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The Journal of Physiology logoLink to The Journal of Physiology
. 2005 Apr 28;566(Pt 1):273–285. doi: 10.1113/jphysiol.2005.086025

Limitations to systemic and locomotor limb muscle oxygen delivery and uptake during maximal exercise in humans

Stefan P Mortensen 1, Ellen A Dawson 1,2, Chie C Yoshiga 1,2, Mads K Dalsgaard 1,2, Rasmus Damsgaard 1, Niels H Secher 1,2, José González-Alonso 1
PMCID: PMC1464731  PMID: 15860533

Abstract

Reductions in systemic and locomotor limb muscle blood flow and O2 delivery limit aerobic capacity in humans. To examine whether O2 delivery limits both aerobic power and capacity, we first measured systemic haemodynamics, O2 transport and O2 uptake Inline graphic during incremental and constant (372 ± 11 W; 85% of peak power; mean ± s.e.m.) cycling exercise to exhaustion (n = 8) and then measured systemic and leg haemodynamics and Inline graphic during incremental cycling and knee-extensor exercise in male subjects (n = 10). During incremental cycling, cardiac output Inline graphic and systemic O2 delivery increased linearly to 80% of peak power (r2 = 0.998, P < 0.001) and then plateaued in parallel to a decline in stroke volume (SV) and an increase in central venous and mean arterial pressures (P < 0.05). In contrast, heart rate and Inline graphic increased linearly until exhaustion (r2 = 0.993; P < 0.001) accompanying a rise in systemic O2 extraction to 84 ± 2%. In the exercising legs, blood flow and O2 delivery levelled off at 73–88% of peak power, blunting leg Inline graphic per unit of work despite increasing O2 extraction. When blood flow increased linearly during one-legged knee-extensor exercise, Inline graphic per unit of work was unaltered on fatigue. During constant cycling, Inline graphic, SV, systemic O2 delivery and Inline graphic reached maximal values within ∼5 min, but dropped before exhaustion (P < 0.05) despite increasing or stable central venous and mean arterial pressures. In both types of maximal cycling, the impaired systemic O2 delivery was due to the decline or plateau in Inline graphic because arterial O2 content continued to increase. These results indicate that an inability of the circulatory system to sustain a linear increase in O2 delivery to the locomotor muscles restrains aerobic power. The similar impairment in SV and O2 delivery during incremental and constant load cycling provides evidence for a central limitation to aerobic power and capacity in humans.

From rest to maximal exercise, the cardiovascular system must adjust to the increasing metabolic demand by ensuring the delivery of O2 and substrates to all body cells, in particular to the myocytes, without compromising arterial pressure. The prevailing theory is that the cardiovascular system responds to exercise of increasing intensity up to aerobic power (maximal oxygen uptake Inline graphic) by increasing systemic and contracting skeletal muscle O2 delivery in proportion to the rise in O2 demand, while increasing the perfusion pressure (Holmgren, 1956; Åstrand et al. 1964; Ekelund & Holmgren, 1967; Higginbotham et al. 1986; Reeves et al. 1990; Pawelczyk et al. 1992; Rowell, 1993; Rowell et al. 1996). However, recent findings during constant load maximal cycling exercise indicate that, following early adjustments that allow Inline graphic to be reached and maintained for 1–2 min, cardiac output Inline graphic, leg blood flow (LBF), perfusion pressure and O2 delivery decline leading to reductions in Inline graphic and leg Inline graphic despite increases in O2 extraction (González-Alonso & Calbet, 2003; González-Alonso et al. 2004). These findings suggest that a reduction in systemic and locomotive skeletal muscle O2 delivery limits aerobic and maximal endurance capacity in trained individuals. The question then arises whether systemic and locomotor limb muscle O2 delivery is also impaired during incremental exercise and whether this could explain the plateau or decline in Inline graphic observed sometimes before exhaustion (Åstrand, 1952; Taylor et al. 1955; Mitchell et al. 1958; Froelicher et al. 1972; Pollock et al. 1976; Meyers et al. 1990; Knight et al. 1992; Day et al. 2003).

Indirect evidence indicates that O2 delivery might impose a limitation to Inline graphic at intensities close to Inline graphic. Firstly, in humans the increase in Inline graphic per unit of work is attenuated at high compared to low exercise intensities (Hill & Lupton, 1923; Åstrand & Saltin, 1961; Whipp & Wasserman, 1972). Secondly, the increase in Inline graphic per litre increase in Inline graphic is attenuated at intensities above 40–70% of Inline graphic in humans, as in miniature swine (Saltin, 1964; Åstrand et al. 1964; Armstrong et al. 1987). These early observations lack conclusive support and are therefore not widely accepted. The general belief is that Inline graphic and O2 delivery increase linearly from rest to Inline graphic, implying that O2 delivery to locomotor limb muscle does not limit Inline graphic (Asmussen & Nielsen, 1952; Chapman et al. 1960; Bevegård et al. 1963; Rowell et al. 1964; Grimsby et al. 1966; Poliner et al. 1980; Higginbotham et al. 1986). This theory, however, is based on linear regression analysis of Inline graphic data that have not been normalized and on the assumption that systemic haemodynamics closely reflect skeletal muscle haemodynamics. At the skeletal muscle level, not only restrictions in the systemic supply of O2, but also limitations in diffusive O2 transport from the muscle capillary to the mitochondrial cytochrome and oxidative capacity of mitochondria could restrict Inline graphic (Roca et al. 1989). In favour of a dominant O2 supply limitation, quadriceps muscle blood flow and Inline graphic might reach ∼2.3 and ∼0.35 l kg−1 min−1 during maximal knee-extensor exercise, suggesting that only 10–15 kg of muscle needs to be recruited during whole body exercise to surpass the capacity of the human circulation to deliver O2 (Andersen & Saltin, 1985). Whether the O2 delivery to muscles and uptake of the quadriceps femoris are restricted during whole body compared to knee-extensor exercise remains unknown.

