 response, regardless of arm or leg position. These data indicate a sensitivity of QO2 kinetics to the adaptation of blood flow under these exercise conditions and suggest that the proportion of bulk muscle blood flow going to working and nonworking fibers within the muscle might adjust differently than the total bulk flow. Such an effect might be anticipated given 1) that blood flow through the muscle is determined by the combined effect of the mechanical muscle pump and vasodilation (66, 88, 93), 2) the spatially uncorrelated structure of motor units and vascular units (62), and 3) the heterogeneous and time-varying nature of motor unit recruitment (95). Thus, to achieve appropriate matching of flow to demand, local feedback regulation is required to reduce flow to overperfused and to increase flow to underperfused vascular units.


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  		Fig. 1.   Leg blood flow (solid line) for 1 leg and alveolar O2 uptake (VO2; dotted line) during rest (R) and 6 min of 40-W knee-extension/flexion exercise in upright (A) and supine (B) body positions. Upright posture increased local arterial pressure at the level of quadriceps by ~25 mmHg. This increased pressure head resulted in faster leg blood flow adaptation (mean response times: upright 17.3 ± 4.0 s vs. supine 27.6 ± 3.9 s; mean response time is time to 63% of total response). VO2 kinetics were also accelerated (29.3 ± 3.0 vs. 39.7 ± 3.8 s) but were always slower than blood flow adaptation in both upright and supine positions, suggesting that bulk blood flow to exercising limbs does not adequately describe the adaptation of O2 delivery to active fibers. [From MacDonald et al. (70).]

Evidence from the comparison of the adaptation of heart rate in submaximal rest-to-exercise vs. exercise-to-exercise transitions indicates a similar impact of central circulatory adaptation on the time course of VO2 kinetics. Hughson and Morrissey (59) observed that heart rate kinetics (and, therefore, presumably cardiac output kinetics) were markedly faster in a transition from rest to 40 or 80% Tvent, compared with a transition from 40% Tvent to 80% Tvent, and were accompanied by faster VO2 kinetics. The slower heart rate adaptation from prior exercise is consistent with slower acting sympathetic heart rate control predominating at heart rates >100 beats/min (84).

PCr and VO2 kinetics. Since the initial experiments of Mahler (71, 72) in frog sartorius muscle, similarities between PCr kinetics and VO2 or QO2 kinetics have repeatedly been demonstrated in both animal and human models across a range of work rates (4, 5, 12, 13, 73). This reflects what is believed to be the first-order nature of respiratory control (41, 72, 74, 75). These data have been interpreted as evidence that metabolic controllers determine the rate of adaptation of O2 consumption (74, 97). In addition, QO2 during the transition from rest to exercise in electrically stimulated dog muscle can be adequately described as the result of changes in phosphorylation potential and redox potential (20). Interpreting these observations to mean that the kinetic response of these metabolites controls the increase in oxidative phosphorylation may be valid under conditions where O2 is present in saturating amounts, but they do not confirm that O2 supply is adequate. Analysis by Binzoni and colleagues (12) has shown that, at moderate exercise levels where little glycolytic contribution to ATP production occurs during the exercise onset, the kinetics of PCr will mirror those of QO2. This is because the net ATP demand is met by aerobic and PCr sources, and as aerobic supply of ATP increases exponentially the net breakdown of PCr decreases proportionally. It can be shown mathematically that, under conditions of no glycolytic contribution to ATP production, the time constant of PCr breakdown will always be equivalent to that of aerobic metabolism, regardless of whether PCr is acting as a primary controller of mitochondrial respiration or a buffer of ATP levels (Fig. 2). This means that, if the adaptation of aerobic metabolism was being limited by inadequate O2 availability, the similarity in PCr and QO2 kinetics could simply be caused by the need for PCr depletion to compensate for the greater O2 deficit in the face of minimal contribution by anaerobic glycolysis.


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  		Fig. 2.   Adaptation of ATP supply at onset of moderate exercise where it is assumed that the contribution of anaerobic glycolysis is negligible. Therefore, energy not supplied by aerobic metabolism will be supplied by hydrolysis of phosphocreatine (PCr). A: step change in ATP demand. B: rate of change in ATP supplied (arbitrary units) via oxidative phosphorylation (Phosph) [time constant (tau) = 30 s; solid line] and whether an O2 delivery limitation slows adaptation of aerobic metabolism (tau = 40 s; dotted line). C: resultant ATP supplied by PCr to buffer ATP demand as aerobic metabolism adapts, where ATP via PCr = ATP demand - ATP via O2. D: with an O2 limitation during on-transient there is a greater buffering of ATP by PCr at any given time during on-transient, resulting in greater PCr depletion at all time points during exercise, but time constant is equivalent to that of the adaptation of O2 uptake. Brackets indicate concentration.

A linear relationship between PCr depletion and steady-state levels of QO2 in normoxia was first observed by di Prampero and Margaria (25). Subsequent studies have confirmed this relationship (71, 74, 75). It implicates phosphorylation potential in the determination of cellular respiration rate. However, observation of different levels of PCr for the same QO2 or VO2 under different arterial oxygenation conditions (40, 46, 49, 50) indicates that O2 can exert a modulatory effect on the level of metabolic controllers required to achieve, or associated with, a given rate of mitochondrial respiration. Such a model has been proposed by Arthur and colleagues (1). If this is the case for steady-state exercise, then it is likely to also apply during the non-steady state, since the cytochrome-c oxidase reaction is a function of the combined drive of the phosphorylation potential, the redox potential, H+ concentration, and the PO2 (101, 102). An important implication of this, which is discussed in detail below (PmitoO2), is that the level of proposed metabolic controllers does not have to change as much to achieve the same rate of ATP production by oxidative phosphorylation when more O2 is made available.

Determinants of QO2 Kinetics: Cellular Metabolic State, Enzyme Activation, and PmitoO2

Limitations of experimental and theoretical approaches have contributed to the scope of conflicting evidence in this field. If QO2 kinetics truly were limited only by intrinsic metabolic inertia or extrinsic O2 transport inertia in a mutually exclusive manner, it is unlikely that such a degree of conflict would exist. Therefore, we must try to understand how metabolic controllers and mitochondrial O2 supply interact to determine mitochondrial respiration at any given instant during exercise. This research has dealt almost exclusively with steady-state levels of O2 consumption. Nevertheless, the principles governing control of steady-state mitochondrial respiration can be applied to the non-steady state for reasons mentioned previously.

The overall reaction of oxidative phosphorylation is
NADH + ½O<SUB>2</SUB> + H<SUP>+</SUP> + 3ADP + 3P<SUB>i</SUB>
⇒ 3ATP + NAD<SUP>+</SUP> + H<SUB>2</SUB>O (1)
Oxidation of fuels in the TCA cycle provides reducing equivalents (NADH, FADH: "electron donors") for the electron transport chain (ETC). The ETC is composed of four coenzyme complexes, with the terminal one being cytochrome-c. O2 acts as the terminal electron acceptor from cytochrome-c, in an irreversible reaction catalyzed by cytochrome-c oxidase, resulting in the formation of H2O and allowing for a continued ETC flux. ATP synthesis from ADP and Pi is not directly involved in the terminal reaction of the ETC but coupled to it, such that changes in concentrations of ATP/ADP Pi ([ATP]/[ADP] · [Pi]) can considerably alter the rate of electron transfer (102). The release of free energy in the transfer of electrons down the ETC is used to "pump" H+ ions from the matrix side to the outside of the inner mitochondrial membrane, creating an electrochemical gradient. The H+ ions then flow back along this gradient into the mitochondrial matrix through protein channels with associated ATP synthase complexes. The energy from the flow of H+ is used to rephosphorylate ADP, forming ATP (Fig. 3).


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  		Fig. 3.   Local factors that might interact to determine muscle VO2 kinetics. 1: µM Ca2+ levels in mitochondrial matrix activate dehydrogenases and ATP synthase, which affect mitochondrial resistance and redox potential. Flux kinetics of separate import and export transporters will determine mitochondrial matrix [Ca2+]. 2: [ATP]/[ADP] · [Pi] and [NAD+]/[NADH] contribute to net electron transport chain (ETC) flux rate, where the former is likely the main controller, and the latter a modulator of respiratory rate. 3: mitochondrial PO2 (PmitoO2) interacts with [ATP]/[ADP] · [Pi] and [NAD+]/[NADH] to determine ETC flux via its effects on mitochondrial resistance. PmitoO2 is dependent on balance between O2 consumption and O2 flux into cell [a product of capillary PO2 (PcO2), which is, in turn, dependent on local capillary blood flow and Hb affinity for O2]. Cr, creatine; Cyt. c, cytochrome-c; PDH, pyruvate dehydrogenase; SR, sarcoplasmic reticulum.

