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The Journal of Physiology logoLink to The Journal of Physiology
. 2012 Jun 18;590(Pt 17):4363–4376. doi: 10.1113/jphysiol.2012.233064

Influence of exercise intensity on skeletal muscle blood flow, O2 extraction and O2 uptake on-kinetics

Andrew M Jones 1, Peter Krustrup 1,2, Daryl P Wilkerson 1, Nicolas J Berger 3, José A Calbet 4, Jens Bangsbo 2
PMCID: PMC3473291  PMID: 22711961

Abstract

Following the start of low-intensity exercise in healthy humans, it has been established that the kinetics of skeletal muscle O2 delivery is faster than, and does not limit, the kinetics of muscle O2 uptake (Inline graphic). Direct data are lacking, however, on the question of whether O2 delivery might limit Inline graphic kinetics during high-intensity exercise. Using multiple exercise transitions to enhance confidence in parameter estimation, we therefore investigated the kinetics of, and inter-relationships between, muscle blood flow (Inline graphic), a–Inline graphic difference and Inline graphic following the onset of low-intensity (LI) and high-intensity (HI) exercise. Seven healthy males completed four 6 min bouts of LI and four 6 min bouts of HI single-legged knee-extension exercise. Blood was frequently drawn from the femoral artery and vein during exercise and Inline graphic, a–Inline graphic difference and Inline graphic were calculated and subsequently modelled using non-linear regression techniques. For LI, the fundamental component mean response time (MRTp) for Inline graphic kinetics was significantly shorter than Inline graphic kinetics (mean ± SEM, 18 ± 4 vs. 30 ± 4 s; P < 0.05), whereas for HI, the MRTp for Inline graphic and Inline graphic was not significantly different (27 ± 5 vs. 29 ± 4 s, respectively). There was no difference in the MRTp for either Inline graphic or Inline graphic between the two exercise intensities; however, the MRTp for a–Inline graphic difference was significantly shorter for HI compared with LI (17 ± 3 vs. 28 ± 4 s; P < 0.05). Excess O2, i.e. oxygen not taken up (Inline graphic×Inline graphic), was significantly elevated within the first 5 s of exercise and remained unaltered thereafter, with no differences between LI and HI. These results indicate that bulk O2 delivery does not limit Inline graphic kinetics following the onset of LI or HI knee-extension exercise.

Key points

  • Following the start of low-intensity exercise in healthy humans, it has been established that the kinetics of muscle O2 delivery is faster than, and does not limit, the kinetics of muscle O2 uptake.

  • Direct data are lacking, however, on the question of whether O2 delivery might limit O2 uptake kinetics during high-intensity exercise.

  • In this study, we made frequent measurements of muscle blood flow, arterial-to-venous O2 difference (a–Inline graphicdifference) and O2 uptake following the onset of multiple transitions of both low-intensity and high-intensity knee-extension exercise in the same subjects.

  • We show that although blood flow kinetics is slower for high-intensity compared with low-intensity exercise, this does not result in slower O2 uptake kinetics.

  • These results indicate that muscle O2 delivery does not limit O2 uptake during knee-extension exercise in healthy humans.

Introduction

Following the onset of exercise, the rate of ATP resynthesis in the active myocytes increases immediately to prevent a rapid fall in ATP concentration ([ATP]) and to sustain contractions. It has been known since the early work of Krogh & Lindhard (1920), however, that the rate of pulmonary O2 uptake (Inline graphic) rises more slowly, only reaching a steady state several minutes following the start of exercise. This obligates an increased rate of ATP supply from non-oxidative metabolic pathways in this transient phase, resulting in a reduction of muscle [PCr] and an accumulation of muscle lactate, the magnitude of which will depend on the work rate.

The limitation(s) to the dynamic adaptation of skeletal muscle O2 utilization (Inline graphic) following the onset of contractions remains unclear. In particular, controversy continues to surround the extent to which the systemic (bulk) delivery of O2 to muscle might constrain Inline graphic kinetics as opposed to some intrinsic cellular limitation to O2 utilization (Hughson et al. 2001; Grassi, 2006; Poole et al. 2008). It has been suggested that muscle blood flow (Inline graphic) may limit Inline graphic kinetics in the transition from rest to exercise, at least in certain circumstances. For example, Hughson et al. (1996) reported that forearm Inline graphic and Inline graphic increased more rapidly at the onset of intermittent static handgrip exercise when the arm was positioned below compared with above the level of the heart. It has also been reported that reducing O2 availability to the working muscles using interventions such as hypoxia (Engelen et al. 1996) and β-blockade (Hughson, 1984), and during exercise in the supine compared with the upright position (Koga et al. 1999), can slow Inline graphic kinetics. On the other hand, there is evidence to suggest that a limited extraction of O2 by the contracting muscle cells causes the delay in Inline graphic in the initial phase of exercise, at least during low-intensity exercise. Using an isolated canine gastrocnemius model, Grassi et al. (1998) reported that Inline graphic kinetics was significantly faster than Inline graphic kinetics following the onset of contractions requiring ∼60%Inline graphic but that Inline graphic and Inline graphic kinetics were similar following the onset of contractions requiring ∼100%Inline graphic (Grassi et al. 2000).

Few studies have addressed the question of whether Inline graphic kinetics is limited by Inline graphic kinetics in humans. Grassi et al. (1996) made direct measurements of Inline graphic and arterio-venous O2 content difference across the leg during the transition from unloaded pedalling to moderate-intensity (i.e. below the lactate threshold, LT) cycle exercise. The results of this study indicated that Inline graphic (and O2 delivery) increased considerably faster than Inline graphic over the first 10–15 s of exercise, after which Inline graphic and Inline graphic increased with a similar time course to their respective steady-state values. Bangsbo et al. (2000) reported that the difference between muscle O2 delivery and Inline graphic was greatest at the onset of intense exercise (becoming reduced to a constant level after ∼15 s), indicating that O2 supply exceeds demand in the initial phase of dynamic exercise and that O2 delivery is not limiting Inline graphic kinetics. The possibility cannot be excluded, however, that a non-maximal muscle O2 extraction in the initial phase of exercise is due to an inefficient flow distribution, i.e. heterogeneity of local blood flow relative to metabolic rate. Using non-invasive Doppler ultrasound techniques, a number of other studies have indicated that Inline graphic adapts more rapidly than Inline graphic such that bulk muscle O2 delivery cannot be considered to limit the rate at which Inline graphic increases, at least following the onset of low-intensity exercise (MacDonald et al. 1998; van Beekvelt et al. 2001; Fukuba et al. 2004; Koga et al. 2005). However, the ‘excess’ of O2 delivery relative to O2 utilisation appears to be reduced during high-intensity compared with low-intensity exercise such that O2 availability might play a role in limiting Inline graphic kinetics during more intense exercise (Grassi et al. 2000; Koga et al. 2005; Poole et al. 2008). If so, this would be expected to be manifest in a slowing of the initial Inline graphic kinetics for high-intensity compared with low-intensity exercise. The possibility that Inline graphic might limit Inline graphic kinetics in an intensity-dependent fashion has never been directly investigated.