For sustained ATP turnover to occur during skeletal muscle contractions, ATP demand needs to be matched by aerobic ATP supply. For this to occur, regulation of mitochondrial O2 consumption must be achieved by a precise communication of ATP demand to the mitochondrial ATP-producing machinery. Early investigations (18) into respiratory control centered around Michaelis-Menten kinetic control via substrate (ADP) levels. However, as pointed out by Hochachka and Matheson (44), such a kinetic model has been unable to account for the large changes in ATP turnover achieved in skeletal muscle when going from rest to exercise. This is because regulation processes based on Michaelis-Menten kinetics require that the kinetic order cannot exceed 1, which means that the percent increase in the rate of ATP production cannot exceed the percent change in substrate concentration driving the reaction (45). Therefore, other mechanisms have been proposed as regulators of mitochondrial respiration. The following are likely most important in determining its rate of adaptation.

Cellular metabolic state. Thermodynamic (4, 20, 74, 75) models of respiratory control predict that mitochondrial redox potential, reflecting the degree of cytochrome-c reduction (21, 102), and phosphorylation potential ([ATP]/[ADP] · [Pi]) (4, 20, 21, 102) determine respiratory rate such that it is not the absolute concentrations of substrates but rather the ratio of substrate to product which is the determining factor (75). For the same QO2, these ratios can vary considerably, depending on which substrates are providing acetyl CoA to the TCA cycle (30). In addition, if either redox or phosphorylation potential is fixed under saturating O2 conditions, the mitochondrial respiration rate is strongly dependent on the other (102). Finally, when cellular O2 tension is altered, both redox and phosphorylation potential change, and it has been proposed that this is a compensatory response that provides a means of maintaining QO2 when O2 availability is reduced (2, 21). This evidence implicates cellular metabolic state as a contributor to mitochondrial respiratory rate but not as the sole determinant. Rather, cellular metabolic state must interact with other factors controlling or modulating mitochondrial respiration, the most predominant of which appears to be the O2 tension (2, 46, 49, 50).

Latent mitochondrial enzyme activation. Pyruvate dehydrogenase (PDH) is a highly regulated enzyme. Its regulation determines the availability of substrate for the TCA cycle and, subsequently, the ETC. Increases in mitochondrial Ca2+ concentration ([Ca2+]) result in the conversion of PDH to its active form (39, 78). TCA cycle enzymes isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase are also regulated by Ca2+ (15). Changes in cytosolic and mitochondrial Ca2+ levels at the micromolar level could, therefore, determine the rate of supply of reducing equivalents to the ETC and the resultant level of reduction of cytochrome-c, which has been shown to influence mitochondrial respiration rate (76, 102). Timmons et al. (92) have shown that activation of PDH via dichloroacetate before the onset of heavy exercise in humans substantially elevated acetylcarnitine concentrations and that, at 3 min of exercise, PCr depletion and muscle lactate accumulation were clearly reduced, suggesting an improvement in the rate of adaptation of oxidative phosphorylation under the specific exercise conditions of their study (i.e., heavy exercise). This research group has also recently examined the effects of PDH activation at the onset of ~45% peak work rate, single-leg, knee-extension exercise (91). Timmons et al. found a fivefold increase in acetylcarnitine at rest that appeared to be mechanistically linked to the reduction in PCr utilization during the 8-min exercise bout. However, there was no significant effect on intramuscular lactate concentration. These data suggest that under a given set of conditions supply of more substrate for oxidative phosphorylation can reduce reliance on muscle high-energy phosphate stores. It is not known what effect increases or decreases in O2 availability might have under these altered intracellular conditions.

Brown (13) has reviewed data showing that inhibited mitochondrial ATP synthase can be activated by Ca2+ binding of an inhibitory protein at ~1 µM [Ca2+]. Therefore, the net flux of Ca2+ into the mitochondria would establish the magnitude of the signal for activation of PDH, TCA cycle enzymes, and ATP synthases. The mitochondrial matrix [Ca2+] is determined by the net activity of independent uptake and release pathways (15). These mechanisms might therefore play an important role in determining the rate of increase in oxidative phosphorylation. Whereas measurements of mitochondrial [Ca2+] during the on-transient of exercise are at present not possible, they constitute an important focus for future research once adequate techniques can be developed.

The role of such an activation of a latent mitochondrial enzyme pool (44) in contributing to the adaptation of respiration rate has been suggested by Hochachka (43) to explain the large increases in O2 consumption attainable with apparently inadequate changes in substrates such as ADP. He has proposed that the upregulation of a latent enzyme pool is the principal determinant of ATP turnover, whereas redox and phosphorylation potential likely serve to fine-tune the mitochondrial respiration rate in vivo.

PmitoO2. In isolated, respiring mitochondria under optimal conditions, the Michaelis constant (Km) for O2 (PO2 at half maximal respiration) was found to be ~0.03-0.1 Torr in the early work of Chance and Williams (17), although these authors also suggested that this Km appeared to change with metabolic rate. This definition of the critical level for maximal respiration rate has been used by some investigators as a criterion for determining whether an O2 limitation to mitochondrial respiration exists at the onset of exercise (20, 32, 33). However, it must be noted that redox potential and phosphorylation state are altered at much higher cellular PO2 levels in intact exercising muscle (21, 49, 61, 100-103), likely as a necessary response to maintain mitochondrial respiration rate in the face of the reduced cellular PO2 (2, 21, 59, 101).

Wilson and Rumsey (102) have neatly summarized evidence from experiments utilizing mitochondrial and intact cell suspensions, which outline the dependence of mitochondrial respiration on physiological levels of PO2. At a high [ATP]/[ADP] · [Pi], the PO2 of the mitochondrial suspension medium at which maximal mitochondrial respiration rate begins to decrease is greater (~5 Torr) than at low [ATP]/[ADP] · [Pi] (~0.1 Torr). However, it must be remembered here that these PO2 values represent conditions where compensatory changes in redox state are no longer able to prevent a drop in maximal mitochondrial respiration. Mitochondrial respiration would be expected to decline at a higher PO2 without such changes in cytochrome-c reduction or phosphorylation potential. In suspensions of intact cells, oxidative phosphorylation begins to decline when the suspension medium PO2 is 20 Torr, with cytochrome-c reduction (likely a compensation for lowering PO2 levels) already increasing at 30 Torr (102). In an intact-cell suspension, the obvious question arises: Does the PO2 of the medium represent PmitoO2? Based on the difference between coupled and uncoupled mitochondrial respiration rate, Wilson and Rumsey suggest a gradient in their experimental preparation of ~0.4 Torr between the extracellular medium and the mitochondria.

The impact in vivo of this O2 dependence of mitochondrial respiration on the metabolic state of the exercising muscle is evident from observations by Hogan et al. (49) that levels of PCr for the same QO2 during exercise were dramatically lower when O2 delivery was reduced by ~50% in isolated working dog muscle. Haseler et al. (40) recently showed that PCr concentration ([PCr]) during calf exercise in humans was highly sensitive to both increases and decreases in local PO2 (induced by hyperoxia and hypoxia, respectively), during both the on-transient and the steady state. Although these authors did not calculate the rate of adaptation to steady state, it is evident from their Fig. 5 (40) that the [PCr] achieved a plateau earlier in the hyperoxic tests than in normoxia, which were, in turn, faster than the hypoxic tests. This is exactly as predicted by Fig. 2 in which PCr kinetics mirror QO2 kinetics under varying conditions of adaptation of O2 delivery and, hence, O2 uptake.

Given that there is a range of PmitoO2 across which cellular metabolic state is modulated to varying degrees and that the Km for PmitoO2 varies with exercise intensity, what constitutes "saturating" levels of O2 at the onset of exercise cannot be clearly defined for all conditions and all time points during the adaptation of mitochondrial respiration to a new steady state. However, the evidence cited (102) would suggest that a cellular PO2 of 30 Torr already requires compensatory changes in phosphorylation and redox potential to maintain mitochondrial respiration rate. Recently, Richardson et al. (81), using proton magnetic resonance spectroscopy to detect myoglobin saturation in the quadriceps muscle during supine knee-extension exercise, have observed a rapid (within 20 s) desaturation of myoglobin to levels representing a 3.5-Torr cellular PO2 in a rest to 25% maximal work rate transition. This value actually represents an average for all the fibers in the sample site. Because not all muscle fibers would be expected to be active at 25% of maximal exercise (95), it is likely that many contracting fibers have an even greater myoglobin desaturation. Even in isolated dog muscle preparations, PmitoO2 as low as 2.5 Torr have been observed 30 s into the onset of exercise (see Fig. 4 in Ref. 32). Because cellular O2 tensions in this range clearly exert a modulatory effect on mitochondrial respiration (100-103), it is important to understand what determines PmitoO2 at exercise onset in humans in order to assess the likelihood of a contribution of O2 availability to the rate of adaptation of QO2 under a given exercise condition.

Factors determining PmitoO2. PmitoO2 is determined by the capillary O2 driving pressure (PcO2) and the local diffusion capacity (96) interacting with the rate of O2 utilization. Both muscle blood flow and O2 dissociation from Hb determine PcO2 (85), and improvements in one or both would, therefore, be expected to elevate intracellular PO2 at a given rate of mitochondrial O2 consumption (82). A detailed discussion of specific regulatory mechanisms linking the adaptation of blood flow with metabolism is beyond the scope of this review, but the reader is referred to two excellent recent reviews by Saltin et al. (86) and Delp and Laughlin (23). Blood flow to exercising muscle will be determined by factors affecting the local arteriovenous pressure gradient (cardiac output, total peripheral resistance, and the local contribution of the muscle pump) and vascular conductance (local vasodilatory and vasoconstrictor influences) (88, 93). The change in blood flow in the exercising muscle is biphasic (60, 89, 90), with a rapid initial response due to the combination of vasodilation and the muscle pump, followed by a second slower vasodilation phase beginning after 15-20 s that is likely to be predominantly feedback controlled (89). A secondary mechanical influence on vascular conductance is the intermittent compression of the muscle vasculature by contraction. Even mild contraction (10% maximal vasculatory contraction) results in severe impairment of blood flow compared with relaxation (63). Thus bulk muscle blood flow for a given vascular conductance will also be dependent on the duty cycle of muscle contractions (83). However, the magnitude of contraction interference with blood flow may vary between muscles because of muscle structure (pennate vs. fusiform fiber alignment), fiber type composition, and location of the muscle relative to other muscle groups (67).

A reduction in the affinity of O2 for Hb [right shift of the Hb-O2 dissociation curve, increased PO2 at 50% of Hb saturation (P50) (Fig. 4)], as it occurs progressively with exercise because of increased local CO2, H+, and temperature, will mean that O2 dissociates from Hb more easily, increasing the PcO2 and, subsequently, PmitoO2. The O2 transport and utilization model of Cochrane and Hughson (18) suggests that the time-dependent shift of the Hb-O2 curve might be critical in determining the release of O2 at exercise onset. Additionally, Hogan and colleagues (47) have shown that maximal rates of O2 consumption for in situ dog muscle are increased when Hb-O2 affinity is decreased. The effect of altering the P50 on intracellular PO2 and QO2 kinetics has recently been investigated in situ by using a dog model (36). These investigators observed that the additional effects of hyperoxic breathing and pharmacologically right shifting of the Hb-O2 dissociation curve did not affect the rate of increase in O2 consumption. However, these experiments were performed under conditions in which blood flow to the muscle before the onset of contractions was elevated to steady-state exercise level; i.e., there was already a substantial increase in PcO2. Investigations into an effect of Hb-O2 affinity have yet to be performed in humans in whom the muscle begins to exercise under conditions of normal resting blood flow.


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  		Fig. 4.   Effect of a transition from rest (solid line) to exercise (dotted line) is shown on Hb-O2 curve using pH and PCO2 data for venous blood draining an exercising forearm. Rightward shift with exercise facilitates release of O2 at any PcO2, which then effectively raises the PcO2. [Data obtained from Douguet et al. (26).]

Changes in the diffusion capacity for O2 from the red blood cell into the myocyte is a function of diffusion distances and surface area, both of which are dependent on capillary recruitment. In dog muscle, capillary recruitment is rapid and is essentially complete within 15 s, whereas bulk flow continues to increase for at least 2 min (51). Furthermore, during steady-state exercise, spatial blood flow heterogeneity exists (80). It is not presently possible to measure capillary recruitment in exercising humans, but, as evidence presented in Fig. 1 indicates, improvement in the distribution of blood flow does appear to play a role in the adaptation of O2 delivery.

Therefore, the following is at least a partial list of exercise conditions in which the blood flow adaptation to step increases in exercise intensity might result in PmitoO2 levels that require compensatory changes in redox or phosphorylation potential to achieve a given ATP supply via aerobic metabolism (48) during the on-transient.

1) Exercise intensities where the adaptation of the heart rate and stroke volume components determining cardiac output are predominantly in the realm mediated by the slower acting sympathetic nervous system (SNS) and where SNS-mediated redistribution of blood flow via resting tissue vasoconstriction also plays a role. This is because the SNS is a slower acting effector of cardiovascular changes than is the parasympathetic nervous system, and, therefore, the slower rate of increase in determinants of arterial driving pressure (heart rate, stroke volume, total peripheral resistance) would be expected to result in a slower adaptation of blood flow.

2) Exercise in the supine position in which stroke volume does not change appreciably and, therefore, the rate of change in cardiac output is dependent entirely on heart rate. Adjustment in whole body blood flow distribution from rest to exercise also becomes important, since cardiac output is higher in the supine position and total peripheral resistance is lower, meaning that more blood will be going to nonexercising tissue at the onset of exercise.

3) Muscles exercising at or above heart level, where the local arterial pressure is lower and where no significant gain in local pressure gradient can be achieved by venous emptying on contraction.

4) Exercise in which relaxation time is limited, thereby reducing the time allowed for blood flow and necessitating a greater change in vascular conductance and arterial pressure in an attempt to attain adequate steady-state blood flow.

Interaction of cellular metabolic state, enzyme activation, and PO2. An intrinsic metabolic inertia implies that intracellular oxygenation is adequate throughout the phase of adjustment, but other substrates of oxidative phosphorylation limit rephosphorylation of ADP. The evidence that has been reviewed in this paper indicates that a given rate of mitochondrial respiration can be achieved by different interactions of cellular metabolic state (phosphorylation potential and redox potential), mitochondrial enzyme activation (PDH and, possibly, F1-ATP synthase), and PmitoO2. This must hold true for all time points of exercise, such that the rate of mitochondrial respiration at any given time during the adaptation to a new ATP demand will be determined by the interaction of cellular metabolic state and mitochondrial enzyme activation with PmitoO2, unless O2 is available at concentrations above that at which compensatory adjustments in redox and phosphorylation potentials are necessary (2, 40, 102). The implication of this for the initial adaptation phase of exercise is as follows: if a higher PmitoO2 were maintained during the on-transient of exercise, it would necessitate less of a change in cellular metabolic state to achieve a given rate of oxidative phosphorylation. Data in Fig. 5 from the recent work of Haseler and colleagues (40) are consistent with this effect. Figure 5 in the present review illustrates the predicted effects of hyperoxia and of an elevated blood flow on the metabolic compensations necessary to achieve a given rate of mitochondrial respiration. It suggests a smaller (and, therefore, more rapidly achieved) change in steady-state redox and phosphorylation potential when PmitoO2 is higher. This smaller change should occur in a shorter time, leading to a more rapid increase in mitochondrial respiration. The message is that an interaction of O2 utilization (metabolic) and O2 transport inertia can determine QO2 kinetics under a number of physiological conditions, where O2 transport consists of the individual or combined effects of bulk O2 transport, muscle blood flow distribution, and release of O2 from Hb that determine PmitoO2. It should be acknowledged here that, whereas metabolic compensations are observed to occur at PO2 as high as 30 Torr in isolated cell suspensions (101), the alterations are minor until PO2 drops below the 7-12 Torr range. At this point, the degree of metabolic compensation required for a given drop in PO2 becomes increasingly larger. It may be that an effect on QO2 kinetics measurable with current techniques requires a PO2 well below that at which alterations in phosphorylation and redox potential are already observable. Nevertheless, the data of Haseler et al. (40) and Richardson et al. (81) suggest that such a PO2 can occur in normoxic human exercise, indicating the importance of considering the role of O2 in determining the metabolic response at the onset of exercise.


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  		Fig. 5.   Compensatory changes in phosphorylation potential and redox potential (metabolic compensation) required to maintain a given respiratory metabolic rate as PmitoO2 is decreased. Curved lines from top to bottom represent constant metabolic rates at rest and exercise, respectively. A right-arrow B represents predicted change in phosphorylation potential for a typical normoxic rest-to-exercise transition, based on reported submaximal exercising values of myoglobin PO2 by Richardson et al. (81, 82). B1 represents predicted change in phosphorylation potential if PmitoO2 were to be elevated via hyperoxia as in Richardson et al. (82). B right-arrow B1 indicates predicted effect on phosphorylation potential of elevating blood flow or arterial PO2 during steady state at a given metabolic rate [consistent with results of Haseler et al. (40)]. The larger changes in phosphorylation and redox potential from rest to exercise to accommodate the lower PmitoO2 in normoxia would be expected to require more time, therefore slowing the rate of adaptation of aerobic metabolism to a new steady state. [Adapted from Wilson et al. (101).]