To address this issue, we aimed to extend the work of Grassi et al. (1996) by investigating the relationship between the kinetics of Inline graphic (and hence muscle O2 delivery), a–Inline graphic difference and Inline graphic following the onset of low-intensity and high-intensity knee-extensor exercise. We reasoned that any slowing of Inline graphic kinetics during high-intensity (HI) compared with low-intensity (LI) exercise would not appreciably impact on Inline graphic kinetics given the apparent surplus of O2 delivery relative to O2 utilization for this mode of exercise (Bangsbo et al. 2000; Nyberg et al. 2010). We hypothesized that: (1) Inline graphic kinetics would be faster than Inline graphic kinetics during LI but not HI exercise; (2) a–Inline graphic difference kinetics would be faster in HI compared with LI exercise; and (3) Inline graphic kinetics would not be significantly different between LI and HI exercise.

Methods

Subjects

Seven healthy male subjects participated in the experiment. The subjects had a mean ± SD age, height, mass and body fat percentage of 23 ± 2 years, 1.82 ±0.03 m, 78.4 ± 6.9 kg, and 18.2 ± 5.1%, respectively. The subjects were untrained or recreationally active with a peak O2 uptake (Inline graphic) during cycle ergometry of 3.84 ± 0.50 l min−1 or 49.0 ± 5.1 ml min−1 kg−1. The subjects were fully informed of the risks and discomforts associated with the experimental procedures, and all provided written consent. The study was carried out in accordance with the guidelines contained in the Declaration of Helsinki and was approved by the Ethics Committee of Copenhagen and Frederiksberg communities (H-B-2007-098).

Exercise model and pre-experimental procedures

On the first day a progressive cycle ergometer test was performed for determination of whole-body Inline graphic. The subject cycled for 4 min at 100 W after which the load was increased by 20 W each 30 s until volitional exhaustion. Pulmonary gas exchange and ventilation were measured (CPX/D MedGraphics, St Paul, MN, US) throughout the incremental test. Inline graphic was defined as the highest 30 s mean value recorded before the subject's volitional termination of the test. On a separate day, a resting needle muscle biopsy sample was obtained under local anaesthesia (1 ml of 20 mg ml−1 lidocaine) from m. vastus lateralis of the experimental (right) leg (Bergstøm et al. 1962).

Subjects performed dynamic single-legged knee-extension exercise in a semi-supine position on an ergometer that permitted the exercise to be confined to the quadriceps muscle (Andersen et al. 1985; Bangsbo et al. 1990). The subjects had several visits to the laboratory in order to become familiarized with the exercise model. After at least three familiarization sessions, the subjects performed a single-legged incremental knee-extension test in order to determine the maximal power output, which was 66 ± 4 (54–82) W. Force tracings and kicking frequency were continuously monitored and pulmonary gas exchange and ventilation were measured throughout the incremental test. Inline graphic was defined as the highest 30 s mean value recorded before the subject's volitional termination of the test. The gas exchange threshold (GET) was determined from a cluster of measures including: (1) the first disproportionate increase in carbon dioxide output (Inline graphic) from visual inspection of individual plots of Inline graphic vs. Inline graphic; (2) an increase in Inline graphic (Inline graphic, expiratory ventilation) with no increase in Inline graphic; (3) an increase in end-tidal O2 tension with no fall in end-tidal CO2 tension. The power outputs that would require 60% of the GET (i.e. low-intensity exercise, LI: 18 ± 1 (14–22) W) and 50% of the difference (Δ) between the GET and Inline graphic (i.e. high-intensity exercise, HI: 47 ± 3 (38–58) W) were calculated and used in the main experiment. These power outputs were selected in order that the subjects could complete several like-transitions at each intensity (to increase confidence in the model fits) without fatigue.

Main experiment

Subject preparation

The subjects arrived at the laboratory at 8.00 a.m. after consuming a standard breakfast including fruit juice and cereal. Subjects were placed in the supine position and one arterial and two venous catheters were placed under local anaesthesia. The arterial catheter, used for collection of blood samples and for green dye measurement, was inserted antegrade into the femoral artery of the right leg (experimental leg) with the tip positioned ∼2 cm proximal to the inguinal ligament. The second catheter, used for collection of venous blood samples and for green dye measurements, was placed retrograde in the femoral vein of the left leg with the tip positioned 6 cm distal to the inguinal ligament. The third catheter, used for measurements of thigh blood flow, was placed antegrade into the femoral vein with the tip positioned 2 cm distal to the inguinal ligament. A thermistor (Edslab, T.D. Probe, 94-030-2.5F, Baxter A/S, Allerod, Denmark) for measurement of blood temperature was advanced ∼8 cm beyond the tip of the venous catheter.