As reviewed by Hochachka (43), in the flight muscle of locusts where intracellular O2 supply is tracheole mediated rather than constrained by circulatory adjustments, the square-wave change in ATP demand is met by a square-wave adaptation of mitochondrial respiration. In human heart muscle, where cellular PO2 does not appear to drop over a range of work intensities, neither phosphorylation potential nor redox potential change in response to a threefold increase in mitochondrial respiration (62, 64). This suggests that there was virtually no need for PCr contribution to ATP supply when the work rate of the heart was suddenly elevated and that mitochondrial respiration adapted almost instantaneously. However, estimates of mitochondrial O2 consumption at the onset of a square-wave increase in heart work rate by van Beek et al. (94) indicate a slight delay (time constant ~7 s). In human skeletal muscle, it is likely that such a square-wave response of mitochondrial respiration cannot occur even under saturating levels of O2 (57, 69, 99). Rather, under these conditions, there is only a metabolic inertia, whereby adequate changes in cellular metabolic state and mitochondrial enzyme activation occur over time to adjust mitochondrial respiration rate. Although it has yet to be clearly determined in humans, work by Grassi and colleagues (35) may have identified the time constant of the metabolic inertia in electrically stimulated dog muscle at ~18-20 s in an experiment where steady-state exercise levels of perfusion were achieved before the initiation of muscle contractions, thereby eliminating any delay in O2 delivery to the exercising muscle fibers.

Model predictions. The question to ask now is, How might these proposed controllers and modulators of mitochondrial respiration determine the characteristics of the adaptation of QO2 at the onset of exercise? The proposed linear, first-order control of mitochondrial respiration (41, 71, 74) and the modeling of Funk et al. (31) provide a basis for answering this question. Figure 6 summarizes the electrical analog for linear first-order respiratory control and describes the chemical equivalents proposed by Meyer (74). This model predicts the following: 1) the observed response of QO2 and PCr to a step change in ATP demand is monoexponential in nature, with a time constant that is independent of work rate; 2) the time constant is a product of mitochondrial "resistance" (a function of the number and properties of the mitochondria) and the capacitance of the phosphate energy pool (total creatine); 3) the steady-state [PCr] is linearly related to QO2, and the slope of this relationship depends on mitochondrial resistance; 4) if mitochondrial redox state is relatively more reduced, the QO2 vs. PCr slope will be unchanged, but the y-intercept will increase.


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  		Fig. 6.   Biochemical equivalents are defined, and predicted sequence of events at onset of a step increase in work rate is shown for the electrical analog model of respiratory control of Meyer (74). Increased ATP demand affects phosphate energy system of the cell, which, in turn, directs the change in respiratory rate of mitochondria such that muscle O2 uptake (QO2) adjusts in response to phosphate energy state until aerobic ATP production matches ATP demand. (See text for explanation of role of phosphate energy state as the main controller of oxidative phosphorylation and of mitochondrial enzyme activation and PO2 as modulators via their effects on mitochondrial redox potential and mitochondrial resistance).

Within the context of this model, the phosphorylation potential assumes the role of communicator of ATP demand to the mitochondria and is, therefore, the main controller of mitochondrial respiration. Each of mitochondrial redox potential, mitochondrial enzyme activation, and PmitoO2 represents the characteristics of the mitochondrial machinery and are, therefore, best described as modulators of mitochondrial respiration. The degree of activation of PDH and TCA cycle dehydrogenases may determine one or both of mitochondrial redox potential and mitochondrial resistance (number of catalytically active mitochondria), whereas Ca2+ activation of the mitochondrial ATP synthases would affect mitochondrial resistance. Based on the observation that PmitoO2 affects the slope of QO2 vs. PCr (2, 40, 46) and the time constant of QO2 in a number of conditions (52, 54, 56, 58, 60, 68, 77), it appears to modulate mitochondrial respiration by its effect on mitochondrial resistance. This role for O2 has not been previously considered within the context of the linear first-order model of respiration. Incorporation of redox potential, mitochondrial enzyme activation, and, particularly, PmitoO2 into this model of mitochondrial respiration allows for the following predictions concerning the effect of altering activation of PDH, TCA cycle hydrogenases and ATP synthases, and PmitoO2 in determining the characteristics of the on-transient QO2 and PCr responses to a step increase in work rate.

1) If the rate at which PDH and TCA cycle enzymes are activated at the onset of exercise plays a role in the rate of adaptation of O2 uptake, then activation of these enzymes before the onset of exercise would be expected to increase the mitochondrial redox potential, such that a faster adaptation of both QO2 and PCr would be observed. Evidence of reduced depletion of PCr stores with dichloroacetate administration (91, 92) is consistent with this. However, a lack of improvement in the rate of O2 uptake in exercise-to-exercise vs. rest-to-exercise transitions (6, 9, 59) argues against such a role.

2) If Ca2+ activation of ATP synthases plays a role at the onset of exercise, then it would be predicted that markedly increased mitochondrial Ca2+ levels before the onset of exercise would accelerate the adaptation of QO2 and PCr.

3) If PmitoO2 is low enough to contribute to mitochondrial resistance during the adaptation to steady state under a given exercise condition, then an increase in the PmitoO2 should result in a a faster adaptation of QO2 and PCr. Based on the observations of Richardson et al. (81), who show that PmitoO2 drops within 20 s to a stable plateau and that this plateau is similar across a range of work rates within a given arterial oxygenation state, the QO2 and PCr responses would still be expected to remain monoexponential in nature, in agreement with experimental evidence to date.

Summary and Conclusions

Investigations into a rate-limiting step for QO2 kinetics have tried to determine whether an intrinsic metabolic inertia or an extrinsic O2 transport inertia is the limiting factor. Whether the evidence from a given experiment supported an intrinsic metabolic inertia or an extrinsic O2 transport inertia depended on the nature of the experimental control condition. This is likely because different exercise conditions can impact O2 delivery kinetics in dramatically different ways, whereas the mechanisms determining metabolic adjustments are likely more uniform across a wide variety of exercise conditions (e.g., supine vs. upright leg exercise). An exception to this may be prior exercise, which might alter the rate of adjustment of metabolic controllers, as suggested by data from Yoshida et al. (104), and, perhaps, PDH activation level (91, 92).

We propose that metabolic inertia and O2 transport inertia likely interact to determine the adaptation of muscle aerobic metabolism at exercise onset under a number of common exercise conditions. Figure 3 identifies possible sites of limitation that need to be investigated. However, it must be recognized that experimental alterations to any one of the potential contributors to a limitation could result in compensatory adjustments in other contributors [e.g., manipulations in O2 result in different states of phosphorylation and redox potential during the on-transient of exercise (40)]. Determination of mitochondrial Ca2+ transients may be of key importance in furthering our understanding of the metabolic inertia limiting the adaptation of QO2 kinetics. Similarly, the in vivo matching of blood flow to sites of metabolic demand needs to be characterized under a number of different exercise conditions, and the resulting PmitoO2 across the population of active fibers needs to be quantified.


    ACKNOWLEDGEMENTS

The authors thank Dr. David Wilson for valuable criticism and direction during the writing of this review.


    FOOTNOTES

Research in the authors' laboratory has been supported by operating and equipment grants from the Natural Sciences and Engineering Research Council of Canada (NSERC). M. E. Tschakovsky was supported by a NSERC postgraduate scholarship and by a Foundation Research Grant for Doctoral Students from the American College of Sports Medicine.

Address for reprint requests: R. L. Hughson, Dept. of Kinesiology, Univ. of Waterloo, Waterloo, ON, Canada N2L 3G1 (E-mail: hughson{at}cgsa.uwaterloo.ca).


    REFERENCES
TOP
ABSTRACT
ARTICLE
REFERENCES

1.   Arthur, P. G., M. C. Hogan, D. E. Bebout, P. D. Wagner, and P. W. Hochachka. Modeling the effects of hypoxia on ATP turnover in exercising muscle. J. Appl. Physiol. 73: 737-742, 1992[Abstract/Free Full Text].

2.   Balaban, R. S. Regulation of oxidative phosphorylation in the mammalian cell. Am. J. Physiol. 258 (Cell Physiol. 27): C377-C389, 1990[Abstract/Free Full Text].

3.   Barstow, T. J., S. Buchthal, S. Zanconato, and D. M. Cooper. Muscle energetics and pulmonary oxygen uptake kinetics during moderate exercise. J. Appl. Physiol. 77: 1742-1749, 1994[Abstract/Free Full Text].

4.   Barstow, T. J., S. D. Buchthal, S. Zanconato, and D. M. Cooper. Changes in potential controllers of human skeletal muscle respiration during incremental calf exercise. J. Appl. Physiol. 77: 2169-2176, 1994[Abstract/Free Full Text].

5.   Barstow, T. J., R. Casaburi, and K. Wasserman. O2 uptake kinetics and the O2 deficit as related to exercise intensity and blood lactate. J. Appl. Physiol. 75: 755-762, 1993[Abstract/Free Full Text].

6.   Barstow, T. J., N. Lamarra, and B. J. Whipp. Modulation of muscle and pulmonary O2 uptake by circulatory dynamics during exercise. J. Appl. Physiol. 68: 979-989, 1990[Abstract/Free Full Text].

7.   Barstow, T. J., and P. A. Molé. Simulation of pulmonary O2 uptake during exercise transients in humans. J. Appl. Physiol. 63: 2253-2261, 1987[Abstract/Free Full Text].

8.   Barstow, T. J., and P. A. Molé. Linear and nonlinear characteristics of oxygen uptake kinetics during heavy exercise. J. Appl. Physiol. 71: 2099-2106, 1991[Abstract/Free Full Text].

9.   Berg, B. R., K. D. Cohen, and I. H. Sarelius. Direct coupling between blood flow and metabolism at the capillary level in striated muscle. Am. J. Physiol. 272 (Heart Circ. Physiol. 41): H2693-H1222, 1997[Abstract/Free Full Text].

10.   Berg, W. Individual differences in respiratory gas exchange during recovery from moderate exercise. Am. J. Physiol. 149: 597-610, 1947.

11.   Binzoni, T., and P. Cerretelli. Bioenergetic approach to transfer function of human skeletal muscle. J. Appl. Physiol. 77: 1784-1789, 1994[Abstract/Free Full Text].

12.   Binzoni, T., G. Ferretti, K. Schenker, and P. Cerretelli. Phosphocreatine hydrolysis by 31P-NMR at the onset of constant-load exercise in humans. J. Appl. Physiol. 73: 1644-1649, 1992[Abstract/Free Full Text].

13.   Brown, G. C. Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochem. J. 284: 1-13, 1992.

14.   Carafoli, E. Regulation of aerobic metabolism in muscle. In: Exercise Bioenergetics and Gas Exchange: Proceedings of the International Symposium on Exercise Bioenergetics and Gas Exchange, edited by P. Cerretelli, and B. J. Whipp. Amsterdam: Elsevier/North-Holland Biomedical, 1980, p. 3-23.

15.   Cerretelli, P., D. Pendergast, W. C. Paganelli, and D. W. Rennie. Effects of specific muscle training on VO2 on-response and early blood lactate. J. Appl. Physiol. 47: 761-769, 1979[Abstract/Free Full Text].

16.   Cerretelli, P., R. Sikand, and L. E. Farhi. Readjustments in cardiac output and gas exchange during onset of exercise and recovery. J. Appl. Physiol. 21: 1345-1350, 1966[Free Full Text].

17.   Chance, B., and C. M. Williams. The respiratory chain and oxidative phosphorylation. Adv. Enzymol. 17: 65-134, 1956.

18.   Cochrane, J. E., and R. L. Hughson. Computer simulation of O2 transport and utilization mechanisms at the onset of exercise. J. Appl. Physiol. 73: 2382-2388, 1992[Abstract/Free Full Text].

19.   Connett, R. J. Factors governing the recruitment of glycolysis and oxygen consumption during the rest-work transition in red skeletal muscle. In: Biochemical Aspects of Physical Exercise, edited by G. Benzi, L. Packer, and N. Siliprandi. Amsterdam: Elsevier Science Biomedical, 1986, p. 113-127.

20.   Connett, R. J., C. R. Honig, T. E. J. Gayeski, and G. A. Brooks. Defining hypoxia: a systems view of VO2, glycolysis, energetics, and intracellular PO2. J. Appl. Physiol. 68: 833-842, 1990[Abstract/Free Full Text].

21.   Davies, C. T. M., P. E. Di Prampero, and P. Cerretelli. Kinetics of cardiac output and respiratory gas exchange during exercise and recovery. J. Appl. Physiol. 32: 618-625, 1972[Free Full Text].

22.   De Cort, S. C., J. A. Innes, T. J. Barstow, and A. Guz. Cardiac output, oxygen consumption and arteriovenous oxygen difference following a sudden rise in exercise level in humans. J. Physiol. (Lond.) 441: 501-512, 1991[Abstract/Free Full Text].

23.   Delp, M. D., and M. H. Laughlin. Regulation of skeletal muscle perfusion during exercise. Acta Physiol. Scand. 162: 411-419, 1998[Medline].

24.   Di Prampero, P. E., P. Mahler, D. Giezendanner, and P. Cerretelli. The effects of priming exercise on VO2 kinetics and O2 deficit at the onset of stepping and cycling. J. Appl. Physiol. 66: 2023-2031, 1989[Abstract/Free Full Text].

25.   Di Prampero, P. E., and R. Margaria. Relationship between O2 consumption, high-energy phosphates and the kinetics of the O2 debt in exercise. Pflügers Arch. 304: 11-19, 1968[Medline].

26.   Douguet, D., J. Raynaud, A. Capderou, C. Pannier, G. Reiss, and J. Durand. Muscular venous blood metabolites during rhythmic forearm exercise while breathing air or normoxic helium and argon gas mixtures. Clin. Physiol. 8: 367-378, 1988[Medline].

27.   Eriksen, M., B. A. Waaler, L. Walloe, and J. Wesche. Dynamics and dimensions of cardiac output changes in humans at the onset and at the end of moderate rhythmic exercise. J. Physiol. (Lond.) 426: 423-437, 1990[Abstract/Free Full Text].

28.   Essfeld, D., U. Hoffman, and J. Stegemann. A model for studying the distortion of muscle oxygen uptake patterns by circulation parameters. Eur. J. Appl. Physiol. 62: 83-90, 1991.

29.   Folkow, B., U. Haglund, M. Jodal, and O. Lundgren. Blood flow in the calf muscle of man during heavy rhythmic exercise. Acta Physiol. Scand. 81: 157-163, 1971[Medline].

30.   From, A. H., S. K. Zimmer, S. P. Michurski, P. Mohanakrishnan, V. K. Ulstad, W. J. Thoma, and K. Ugurbil. Regulation of the oxidative phosphorylation rate in the intact cell. Biochemistry 29: 3731-3743, 1990[Medline].

31.   Funk, C. I., A. J. Clark, and R. J. Connett. A simple model of aerobic metabolism: applications to work transitions in muscle. Am. J. Physiol. 258 (Cell Physiol. 27): C995-C1005, 1990[Abstract/Free Full Text].

32.   Gayeski, T. E., R. J. Connett, and C. R. Honig. Oxygen transport in rest-work transition illustrates new functions for myoglobin. Am. J. Physiol. 248 (Heart Circ. Physiol. 17): H914-H921, 1985[Abstract/Free Full Text].

33.   Gayeski, T. E., R. J. Connett, and C. R. Honig. Minimum intracellular PO2 for maximum cytochrome turnover in red muscle in situ. Am. J. Physiol. 252 (Heart Circ. Physiol. 21): H906-H915, 1987[Abstract/Free Full Text].

34.   Gerbino, A., S. A. Ward, and B. J. Whipp. Effects of prior exercise on pulmonary gas-exchange kinetics during high-intensity exercise in humans. J. Appl. Physiol. 80: 99-107, 1996[Abstract/Free Full Text].

35.   Grassi, B., L. B. Gladden, M. Samaja, C. M. Stary, and M. C. Hogan. Faster adjustment of O2 delivery does not affect VO2 on-kinetics in isolated in situ canine muscle. J. Appl. Physiol. 85: 1394-1403, 1998[Abstract/Free Full Text].

36.   Grassi, B., L. B. Gladden, C. M. Stary, P. D. Wagner, and M. C. Hogan. Peripheral O2 diffusion does not affect O2 on-kinetics in isolated in situ canine muscle. J. Appl. Physiol. 85: 1404-1412, 1998[Abstract/Free Full Text].

37.   Grassi, B., C. Marconi, M. Meyer, M. Rieu, and P. Cerretelli. Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients. J. Appl. Physiol. 82: 1952-1962, 1997[Abstract/Free Full Text].

38.   Grassi, B., D. C. Poole, R. S. Richardson, D. R. Knight, B. K. Erickson, and P. D. Wagner. Muscle O2 uptake kinetics in humans: implications for metabolic control. J. Appl. Physiol. 80: 988-998, 1996[Abstract/Free Full Text].