Experimental protocol

The exercise protocol (Fig. 1) consisted of four 6 min LI bouts (EX 1–4) followed by four 6 min HI bouts (EX 5–8). The LI bouts and HI bouts were interspersed with 30 min and 45 min rest periods, respectively. These recovery durations were selected to ensure that muscle blood flow, blood gases and metabolites, and Inline graphic had returned to baseline before the commencement of the next exercise bout. An occlusion cuff placed below the knee was inflated (240 mmHg) 30 s prior to exercise and remained inflated throughout exercise in order to avoid contribution of blood from the lower leg. Before and during EX1–2 and EX5–6, blood flow was measured and femoral arterial and venous blood samples were obtained. During EX3 and EX6, venous blood samples were obtained at rest, during passive exercise and frequently during exercise. For 180 s prior to the onset of the single-legged knee-extension exercise, the leg was passively moved in order to accelerate the ergometer flywheel and ensure a constant power output from the onset of exercise. Blood was drawn from the femoral artery and vein during passive exercise and frequently during the initial phase of exercise, i.e. five arterial and six venous samples were obtained between −3 and 20 s of exercise using racks of stop-cocks (Bangsbo et al. 2000; Krustrup, 2004). Further arterial and venous samples were collected at 30, 45, 60 and 75 s and 1.5, 2, 2.5, 3, 4, 5 and 6 min of exercise. Blood flow was measured at rest, during passive exercise, and as frequently as possible during the first 60 s of exercise (8–10 measurements in EX1–2 and EX5–6) as well as from 70–85, 100–115, 140–155, 175–190, 240–255, 295–310 and 330–345 s of exercise (see Fig. 1). The multiple transitions used in the present study allowed us to obtain a high time resolution for the measurement of blood flow and arterio-venous difference across the exercise transient, i.e. the high measurement frequency was obtained by using a composite of measurements made at different times during the repeat exercise transitions.

Figure 1. Schematic representation of the experimental protocol.

Figure 1

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Four consecutive 6 min low-intensity single-legged knee-extension exercise bouts (LI, EX1–4) were performed interspersed with 30 min rest periods, followed by four 6 min high-intensity single-legged knee-extension exercise bouts (HI, EX5–8) interspersed with 45 min rest periods. During EX1–2 and EX5–6, femoral arterial blood samples (BSa) and venous blood samples (BSv) were collected and thigh blood flow was measured. During EX3 and EX7, the vein-to-artery transit time (TTv–a) was determined and venous blood samples were collected. During EX4 and EX8, the artery-to-vein transit time (TTa–v) was determined.

Between 0.5 to 1.5 min of exercise the arterial blood samples were taken approximately 6 s before the venous samples and for the remainder of the exercise 5 s before, in order to account for the transit time of blood from the artery through the muscle capillary bed and to the collection point at the vein (Bangsbo et al. 2000). Afterwards, all measurements were time-corrected to represent the time in the muscle capillaries based on the individual artery-to-vein transit times determined in EX4 and EX8. During EX4 and EX8, artery-to-vein mean transit time was measured at rest, during passive exercise and as frequently as possible during exercise, i.e. after 6, 35, 60, 90, 120, 180 and 270 s of exercise (Fig. 1).

Measurements and analyses

Thigh blood flow measurements

Femoral venous blood flow (i.e. thigh blood flow) was measured by the constant infusion thermodilution technique (Andersen & Saltin, 1985). Briefly, venous and infusate temperatures were measured continuously before and during ice-cold saline infusion (10–15 s) at a rate of 120 ml min−1 to achieve a drop in venous blood temperature of ∼0.6–2°C. Resting blood flow measurements were made with an infusion rate of ∼30 ml min−1 for 30–45 s. Venous temperature was measured with the thermistor positioned through the venous catheter. Infusate temperature (0–4°C) was measured at the site of entry to the catheter (Edslab flow-through thermister). Venous blood temperature and saline infusate temperatures were recorded at 400 Hz analog-to-digital sampling rate (Powerlab 16 s data acquisition system, Chart v4.13 software, ADInstruments, Sydney, Australia) onto the hard drive of a computer.

Artery-to-vein transit times

To determine the femoral artery-to-vein mean transit time (MTTa–v), 3 mg of indocyanine green (ICG, Becton Dickenson) at a concentration of 5 mg ml−1 was rapidly injected into the femoral artery, immediately followed by a flush of 5 ml isotonic saline. Blood was withdrawn from the femoral vein at a rate of 30 ml min−1 for measurements of ICG concentration with a linear densitometer. The densitometer output was sampled at a frequency of 100 Hz. The time from injection to the time of appearance and the time when the curve peaked was calculated as described by Bangsbo et al. (2000) and corrected by the transit time of the catheter (i.e. the dead space of the catheter divided by the pump flow). The mean transit time from femoral artery to the muscle capillaries and from the muscle capillaries to the femoral vein was estimated to be 1/3 and 2/3, respectively, of the total femoral artery-to-vein transit time (Bangsbo et al. 2000).

Blood analyses

Arterial and venous blood samples were immediately analysed for Inline graphic, O2 saturation and haemoglobin (ABL510, Radiometer, Copenhagen, Denmark) from which O2 content was calculated. For the determination of blood lactate and glucose (YSI 2300, Yellow Spring Instruments (YSI), Yellow Springs, OH, USA), 200 μl of whole blood was haemolysed within 10 s of sampling by adding to 200 μl of buffer (YSI; 0.5% Triton X-100).

Muscle fibre type and capillary determination

Muscle biopsies were mounted in an embedding medium (OCT Compound Tissue-Tek, Sakura Finetek, Zoeterwoude, The Netherlands) and frozen in isopentane that was cooled to the freezing point in liquid nitrogen. These samples were stored at –80°C prior to histochemical analysis for fibre type distribution and fibre type specific capillarisation. Five serial 10-μm-thick sections were cut at –20°C and incubated for myofibrillar ATPase reactions at pH 9.4 after preincubation at pH 4.3, 4.6 and 10.3. Based on the myofibrillar ATP staining, individual fibres were classified under light microscopy as slow twitch (ST), fast twitch (FT)a or FTx.

Quadriceps muscle mass determination

The mass of the quadriceps femoris muscle of the experimental leg was estimated anthropometrically by measurements of the thigh length, and thigh circumference and skin fold thickness at three sites and corrected based on a comparison between MR-scan and anthropometric determinations (Krustrup et al. 2004c).

Calculations and mathematical modelling

Thigh Inline graphic was calculated by multiplying Inline graphic with the a–Inline graphic difference, and thigh lactate release was calculated by multiplying Inline graphic with the venous–arterial lactate difference. A continuous blood flow curve was constructed for each subject by linear interpolation of the measured blood flow data points to obtain time-matched values of Inline graphic with the blood variables.

For Inline graphic and Inline graphic, the mean value for each of the sampling periods throughout exercise was calculated and used in subsequent curve fitting. The data were modelled from the onset of exercise using eqn (1) for LI and eqn (2) for HI.

graphic file with name tjp0590-4363-m1.jpg (1)
graphic file with name tjp0590-4363-m2.jpg (2)

where: Inline graphic represents the absolute Inline graphic at a given time t; Inline graphic represents the mean Inline graphic in the final 30 s of the baseline period; Ap, Tdp and τp represent the amplitude, time delay and time constant, respectively, describing the fundamental increase in Inline graphic above baseline; and As, Tds and τs represent the amplitude, time delay before the onset of, and time constant describing the development of, the Inline graphic slow component, respectively. The Inline graphic slow component was also described as the difference in Inline graphic between 6 min and 2 min of exercise (6–2 min). An iterative process was used to minimize the sum of the squared errors between the fitted function and the observed values. Inline graphic and a–Inline graphic difference data were modelled in the same way.

For Inline graphic, the mean response time (MRTp) for the fundamental phase of the response in both LI and HI was calculated by summing the Tdp and τp since this parameter best describes the overall Inline graphic kinetics following the onset of contractions (Koga et al. 2005; Whipp & Rossiter, 2005). In addition, the mean response time for the entire Inline graphic response (MRTt) was calculated by fitting a single exponential curve through the data from the onset of exercise.

Statistics

Data were analysed using a two-factor (condition × time) repeated measure analysis of variance (ANOVA), with significance set at P < 0.05. Significant interactions and main effects were subsequently analysed using a Newman–Keuls post hoc test. Differences in Inline graphic, Inline graphic and a–Inline graphic difference kinetics were tested using the Student's paired t test and relationships were explored using Pearson product moment correlation coefficients. Data are presented as means ± SEM, unless otherwise stated.

Results

Inline graphic, Inline graphic and a–Inline graphic difference kinetics for LI and HI

The parameters derived from modelling the Inline graphic, Inline graphic and a–Inline graphic difference data for LI and HI are presented in Table 1 and the responses are illustrated in Fig. 2 and Fig. 3. Equation (1) provided an adequate fit to the Inline graphic, Inline graphic and a–Inline graphic difference data for LI. However, for HI, eqn (2) provided a better fit to the Inline graphic data in four subjects and a better fit to the Inline graphic data in two subjects.

Table 1.

Muscle blood flow (Inline graphic), arterio-venous O2 difference (a–v O2 diff) and oxygen uptake (Inline graphic) kinetics variables for 6 min bouts of low-intensity (LI) and high-intensity (HI) knee-extensor exercise

Low intensity High intensity
Inline graphic (l min−1) a–v O2 diff (ml l−1) Inline graphic (ml min−1) Inline graphic (l min−1) a–v O2 diff (ml l−1) Inline graphic (ml min−1)
Baseline values 1.08 ± 0.08 47 ± 8 48 ± 6 1.52 ± 0.11 43 ± 7 46 ± 8
Td (s) −1 ± 2 8 ± 1 4 ± 1 1 ± 1 5 ± 0 4 ± 1
Tau (s) 19 ± 4 21 ± 3 26 ± 3 26 ± 5 12 ± 3$*# 25 ± 4
Amplitude 2.06 ± 0.29 70 ± 6 327 ± 32 4.32 ± 0.47# 89 ± 5 687 ± 55#
MRTp (s) 18 ± 4* 28 ± 4 30 ± 4 27 ± 5 17 ± 3$*# 29 ± 4
6–2 min 0.07 ± 0.09 5 ± 2 32 ± 8 0.47 ± 0.19# 11 ± 3 112 ± 21#
End exercise 3.20 ± 0.3 117 ± 5 375 ± 37 6.05 ± 0.59# 132 ± 6# 790 ± 61#
MRTt (s) 16 ± 4* 35 ± 5 34 ± 4 31 ± 7 21 ± 3 37 ± 5
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Data are presented as means ± SEM. Td, time delay; MRTp, mean response time for the fundamental phase of the response; 6–2 min, the difference in Inline graphic between 6 min and 2 min of exercise; MRTt, mean response time for the entire Inline graphic response; End exercise, end-exercise value for Inline graphic. *Significantly different from Inline graphic. $Significantly different from Inline graphic. #Significantly different from LI.

Figure 2. Thigh blood flow (A), arterial and venous O2 content (B) and muscle O2 extraction (C) before and during 6 min of low-intensity (LI, filled symbols) and high-intensity (HI, open symbols) single-legged knee-extension exercise.

Figure 2

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Values are mean ± SEM. #LI significantly different from HI.

Figure 3. Muscle oxygen uptake before and during 6 min of low-intensity (LI, filled symbols) and high-intensity (HI, open symbols) single-legged knee-extension exercise.

Figure 3

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Values are mean ± SEM. #LI significantly different from HI.

For LI, following a short time delay of ∼4 s, Inline graphic rose exponentially with a τp of 26 ± 3 s. Inline graphic increased with no discernible delay at the onset of exercise with a τp of 19 ± 4 s. The MRTp for Inline graphic kinetics was smaller (P < 0.05) than the MRTp for Inline graphic kinetics, i.e. the kinetic adaptation was faster. Similarly, the MRTt for Inline graphic was smaller (P < 0.05) than the MRTt for Inline graphic. The a–Inline graphic difference was unchanged for ∼8 s after which it increased with a τp of 21 ± 3 s. The MRTp for a–Inline graphic difference was not different from the MRTp for Inline graphic or Inline graphic (Table 1).

For HI, following a modelled time delay of ∼4 s, Inline graphic rose with a τp of 25 ± 4 s. Inline graphic increased with no delay at the onset of exercise with a τp of 26 ± 5 s. The MRTp for Inline graphic kinetics and the MRTp for Inline graphic kinetics were not different. The a–Inline graphic difference was unchanged for ∼5 s after which it increased with a τp of 12 ± 3 s. The MRTp for a–Inline graphic difference was shorter than the MRTp for both Inline graphic and Inline graphic (P < 0.05; Table 1).