39.   Hansford, R. G. Role of calcium in respiratory control. Med. Sci. Sports Exerc. 26: 44-51, 1994[Medline].

40.   Haseler, L. J., R. S. Richardson, and M. C. Hogan. Phosphocreatine hydrolysis during submaximal exercise: the effect of FIO2. J. Appl. Physiol. 85: 1457-1463, 1998[Abstract/Free Full Text].

41.   Henry, F. M. Aerobic oxygen consumption and alactic debt in muscular work. J. Appl. Physiol. 3: 427-438, 1951[Free Full Text].

42.   Henry, F. M., and J. C. De Moor. Lactic and alactic oxygen consumption in moderate exercise of graded intensity. J. Appl. Physiol. 8: 608-614, 1956[Free Full Text].

43.   Hochachka, P. W. Integrating ATP supply and demand. In: Muscles as Molecular and Metabolic Machines, edited by P. W. Hochachka. Boca Raton, FL: CRC Press, 1994, p. 95-118.

44.   Hochachka, P. W., and G. O. Matheson. Regulating ATP turnover rates over broad dynamic work ranges in skeletal muscles. J. Appl. Physiol. 73: 1697-1703, 1992[Abstract/Free Full Text].

45.   Hochachka, P. W., and G. B. McClelland. Cellular metabolic homeostasis during large-scale change in ATP turnover rates in muscles. J. Exp. Biol. 200: 381-386, 1997[Abstract].

46.   Hogan, M. C., P. G. Arthur, D. E. Bebout, P. W. Hochachka, and P. D. Wagner. Role of O2 in regulating tissue respiration in dog muscle working in situ. J. Appl. Physiol. 73: 728-736, 1992[Abstract/Free Full Text].

47.   Hogan, M. C., D. E. Bebout, and P. D. Wagner. Effect of increased Hb-O2 affinity on VO2 max at constant O2 delivery in dog muscle in situ. J. Appl. Physiol. 70: 2656-2662, 1991[Abstract/Free Full Text].

48.   Hogan, M. C., L. B. Gladden, B. Grassi, C. M. Stary, and M. Samaja. Bioenergetics of contracting skeletal muscle after partial reduction of blood flow. J. Appl. Physiol. 84: 1882-1888, 1998[Abstract/Free Full Text].

49.   Hogan, M. C., S. Nioka, W. F. Brechue, and B. Chance. A 31P-NMR study of tissue respiration in working dog muscle during reduced O2 delivery conditions. J. Appl. Physiol. 73: 1662-1670, 1992[Abstract/Free Full Text].

50.   Hogan, M. C., and H. G. Welch. Effect of altered arterial O2 tensions on muscle metabolism in dog skeletal muscle during fatiguing work. Am. J. Physiol. 251 (Cell Physiol. 20): C216-C222, 1986[Abstract/Free Full Text].

51.   Honig, C. R., C. L. Odoroff, and J. L. Frierson. Capillary recruitment in exercise: rate, extent, uniformity, and relation to blood flow. Am. J. Physiol. 238 (Heart Circ. Physiol. 7): H31-H42, 1980[Abstract/Free Full Text].

52.   Hughson, R. L. Alterations in the oxygen deficit-oxygen debt relationships with beta -adrenergic receptor blockade in man. J. Physiol. (Lond.) 349: 375-387, 1984[Abstract/Free Full Text].

53.   Hughson, R. L. Exploring cardiorespiratory control mechanisms through gas exchange dynamics. Med. Sci. Sports Exerc. 22: 72-79, 1990[Medline].

54.   Hughson, R. L., J. G. Cochrane, and G. C. Butler. Faster oxygen uptake kinetics at onset of supine exercise with lower body negative pressure. J. Appl. Physiol. 75: 1962-1967, 1993[Abstract/Free Full Text].

55.   Hughson, R. L., and M. D. Inman. Faster kinetics of oxygen uptake during arm exercise with circulatory occlusion of the legs (Abstract). Int. J. Sports Med. 7: 22-25, 1986[Medline].

56.   Hughson, R. L., and J. M. Kowalchuk. Beta-blockade and oxygen delivery to muscle during exercise. Can. J. Physiol. Pharmacol. 69: 285-289, 1991[Medline].

57.   Hughson, R. L., and J. M. Kowalchuk. Kinetics of oxygen uptake for submaximal exercise in hyperoxia, normoxia, and hypoxia. Can. J. Appl. Physiol. 20: 199-211, 1995.

58.   Hughson, R. L., and M. A. Morrissey. Delayed kinetics of respiratory gas exchange in the transition from prior exercise. J. Appl. Physiol. 52: 921-929, 1982[Abstract/Free Full Text].

59.   Hughson, R. L., and M. A. Morrissey. Delayed kinetics of VO2 in the transition from prior exercise. Evidence for O2 transport limitation of VO2 kinetics: a review. Int. J. Sports Med. 4: 31-39, 1983[Medline].

60.   Hughson, R. L., J. K. Shoemaker, M. E. Tschakovsky, and J. M. Kowalchuk. Dependence of muscle VO2 on blood flow dynamics at onset of forearm exercise. J. Appl. Physiol. 81: 1619-1626, 1997[Abstract/Free Full Text].

61.   Idstrom, J.-P., V. Harihara Subramanian, B. Chance, T. Schersten, and A.-C. Bylund-Fellenius. Oxygen dependence of energy metabolism in contracting and recovering rat skeletal muscle. Am. J. Physiol. 248 (Heart Circ. Physiol. 17): H40-H48, 1985.

62.   Johnson, P. C., P. D. Wagner, and D. F. Wilson. Regulation of oxidative metabolism and blood flow in skeletal muscle: summary report of the first ACSM Basic Science Specialty Conference. Med. Sci. Sports Exerc. 28: 305-314, 1996[Medline].

63.   Kagaya, A., and F. Ogita. Blood flow during muscle contraction and relaxation in rhythmic exercise at different intensities. Ann. Physiol. Anthrop. 11: 251-256, 1992[Medline].

64.   Katz, L. A., J. A. Swain, M. A. Portman, and R. S. Balaban. Relation between phosphate metabolites and oxygen consumption of heart in vivo. Am. J. Physiol. 256 (Heart Circ. Physiol. 25): H265-H274, 1989[Abstract/Free Full Text].

65.   Krogh, A., and J. Lindhard. The regulation of respiration and circulation during the initial stages of muscular work. J. Physiol. (Lond.) 47: 112-136, 1913.

66.   Laughlin, M. H. Skeletal muscle blood flow capacity: the role of the muscle pump in exercise hyperemia. Am. J. Physiol. 253 (Heart Circ. Physiol. 22): H296-H306, 1987.

67.   Laughlin, M. H., R. J. Korthuis, D. J. Duncker, and R. J. Bache. Control of blood flow to cardiac and skeletal muscle during exercise. In: Handbook of Physiology. Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: Am. Physiol. Soc., 1996, sect. 12, chapt. 16, p. 705-769.

68.   Linnarsson, D., J. Karlson, L. Fagraeus, and B. Saltin. Muscle metabolites and oxygen deficit with exercise in hypoxia and hyperoxia. J. Appl. Physiol. 36: 399-402, 1974[Free Full Text].

69.   MacDonald, M. J., P. K. Pedersen, and R. L. Hughson. Acceleration of VO2 kinetics in heavy submaximal exercise by hyperoxia and prior high-intensity exercise. J. Appl. Physiol. 83: 1318-1325, 1997[Abstract/Free Full Text].

70.   MacDonald, M. J., M. E. Tschakovsky, and R. L. Hughson. Alveolar oxygen uptake and femoral artery blood flow dynamics in upright and supine exercise in humans. J. Appl. Physiol. 85: 1622-1628, 1998[Abstract/Free Full Text].

71.   Mahler, M. Kinetics and control of oxygen consumption in skeletal muscle. In: Exercise Bioenergetics and Gas Exchange: Proceedings of the International Symposium on Exercise Bioenergetics and Gas Exchange, edited by P. Cerretelli, and B. J. Whipp. Amsterdam: Elsevier/North-Holland Biomedical, 1980, p. 53-66.

72.   Mahler, M. First-order kinetics of muscle oxygen consumption, and an equivalent proportionality between QO2 and phosphorylcreatine level. J. Gen. Physiol. 86: 136-165, 1985.

73.   Marsh, G. D., D. H. Paterson, J. J. Potwarka, and R. T. Thompson. Transient changes in muscle high-energy phosphates during moderate exercise. J. Appl. Physiol. 75: 648-656, 1993[Abstract/Free Full Text].