Differences in Inline graphic, Inline graphic and a–Inline graphic difference between LI and HI

There was no difference in the baseline values of Inline graphic, Inline graphic and a–Inline graphic difference between LI and HI. However, Inline graphic, Inline graphic and a–Inline graphic difference for HI were higher (P < 0.05) than for LI from 13, 10 and 16 s, respectively, and throughout exercise (Figs 2 and 3) with approximately 2-fold higher (P < 0.01) end-exercise values for Inline graphic (790 ± 61 vs. 375 ± 37 ml min−1) and Inline graphic (6.05 ± 0.59 vs. 3.20 ± 0.30 l min−1) and 17% higher (P < 0.05) end-exercise a–Inline graphic difference (132 ± 6 vs. 117 ± 5 ml l−1). The amplitude for Inline graphic and Inline graphic were greater for HI compared with LI (P < 0.01), but the a–Inline graphic difference amplitude was not different between LI and HI. The ratio of the amplitude of Inline graphic to the amplitude of Inline graphic, i.e. Inline graphic, was ∼6.3 for both LI and HI.

No ‘slow component’ for Inline graphic, Inline graphic and a–Inline graphic difference data was evident for LI whereas a Inline graphic slow component could be discerned in four subjects and a Inline graphic slow component was measured in two subjects during HI. The change in variables between 2 and 6 min of exercise was greater (P < 0.05) in HI compared with LI for Inline graphic and Inline graphic but not for a–Inline graphic difference (Table 1).

The Td, τp and MRTp values were not significantly different between LI and HI for either Inline graphic or Inline graphic. The Td for a–Inline graphic difference was not different between LI and HI; however, both the τp and MRTp for a–Inline graphic difference was significantly smaller (i.e. the kinetics were faster) for HI compared with LI (P < 0.05; Table 1). Excess O2, i.e. O2 not taken up (Inline graphic×Inline graphic), was ∼160 ml min−1 during passive exercise, was elevated 2-fold within the first 5 s of exercise in LI and HI, and remained unaltered during exercise, with no significant differences (P = 0.08) between LI and HI (Fig. 4).

Figure 4. Excess muscle oxygen before and during 6 min of low-intensity (LI, filled symbols) and high-intensity (HI, open symbols) single-legged knee-extension exercise.

Figure 4

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Values are mean ± SEM.

Figure 5 shows the changes in Inline graphic, Inline graphic and a–Inline graphic difference for the initial phase of LI (panel A) and HI (panel B) exercise when the responses are normalized to 100% of the amplitude attained after 2 min of exercise. The relatively faster kinetics of Inline graphic relative to Inline graphic is evident, especially for LI exercise, while the a–Inline graphic difference falls more rapidly in HI compared with LI.

Figure 5. Schematic illustration, based on the group mean model fits, of the relative changes in muscle blood flow, O2 uptake and arterio-venous O2 difference for the initial phase of low-intensity (A) and high-intensity (B) exercise.

Figure 5

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Notice that muscle blood flow kinetics are faster than muscle O2 uptake kinetics for low-intensity exercise but that the kinetics of muscle blood flow and muscle O2 uptake are similar for high-intensity exercise. Notice also that the arterio-venous O2 difference falls more rapidly following the onset of HI compared with LI exercise.

Blood lactate, pH, Inline graphic and HCO3 −

Blood variables for LI and HI are summarized in Table 2. No difference was observed in baseline values for blood lactate between LI and HI. However, after 30 s and 6 min of exercise, venous blood lactate was 2- and 7-fold higher (P < 0.05) for HI compared with LI (6 min: 5.3 ± 0.9 vs. 0.8 ± 0.1 mmol l−1), with corresponding end-exercise venous pH values of 7.19 ± 0.01 and 7.30 ± 0.01 (Table 2). No differences were observed between LI and HI in blood pH, Inline graphic and HCO3− during the first 30 s of exercise (Table 2).

Table 2.

Blood variables at rest and during 6 min of low- (LI) and high-intensity (HI) knee-extensor exercise

Low intensity High intensity
Rest 30 s 60 s 3 min 6 min Rest 30 s 60 s 3 min 6 min
Blood lactate (mmol−1)
 Artery 0.7 ± 0.0 0.7 ± 0.1 0.8 ± 0.1 0.9 ±0.1 0.9 ± 0.1 0.6 ± 0.1 0.7 ± 0.1 1.1 ± 0.1 2.4 ± 0.4# 3.3 ± 0.6#
 Vein 0.7 ± 0.1 0.9 ± 0.1 0.9 ± 0.1 0.9 ± 0.1 0.8 ± 0.1 0.7 ± 0.1 1.6 ± 0.1# 2.5 ± 0.3# 4.2 ± 0.7# 5.3 ± 0.9#
Blood pH (−log H+)
 Artery 7.40 ± 0.01 7.38 ± 0.01 7.38 ± 0.01 7.37 ± 0.01 7.38 ± 0.01 7.38 ± 0.01# 7.38 ± 0.01 7.36 ± 0.00# 7.35 ± 0.01# 7.35 ± 0.01#
 Vein 7.34 ± 0.01 7.36 ± 0.01 7.33 ± 0.01 7.31 ± 0.01 7.30 ± 0.01 7.35 ± 0.01 7.34 ± 0.01 7.27 ± 0.01# 7.21 ± 0.01# 7.19 ± 0.01#
Blood Inline graphic (mmHg)
 Artery 41.6 ± 0.7 43.8 ± 0.9 43.0 ± 0.5 43.6 ± 0.8 43.3 ± 1.3 42.4 ± 0.7 41.4 ± 0.6 42.9 ± 0.3 42.0 ± 0.6 38.6 ± 0.3#
 Vein 57.2 ± 2.5 52.3 ± 1.4 57.2 ± 1.7 60.8 ± 2.1 63.8 ± 1.9 51.1 ± 1.3# 50.3 ± 0.7 60.6 ± 1.5 73.6 ± 2.8# 74.5 ± 3.1#
Blood HCO3− (mmol l−1)
 Artery 24.5 ± 0.3 25.0 ± 0.4 24.4 ± 0.3 24.5 ± 0.4 24.4 ± 0.7 24.0 ± 0.2 23.6 ± 0.2 23.7 ± 0.2 22.3 ± 0.1# 20.6 ± 0.2#
 Vein 28.6 ± 0.9 27.7 ± 0.4 28.7 ± 0.6 29.0 ± 0.6 29.7 ± 0.7 26.5 ± 0.4 28.7 ± 1.5 27.1 ± 0.2# 27.1 ± 0.3# 26.1 ± 0.3#
Plasma K+ (mmol l−1)
 Artery 4.0 ± 0.0 4.1 ± 0.1 4.2 ± 0.0 4.3 ± 0.1 4.2 ± 0.0 4.2 ± 0.1 4.3 ± 0.1 4.6 ± 0.0# 4.9 ± 0.1# 5.0 ± 0.1#
 Vein 4.1 ± 0.0 4.7 ± 0.1 4.8 ± 0.1 4.8 ± 0.1 4.7 ± 0.0 4.3 ± 0.1 5.3 ± 0.1# 5.4 ± 0.1# 5.7 ± 0.1# 5.6 ± 0.1#
Hb (g dl−1)
 Artery 9.2 ± 0.1 9.0 ± 0.2 9.1 ± 0.1 9.1 ± 0.2 9.1 ± 0.2 8.8 ± 0.1 8.9 ± 0.1 8.9 ± 0.1 9.0 ± 0.1 9.1 ± 0.2
 Vein 9.1 ± 0.2 9.2 ± 0.2 9.2 ± 0.2 9.2 ± 0.1 9.2 ± 0.1 8.8 ± 0.1 8.9 ± 0.1 9.0 ± 0.1 9.1 ± 0.1 9.2 ± 0.2
Open in a new tab