74.   Meyer, R. A. A linear model of muscle respiration explains monoexponential phosphocreatine changes. Am. J. Physiol. 254 (Cell Physiol. 23): C548-C553, 1988[Abstract/Free Full Text].

75.   Meyer, R. A., and J. M. Foley. Testing models of respiratory control in skeletal muscle. Med. Sci. Sports Exerc. 26: 52-57, 1994[Medline].

76.   Moreno-Sanchez, R., B. A. Hogue, and R. G. Hansford. Influence of NAD-linked dehydrogenase activity on flux through oxidative phosphorylation. Biochem. J. 268: 421-428, 1990[Medline].

77.   Murphy, P. C., L. A. Cuervo, and R. L. Hughson. A study of cardiorespiratory dynamics with step and ramp exercise tests in normoxia and hypoxia. Cardiovasc. Res. 23: 825-832, 1989[Medline].

78.   Newsholme, E. A., and A. R. Leech. Biochemistry for the Medical Sciences. Toronto: Wiley, 1983.

79.   Pendergast, D. R., D. Shindell, P. Cerretelli, and D. W. Rennie. Role of central and peripheral circulatory adjustments in oxygen transport at the onset of exercise. Int. J. Sports Med. 1: 160-170, 1980.

80.   Piiper, J. Unequal distribution of blood flow in exercising muscle of the dog. Res. Physiol. 80: 129-136, 1990[Medline].

81.   Richardson, R. S., E. A. Noyszewski, K. F. Kendrick, J. S. Leigh, and P. D. Wagner. Myoglobin O2 desaturation during exercise: evidence of limited O2 transport. J. Clin. Invest. 96: 1916-1926, 1995.

82.   Richardson, R. S., E. A. Noyszewski, K. F. Kendrick, J. S. Leigh, and P. D. Wagner. Myoglobin PO2 as a determinant of maximal mitochondrial O2 consumption (Abstract). Med. Sci. Sports Exerc. 29: S272, 1997.

83.   Robergs, R. A., M. V. Icenogle, T. L. Hudson, and E. R. Greene. Temporal inhomogeneity in brachial artery blood flow during forearm exercise. Med. Sci. Sports Exerc. 29: 1021-1027, 1997[Medline].

84.   Rowell, L. B. Human Cardiovascular Control. New York: Oxford Univ. Press, 1993.

85.   Saltin, B. Hemodynamic adaptations to exercise. Am. J. Cardiol. 55: 42D-47D, 1985[Medline].

86.   Saltin, B., G. Radegran, M. D. Koskolou, and R. C. Roach. Skeletal muscle blood flow in humans and its regulation during exercise. Acta Physiol. Scand. 162: 421-436, 1998[Medline].

87.   Sarelius, I. H. Cell and oxygen flow in arterioles controlling capillary perfusion. Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H1682-H1687, 1993[Abstract/Free Full Text].

88.   Sheriff, D. D., L. B. Rowell, and A. M. Scher. Is rapid rise in vascular conductance at onset of dynamic exercise due to muscle pump? Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H1227-H1234, 1993[Abstract/Free Full Text].

89.   Shoemaker, J. K., J. R. Halliwill, R. L. Hughson, and M. J. Joyner. Contributions of acetylcholine and nitric oxide to forearm blood flow at exercise onset and recovery. Am. J. Physiol. 273 (Heart Circ. Physiol. 42): H2388-H2395, 1997[Abstract/Free Full Text].

90.   Shoemaker, J. K., S. M. Phillips, H. J. Green, and R. L. Hughson. Faster femoral artery blood velocity kinetics at the onset of exercise following short-term training. Cardiovasc. Res. 31: 278-286, 1996[Medline].

91.   Timmons, J. A., T. Gustafsson, C. J. Sundberg, E. Jansson, and P. L. Greenhaff. Muscle acetyl group availability is a major determinant of oxygen deficit in humans during submaximal exercise. Am. J. Physiol. 274 (Endocrinol. Metab. 37): E377-E380, 1998[Abstract/Free Full Text].

92.   Timmons, J. A., T. Gustafsson, C. J. Sundberg, E. Jansson, E. Hultman, L. Kaijser, J. Chwalbinska-Moneta, D. Constantin-Teodosiu, I. A. Macdonald, and P. L. Greenhaff. Substrate availability limits human skeletal muscle oxidative ATP regeneration at the onset of ischemic exercise. J. Clin. Invest. 97: 879-883, 1996[Medline].

93.   Tschakovsky, M. E., J. K. Shoemaker, and R. L. Hughson. Vasodilation and muscle pump contribution to immediate exercise hyperemia. Am. J. Physiol. 271 (Heart Circ. Physiol. 40): H1697-H1701, 1996[Abstract/Free Full Text].

94.   Van Beek, J. H. G. M., and N. Westerhof. Response time of cardiac mitochondrial oxygen consumption to heart rate steps. Am. J. Physiol. 260 (Heart Circ. Physiol. 29): H613-H625, 1991[Abstract/Free Full Text].

95.   Van Bolhuis, B. M., W. P. Medendorp, and C. C. A. M. Gielen. Motor unit firing behavior in human arm flexor muscles during sinusoidal isometric contractions and movements. Exp. Brain Res. 117: 120-130, 1997[Medline].

96.   Wagner, P. D. Central and peripheral aspects of oxygen transport and adaptations with exercise. Sports Med. 11: 133-142, 1991[Medline].

97.   Whipp, B. J., and M. Mahler. Dynamics of pulmonary gas exchange during exercise. In: Pulmonary Gas Exchange, edited by J. B. West. New York: Academic, 1980, vol. II, p. 33-96.

98.   Whipp, B. J., and S. A. Ward. Physiological determinants of pulmonary gas exchange kinetics during exercise. Med. Sci. Sports Exerc. 22: 62-71, 1990[Medline].

99.   Williamson, J. W., P. B. Raven, and B. J. Whipp. Unaltered oxygen uptake kinetics at exercise onset with lower-body positive pressure in humans. Exp. Physiol. 81: 695-705, 1996[Abstract].

100.   Wilson, D. F., M. Erecinska, E. M. Nuutinen, and I. A. Silver. Dependence of cellular metabolism and local oxygen delivery on oxygen tension. Adv. Exp. Med. Biol. 180: 629-634, 1984[Medline].

101.   Wilson, D. F., M. Erecinska, and I. A. Silver. Metabolic effects of lowering oxygen tension in vivo. Adv. Exp. Med. Biol. 159: 293-301, 1983[Medline].

102.   Wilson, D. F., and W. L. Rumsey. Factors modulating the oxygen dependence of mitochondrial oxidative phosphorylation. Adv. Exp. Med. Biol. 222: 121-131, 1988[Medline].

103.   Wilson, D. F., W. L. Rumsey, T. J. Green, and J. M. Vanderkooi. The oxygen dependence of mitochondrial oxidative phosphorylation measured by a new optical method for measuring oxygen concentration. J. Biol. Chem. 263: 2712-2718, 1983[Abstract/Free Full Text].

104.   Yoshida, T., J. Kamiya, and K. Hishimoto. Are oxygen uptake kinetics at the onset of exercise speeded up by local metabolic status in active muscles? Eur. J. Appl. Physiol. 70: 482-486, 1995.

105.   Yoshida, T., and B. J. Whipp. Dynamic asymmetries of cardiac output transients in response to muscular exercise in man. J. Physiol. (Lond.) 480: 355-359, 1994[Abstract/Free Full Text].