Data are presented as means ± SEM.

#

Denotes significant difference from LI.

Muscle mass, fibre types and capillaries

The quadriceps muscle mass of the experimental leg was 2.34 ± 0.11 (2.01–2.69) kg. The distribution of ST, FTa and FTx fibres in m. vastus lateralis was 50 ± 5 (34–68)%, 32 ± 5 (17–49)% and 18 ± 1 (15–23)%, respectively. The number of capillaries per fibre was 4.0 ± 0.5 (2.6–6.7) and the number of capillaries per mm2 was 645 ± 113 (315–1278). No correlations were observed between either the fraction of ST fibres or muscle capillarisation and the parameters describing the Inline graphic, Inline graphic and a–Inline graphic difference kinetics. The fraction of FTx fibres was correlated (P < 0.05) with Inline graphic MRTp for LI (r = 0.85) and Inline graphic 6–2 min for HI (r = 0.77). The correlation between FTx fibres and the end-exercise Inline graphic‘gain’ (i.e. ΔInline graphic/ΔWR) for HI approached significance (r = 0.71; P = 0.07).

Discussion

The purpose of the present study was to investigate the interactions of Inline graphic, Inline graphic and O2 extraction during LI and HI knee-extension exercise in humans. The results confirm our experimental hypotheses and indicate that O2 delivery does not limit Inline graphic kinetics during LI or HI exercise. Despite a tendency for Inline graphic kinetics to become slower at the higher exercise intensity, such that Inline graphic kinetics was faster than Inline graphic kinetics for LI but not HI, the time constant for Inline graphic kinetics was not significantly different between LI and HI (τ = 26 and 25 s, respectively). The somewhat slower Inline graphic kinetics in HI compared with LI was apparently compensated by a more rapid muscle O2 extraction with both the time delay and the time constant for a–Inline graphic difference being significantly reduced in HI compared with LI (Fig. 5).

While our study confirms the results of Grassi et al. (1996) for moderate-intensity cycle exercise, this is the first study, to our knowledge, to directly investigate the inter-relationships between Inline graphic, Inline graphic and O2 extraction kinetics during both LI and HI exercise. This enabled us to address the controversial question of whether Inline graphic (and thus muscle O2 delivery) might limit Inline graphic kinetics following the onset of exercise and, in particular, whether any such limitation might be exercise intensity dependent. Previous studies addressing the influence of exercise intensity on the control of Inline graphic kinetics in humans have typically estimated Inline graphic from Inline graphic, requiring multiple transitions due to the noise inherent in breath-to-breath data, and/or estimated Inline graphic using non-invasive Doppler ultrasound techniques (van Beekvelt et al. 2001; Koga et al. 2005). The few studies that have directly measured Inline graphic and Inline graphic kinetics at more than one intensity in the same study did not use multiple exercise transitions and did not describe the kinetic features of the response (Krustrup et al. 2003, 2004a). Key advances of the present study include that we: (1) made direct and high-frequency measurements of Inline graphic and a–Inline graphic difference across the rest-to-exercise transient and subsequently calculated Inline graphic from the Fick equation; (2) used the artery-to-vein mean transit time to correct our measurements for the transit time of blood from the artery through the muscle capillary bed and to the collection point at the vein; and (3) asked the subjects to complete four repeat exercise transitions at both LI and HI, providing increased confidence in the kinetic parameters derived from the curve-fitting procedures (Lamarra et al. 1987).

Our results indicate that Inline graphic kinetics is not limited by Inline graphic during LI or HI knee-extension exercise. This interpretation is based on the following evidence: (1) the τp for Inline graphic was significantly shorter than the τp for Inline graphic during LI, and there was no significant difference between the τp for Inline graphic and Inline graphic during HI; (2) the τp for Inline graphic was not significantly different between LI and HI, with group mean values of 26 s and 25 s, respectively; and (3) there was an excess of O2 delivery relative to O2 utilization during both LI and HI with a larger excess in the initial phase of exercise (Fig. 4). Nevertheless, although the difference in Inline graphic kinetics between LI (∼19 s) and HI (∼25 s) was not statistically significant, it is evident that O2 extraction increased more rapidly in HI than LI. This suggests that the slight slowing of Inline graphic in HI was compensated by faster O2 extraction kinetics to prevent a slowing of Inline graphic kinetics. However, although these data imply that the system was closer to the so-called ‘tipping point’ beyond which muscle O2 delivery might begin to limit Inline graphic kinetics in HI (Poole et al. 2008), the similarity of τp for Inline graphic for HI and LI indicates that the tipping point was not crossed and that Inline graphic cannot be considered to be ‘limiting’Inline graphic even in HI (Poole et al. 2008).

Our interpretation regarding the role of O2 in regulating Inline graphic kinetics is consistent with several previous studies. Grassi et al. (1996) reported that the half-time for Inline graphic (∼27 s) and Inline graphic (∼28 s) following the onset of LI cycling were not significantly different. However, Inline graphic increased rapidly in the first 10–15 s of exercise whereas Inline graphic rose only slowly, leading to a surplus of O2 supply relative to O2 requirement in the early phase. Also, Bangsbo et al. (2000) reported that the difference between thigh O2 delivery and thigh O2 uptake increased in the early phase of intense knee-extension exercise and was never smaller than the value measured at baseline, suggesting that O2 availability is not limiting Inline graphic kinetics. Koga et al. (2005) used Doppler ultrasonography and measurements of femoral venous O2 content to estimate Inline graphic and Inline graphic during knee-extension exercise. These authors reported that Inline graphic kinetics was significantly faster than Inline graphic kinetics. The majority of the other investigations that have addressed the question of an exercise intensity-dependent modulation of Inline graphic kinetics by muscle O2 delivery have used Doppler techniques to estimate Inline graphic kinetics and Inline graphic kinetics as a surrogate for Inline graphic kinetics (Grassi et al. 1996; Krustrup et al. 2009). The consensus from these studies is that Inline graphic kinetics is faster than Inline graphic kinetics and that the latter is not limited by the former (MacDonald et al. 1998, 2000; Fukuba et al. 2004; Paterson et al. 2005). Our results are also consistent with previous animal studies. Based on measurements of capillary red blood cell flux and microvascular Inline graphic in rats, Behnke et al. (2002) also conclude that, in healthy muscle, Inline graphic kinetics are faster than, and do not limit, Inline graphic kinetics. Using an isolated canine gastrocnemius model, Grassi et al. reported that Inline graphic kinetics was significantly faster than Inline graphic kinetics following the onset of contractions requiring ∼60%Inline graphic (Grassi et al. 1998) but that Inline graphic and Inline graphic kinetics was similar following the onset of contractions requiring ∼100%Inline graphic (Grassi et al. 2000). Interestingly, in those studies, fixing Inline graphic to the steady-state value from the onset of contractions did not alter Inline graphic kinetics at ∼60%Inline graphic (Grassi et al. 1998) but resulted in a significant speeding of Inline graphic kinetics at ∼100%Inline graphic (Grassi et al. 2000). In contrast to the present study, these results suggest an intensity-related O2 dependency of Inline graphic kinetics in this preparation.

It should be noted that the extent to which Inline graphic might limit Inline graphic kinetics will be related to factors such as the muscle mass recruited, muscle contraction regimen, exercise modality, body position and inspired O2 fraction (Jones & Poole, 2005). It has been shown, for example that, for the same exercise intensity, Inline graphic kinetics is slower in hypoxia relative to normoxia (Linnarsson et al. 1974; Engelen et al. 1996) and in the supine compared with the upright body position (MacDonald et al. 1998; Koga et al. 1999). Inline graphic kinetics is also slowed relative to the control condition following ß-blockade (Hughson, 1984). These results indicate that interventions which reduce muscle O2 delivery have the potential to slow Inline graphic kinetics. In contrast, interventions which may enhance muscle O2 delivery such as priming exercise (MacDonald et al. 1997; Burnley et al. 2000) and hyperoxia (Linnarsson et al. 1974; Wilkerson et al. 2006) do not consistently speed Inline graphic kinetics. Moreover, some studies which have reduced Inline graphic using lower body negative pressure (Williamson et al. 1996) or double blockade to inhibit the synthesis of nitric oxide and prostanoids (Nyberg et al. 2010) have not resulted in altered Inline graphic kinetics. We would point out that, although our results suggest that Inline graphic kinetics is not limited by Inline graphic during either LI or HI, our experiments were confined to single-leg knee-extension exercise performed in the semi-supine position. It is known that the quadriceps muscle is well-perfused in this type of exercise (Andersen & Saltin, 1985) and we cannot exclude the possibility that Inline graphic might limit Inline graphic kinetics during HI exercise which engages a larger muscle mass.

Our observation of a short time delay (of ∼4 s) before Inline graphic increased appreciably following the onset of exercise is worthy of comment. Such a delay has been noted previously (Grassi et al. 1998; Bangsbo et al. 2000) but is inconsistent with prevailing theories of metabolic control which relate the regulation of mitochondrial respiration to changes in the concentrations of high-energy phosphates in the cytosol (see Poole et al. 2007, 2008 for review). Oxidative phosphorylation begins to increase with the first muscle contraction in isolated single myocytes (Kindig et al. 2003) and rat skeletal muscle with intact blood supply (Behnke et al. 2002). It is likely therefore that Inline graphic increases with essentially no delay. In this regard, it is important to note that the ‘time delay’ derived from the modelling procedure is simply a parameter that permits the best possible fit of the model to the data. In fact, Inline graphic increased within the first few seconds of exercise, albeit at a slower rate than was observed later in the transition.

Few studies have investigated the influence of exercise intensity on Inline graphic kinetics following the onset of exercise. In the present study, we observed that Inline graphic increased immediately at the onset of loaded contractions and then rose with a τp of ∼19 s for LI and ∼26 s for HI. When the entire Inline graphic response was considered, the MRTt was ∼16 s for LI and ∼31 s for HI. Although these differences were not statistically significant, they suggest that Inline graphic may be somewhat slower at higher relative work rates. In the study of Koga et al. (2005) in which Inline graphic was estimated using Doppler techniques during two-legged upright knee-extension exercise, the MRTt was ∼35 s for LI and ∼46 s for HI, but this ∼30% slowing of Inline graphic at the higher exercise intensity was not statistically significant. Other studies which measured Inline graphic at more than one intensity appear to show a slower Inline graphic response at higher work rates; however, the Inline graphic kinetics was not formally characterized in these studies (van Beekvelt et al. 2001; Krustrup et al. 2004a). The control of vascular conductance and hence Inline graphic is complex and incompletely understood, involving both ‘instantaneous’ processes such as the muscle pump and immediate vasodilatation of unknown origin, as well as subsequent feedback control linked to shear-induced nitric oxide (NO) release, ATP (and NO) released from erythrocytes, prostaglandins, conducted vasodilatation, sympatholysis and metabolite accumulation (Clifford & Hellsten, 2004; Delp & O’Leary, 2004; Tschakovsky & Joyner, 2008). These feedback processes may be inherently slower at higher work rates. Additionally, further recruitment of type II fibres with time (Krustrup et al. 2004b), along with the development of a Inline graphic slow component in HI, would probably act to slow the overall Inline graphic dynamics during HI compared with LI.