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[Abstract] [Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]

Home page
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J. Physiol., October 1, 2003; 552(1): 265 - 272.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
B. Grassi, S. Pogliaghi, S. Rampichini, V. Quaresima, M. Ferrari, C. Marconi, and P. Cerretelli
Muscle oxygenation and pulmonary gas exchange kinetics during cycling exercise on-transitions in humans
J Appl Physiol, July 1, 2003; 95(1): 149 - 158.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
M. Burnley, A. M. Jones, R. L. Hughson, N. Tordi, and S. Perrey
Interpreting VO2 kinetics in heavy exercise revisited
J Appl Physiol, June 1, 2003; 94(6): 2548 - 2550.
[Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
C. A. Kindig, R. A. Howlett, and M. C. Hogan
Effect of extracellular PO2 on the fall in intracellular PO2 in contracting single myocytes
J Appl Physiol, May 1, 2003; 94(5): 1964 - 1970.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
N. Tordi, S. Perrey, A. Harvey, and R. L. Hughson
Oxygen uptake kinetics during two bouts of heavy cycling separated by fatiguing sprint exercise in humans
J Appl Physiol, February 1, 2003; 94(2): 533 - 541.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. A. Howlett and M. C. Hogan
Dichloroacetate accelerates the fall in intracellular PO2 at onset of contractions in Xenopus single muscle fibers
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R481 - R485.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. J Gibala, J. Gonzalez-Alonso, and B. Saltin
Dissociation between muscle tricarboxylic acid cycle pool size and aerobic energy provision during prolonged exercise in humans
J. Physiol., December 1, 2002; 545(2): 705 - 713.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. J Watt, G J F Heigenhauser, T. Stellingwerff, M. Hargreaves, and L. L Spriet
Carbohydrate ingestion reduces skeletal muscle acetylcarnitine availability but has no effect on substrate phosphorylation at the onset of exercise in man
J. Physiol., November 1, 2002; 544(3): 949 - 956.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
P. A Roberts, S. J G Loxham, S. M Poucher, D. Constantin-Teodosiu, and P. L Greenhaff
The acetyl group deficit at the onset of contraction in ischaemic canine skeletal muscle
J. Physiol., October 15, 2002; 544(2): 591 - 602.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
I. Savasi, M. K. Evans, G. J. F. Heigenhauser, and L. L. Spriet
Skeletal muscle metabolism is unaffected by DCA infusion and hyperoxia after onset of intense aerobic exercise
Am J Physiol Endocrinol Metab, July 1, 2002; 283(1): E108 - E115.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
A. M. Jones, H. Carter, J. S. M. Pringle, and I. T. Campbell
Effect of creatine supplementation on oxygen uptake kinetics during submaximal cycle exercise
J Appl Physiol, June 1, 2002; 92(6): 2571 - 2577.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. J Gibala, N. Peirce, D. Constantin-Teodosiu, and P. L Greenhaff
Exercise with low muscle glycogen augments TCA cycle anaplerosis but impairs oxidative energy provision in humans
J. Physiol., May 1, 2002; 540(3): 1079 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. Bangsbo, M. J. Gibala, P. Krustrup, J. Gonzalez-Alonso, and B. Saltin
Enhanced pyruvate dehydrogenase activity does not affect muscle O2 uptake at onset of intense exercise in humans
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2002; 282(1): R273 - R280.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
B. Grassi, M. C Hogan, P. L Greenhaff, J. J Hamann, K. M Kelley, W. G Aschenbach, D. Constantin-Teodosiu, and L B. Gladden
Oxygen uptake on-kinetics in dog gastrocnemius in situ following activation of pyruvate dehydrogenase by dichloroacetate
J. Physiol., January 1, 2002; 538(1): 195 - 207.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
M. K. Evans, I. Savasi, G. J. F. Heigenhauser, and L. L. Spriet
Effects of acetate infusion and hyperoxia on muscle substrate phosphorylation after onset of moderate exercise
Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1144 - E1150.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
H B Rossiter, S A Ward, J M Kowalchuk, F A Howe, J R Griffiths, and B J Whipp
Effects of prior exercise on oxygen uptake and phosphocreatine kinetics during high-intensity knee-extension exercise in humans
J. Physiol., November 15, 2001; 537(1): 291 - 303.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
S. Perrey, M. E. Tschakovsky, and R. L. Hughson
Muscle chemoreflex elevates muscle blood flow and O2 uptake at exercise onset in nonischemic human forearm
J Appl Physiol, November 1, 2001; 91(5): 2010 - 2016.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
R. A Ferguson, D. Ball, P. Krustrup, P. Aagaard, M. Kjaer, A. J Sargeant, Y. Hellsten, and J. Bangsbo
Muscle oxygen uptake and energy turnover during dynamic exercise at different contraction frequencies in humans
J. Physiol., October 1, 2001; 536(1): 261 - 271.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
C. A. Kindig, P. McDonough, H. H. Erickson, and D. C. Poole
Effect of L-NAME on oxygen uptake kinetics during heavy-intensity exercise in the horse
J Appl Physiol, August 1, 2001; 91(2): 891 - 896.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. L. Hughson, J. Bangsbo, P. Krustrup, J. Gonzalez-Alonso, R. Boushel, and B. Saltin
Kinetics of {V}O2 With Very High Intensity Exercise
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2001; 281(2): R681 - R682.
[Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
R. L. Hughson, M. J. MacDonald, M. E. Tschakovsky, A. M. Jones, M. Burnley, H. Carter, and J. H. Doust
Interpreting {V}O2 Kinetics in Heavy Exercise
J Appl Physiol, July 1, 2001; 91(1): 530 - 532.
[Full Text] [PDF]

Home page
 J. Physiol.Home page
F Ozyener, H B Rossiter, S A Ward, and B J Whipp
Influence of exercise intensity on the on- and off-transient kinetics of pulmonary oxygen uptake in humans
J. Physiol., June 15, 2001; 533(3): 891 - 902.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
M. C. Hogan
Fall in intracellular PO2 at the onset of contractions in Xenopus single skeletal muscle fibers
J Appl Physiol, May 1, 2001; 90(5): 1871 - 1876.
[Abstract] [Full Text] [PDF]

Home page
 Integr. Comp. Biol.Home page
P. Cerretelli and B. Grassi
Gas Exchange, MRS and NIRS Assessment of Metabolic Transients in Skeletal Muscle
Integr. Comp. Biol., April 1, 2001; 41(2): 229 - 246.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
B. W Scheuermann, B. D Hoelting, M L. Noble, and T. J Barstow
The slow component of O2 uptake is not accompanied by changes in muscle EMG during repeated bouts of heavy exercise in humans
J. Physiol., February 15, 2001; 531(1): 245 - 256.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
S. Koga, T. J. Barstow, T. Shiojiri, T. Takaishi, Y. Fukuba, N. Kondo, M. Shibasaki, and D. C. Poole
Effect of muscle mass on {V}O2 kinetics at the onset of work
J Appl Physiol, February 1, 2001; 90(2): 461 - 468.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
L. B. Gladden
Lactic acid: New roles in a new millennium
PNAS, January 16, 2001; 98(2): 395 - 397.
[Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
M. J. MacDonald, H. L. Naylor, M. E. Tschakovsky, and R. L. Hughson
Peripheral circulatory factors limit rate of increase in muscle O2 uptake at onset of heavy exercise
J Appl Physiol, January 1, 2001; 90(1): 83 - 89.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
B. Grassi, M. C. Hogan, K. M. Kelley, W. G. Aschenbach, J. J. Hamann, R. K. Evans, R. E. Patillo, and L. B. Gladden
Role of convective O2 delivery in determining VO2 on-kinetics in canine muscle contracting at peak VO2
J Appl Physiol, October 1, 2000; 89(4): 1293 - 1301.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
M. Burnley, A. M. Jones, H. Carter, and J. H. Doust
Effects of prior heavy exercise on phase II pulmonary oxygen uptake kinetics during heavy exercise
J Appl Physiol, October 1, 2000; 89(4): 1387 - 1396.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
M. L. Parolin, L. L. Spriet, E. Hultman, M. P. Matsos, M. G. Hollidge-Horvat, N. L. Jones, and G. J. F. Heigenhauser
Effects of PDH activation by dichloroacetate in human skeletal muscle during exercise in hypoxia
Am J Physiol Endocrinol Metab, October 1, 2000; 279(4): E752 - E761.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. Bangsbo, P. Krustrup, J. Gonzalez-Alonso, R. Boushel, and B. Saltin
Muscle oxygen kinetics at onset of intense dynamic exercise in humans
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2000; 279(3): R899 - R906.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
T. Reybrouck
Gas Exchange Kinetics in Patients With Cardiovascular Disease
Chest, August 1, 2000; 118(2): 285 - 286.
[Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
R. L. Hughson, D. D. O'Leary, A. C. Betik, and H. Hebestreit
Kinetics of oxygen uptake at the onset of exercise near or above peak oxygen uptake
J Appl Physiol, May 1, 2000; 88(5): 1812 - 1819.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
P. A. Mole and J. J. Hoffmann
VO2 kinetics of mild exercise are altered by RER
J Appl Physiol, December 1, 1999; 87(6): 2097 - 2106.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. J Gibala, N. Peirce, D. Constantin-Teodosiu, and P. L Greenhaff
Exercise with low muscle glycogen augments TCA cycle anaplerosis but impairs oxidative energy provision in humans
J. Physiol., May 1, 2002; 540(3): 1079 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
B. Grassi, M. C Hogan, P. L Greenhaff, J. J Hamann, K. M Kelley, W. G Aschenbach, D. Constantin-Teodosiu, and L B. Gladden
Oxygen uptake on-kinetics in dog gastrocnemius in situ following activation of pyruvate dehydrogenase by dichloroacetate
J. Physiol., January 1, 2002; 538(1): 195 - 207.
[Abstract] [Full Text] [PDF]

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