Following the onset of LI exercise, there was a delay of approximately 8 s before the a–Inline graphic difference began to increase (τp of ∼21 s), whereas for HI exercise, both the time delay (∼5 s) and τp (∼12 s) were significantly shorter. An initial time delay of 6–15 s before a widening of the a–Inline graphic difference has been reported previously (Bangsbo et al. 2000; Grassi et al. 2000). This time delay arises as a consequence of a constant (for HI) or slightly higher (for LI) venous O2 content over the first 5–10 s of exercise which, given a constant arterial O2 content, leads to a similar (for HI) or slightly reduced (for LI) a–Inline graphic difference (Fig. 2). It has been proposed that this initial time delay for a–Inline graphic difference represents a period of time where Inline graphic is at least adequate to support Inline graphic (Grassi et al. 2003). As noted previously (Grassi et al. 2005), it is striking that the directly measured values for Td and τ describing the change in a–Inline graphic difference following the onset of exercise are very similar to the Td and τ values that are often reported for the changes in deoxyhaemoglobin concentration measured with near-infra-red spectroscopy and used to estimate changes in muscle fractional O2 extraction (DeLorey et al. 2003; Grassi et al. 2003; Jones et al. 2009). On the one hand, a more rapid increase of the a–Inline graphic difference for HI compared with LI might indicate that O2 delivery has become somewhat less sufficient to support oxidative processes in the myocytes. On the other hand, the fact that τp for Inline graphic kinetics was not different between LI and HI indicates that O2 delivery remains sufficient (an interpretation supported by the excess O2 data) and that Inline graphic kinetics is limited by an inability to increase the a–Inline graphic difference more rapidly following the onset of exercise. This may be a consequence of intrinsic inertia of muscle oxidative metabolism, perhaps related to feedback control through changes in high-energy phosphate concentrations and/or to slow activation of rate-limiting oxidative metabolic enzymes (Grassi, 2006; Korzeniewski & Zoladz, 2006; Poole et al. 2008). Alternatively, it is possible that, whereas bulk O2 delivery to muscle following the onset of exercise is rapid, the regional distribution of O2 within the active musculature is heterogeneous and not well matched to local metabolic rate (Kalliokoski et al. 2003; Koga et al. 2007; Poole et al. 2008).

Several studies have indicated that muscle fibre type and fibre recruitment during exercise can influence Inline graphic kinetics (Barstow et al. 1996; Pringle et al. 2003; Krustrup et al. 2004b, 2008). In the present study, the fraction of FTx fibres in the vastus lateralis tended to be correlated (r = 0.71; P = 0.07) with the end-exercise Inline graphic gain for HI. Given the relatively small sample size in the present study, this may support the notion that a greater fraction of less oxidative, more fatigable fibres may be associated with reduced efficiency (Pringle et al. 2003). The fraction of FTx fibres was also correlated with several indices of Inline graphic kinetics including the MRT for LI and the Inline graphic 6–2 min for HI. These results tentatively suggest that the fraction of FTx fibres might be linked to slower Inline graphic kinetics perhaps as a consequence of differences in the local control of blood flow (McAllister, 2003; Ferreira et al. 2006; Hellsten et al. 2009). Indeed, in the rat, there is evidence that O2 delivery is lower and fractional O2 extraction is higher in muscles that are considered to be FT (e.g. gastrocnemius and peroneal) compared with muscles that are considered to be ST such as the soleus (Behnke et al. 2003; McDonough et al. 2005). The greater sustained microvascular O2 pressure head following the onset of con-tractions in ST muscles might enable a greater oxidative contribution to ATP turnover by facilitating an enhanced blood myocyte O2 flux (McDonough et al. 2005). Applying these results to the present study, it is possible that the recruitment of additional FT fibres in HI compared with LI altered vascular control (and the local relationship between Inline graphic and Inline graphic) and mandated a faster and greater change in fractional O2 extraction following the transition from passive to loaded exercise.

In conclusion, we have, for the first time, investigated the dynamic interactions of Inline graphic, Inline graphic and O2 extraction kinetics following the onset of exercise as a function of exercise intensity (HI vs. LI) in humans. Our results show that Inline graphic kinetics is not limited by bulk O2 delivery during knee-extension exercise, at least at intensities up to approximately 75% of the peak power output elicited during incremental exercise. During LI exercise, Inline graphic kinetics was significantly faster than Inline graphic kinetics, whereas during HI exercise there was no significant difference between Inline graphic kinetics and Inline graphic kinetics. The a–Inline graphic difference increased more rapidly in HI resulting in there being no slowing of Inline graphic kinetics in HI compared with LI. At both intensities, the excess O2 increased between passive exercise and loaded exercise, suggesting a surplus of O2 delivery relative to O2 utilization. These results indicate that, at least for this exercise modality and at these exercise intensities, Inline graphic kinetics is not limited by bulk muscle O2 delivery.

Acknowledgments

Some of the Inline graphic data in this study were previously presented in Krustrup et al. (2009) which focused on the agreement between muscular and pulmonary Inline graphic kinetics. We thank the subjects for their committed participation. The excellent technical assistance of Jens Jung Nielsen, Winnie Taagerup and Helgi W Olsen is greatly appreciated. The study was supported by the Danish National Research Foundation (504-14) and by the Danish Ministry of Culture (Kulturministeriets Udvalg for Idrætsforskning).

Glossary

GET

gas exchange threshold

HI/LI

high/low intensity

MRT

mean response time

Q̇m

muscle blood flow

V̇O2

muscle O2 uptake

Author contributions

A.M.J. contributed to the design of the experiment, analysis and interpretation of the data, and writing of this article. P.K. and J.B. contributed to the design of the experiment, collection, analysis and interpretation of the data, and critical revision of this article. D.P.W., N.J.B. and J.A.C. contributed to the collection and analysis of the data, and critical revision of this article. All authors approved the final version of the manuscript.

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