To investigate the contribution of the O2 transport system to Inline graphic, we determined: (1) whether systemic O2 delivery imposes a limitation to aerobic power and capacity, (2) whether locomotor limb blood flow and O2 delivery are impaired during incremental exercise to exhaustion to the extent that they compromise limb Inline graphic, and (3) whether quadriceps muscle blood flow and Inline graphic are lower during maximal exercise with a large compared to a small muscle mass. To accomplish these aims, we first measured systemic haemodynamics, O2 transport and Inline graphic during incremental and constant cycling exercise to exhaustion in trained male subjects and then measured systemic and exercising leg haemodynamics, O2 transport and Inline graphic during incremental cycle and knee-extensor exercise to exhaustion in another group of active male subjects. We hypothesized that restrictions in O2 supply to locomotor limb muscles imposes a limitation to aerobic power and capacity in humans.

Methods

Eighteen endurance-trained or recreationally active male subjects participated in two studies. They had a mean (±s.d.) age of 27 ± 3 years, body weight of 81.3 ± 9.6 kg, height of 185 ± 9 cm, maximal heart rate (HR) of 192 ± 7 beats min−1 and Inline graphic of 4.80 ± 0.46 l min−1. The subjects were informed of any risks and discomforts associated with the experiments before giving written consent to participate. The study was approved by the Ethics Committee of Copenhagen (KF 01-230/00) and conducted in accordance with the guidelines of the Declaration of Helsinki.

In the first study and on the first visit to the laboratory, eight endurance-trained subjects performed incremental exercise on a cycle ergometer (Excalibur, Lode, The Netherlands) to determine Inline graphic, maximal HR and peak power. Thereafter, they completed four high-intensity training sessions on the cycle ergometer. During the last session, they carried out the same protocol as during the main experiment involving incremental (INC) and constant (CON) maximal exercise separated by one hour of recovery, while continuous measures of Inline graphic, HR and oesophageal temperature were obtained. For the invasive experiment, the subjects arrived at the laboratory one hour prior to the experiment after a light breakfast. Catheters were placed into the brachial artery and an antecubital vein, with the latter catheter being advanced to the right atrium. Following 30 min of supine rest, the subjects completed INC and CON on the cycle ergometer preceded by a 15 min warm-up period (146 ± 6 W; <50% Inline graphic) and 3 min of rest, followed by 10 min of recovery. Throughout the protocol, the arms rested on aerobars simulating the position that cyclists adopt during a time-trial. During the resting and recovery periods, the subjects were allowed to move their legs (0 W). During INC, the workload was increased every minute using a computerized system to elicit 20, 40, 60, 80, 90, 95 and 100% of peak power. During CON, the intensity resulted in exhaustion within 5–7 min and Inline graphic within 4–5 min (i.e. at 372 ± 11 W or at 85% of the 438 ± 13 W peak power of the initial incremental test). The order of the two trials was randomly assigned and counterbalanced across the subjects. Exercise was performed under thermoneutral conditions (∼20°C) with fans directed against the back and the side of the subjects.

Ten subjects participated in the second investigation which was aimed at determining whether convective O2 transport and limb muscle Inline graphic are compromised during incremental cycle exercise to exhaustion and whether quadriceps muscle blood flow and Inline graphic are lower during maximal cycle compared to maximal knee-extensor exercise. In these subjects, an additional catheter was inserted into the femoral vein 2 cm from the inguinal ligament to allow for blood sampling and measurements of LBF (Andersen & Saltin, 1985). During both types of incremental exercise, the workload was increased every 1.5 min to elicit 25, 50, 75, 90 and 100% of peak power.

In study 1, blood samples (1–5 ml) were drawn simultaneously from the brachial artery and the right atrium at rest in the supine and upright positions, during the warm-up (4, 10 and 15 min), immediately before the start of maximal exercise, during maximal exercise and during the recovery (1, 3, 6 and 10 min). In INC, blood samples were drawn after 45 s of each workload and at exhaustion. In CON, they were drawn after 0.75, 1.5, 3, 4 and 5 min and before exhaustion. In study 2, blood samples were drawn simultaneously from the brachial artery, right atrium and the femoral vein after 45 s at each workload, and LBF was measured after 1 min.

Throughout the studies, pulmonary Inline graphic was measured online (Medgraphics CPX/D, Saint Paul, MN, USA; study 1 and Cosmed Quark b2, Italy; study 2). During the invasive experiments, HR was obtained from an electrocardiogram while arterial and central venous pressures were monitored with transducers positioned at heart level (Pressure Monitoring Kit, Baxter). The LBF was measured by the constant-infusion thermodilution method (Andersen & Saltin, 1985; González-Alonso et al. 2000b), while Inline graphic was calculated using the Fick principle (Inline graphic (a–v) O2 difference), assuming negligible differences in blood oxygenation between the right atrium and the pulmonary artery (Barratt-Boyes & Wood, 1956). The Inline graphic data obtained in one subject using the direct Fick principle confirmed the Inline graphic results. Stroke volume (SV) was the quotient between Inline graphic and HR, and systemic and leg vascular conductance were the quotients between Inline graphic and LBF and the perfusion pressure. Perfusion pressure was the difference between mean arterial (MAP) and central venous pressures and pulse pressure was that between the systolic and diastolic blood pressure. The left ventricular contractility index dP/dtmax was calculated as the peak systolic value of the first derivative of the arterial pressure curve over 20 cardiac cycles. For systemic O2 delivery, Inline graphic was multiplied by the arterial O2 content whereas systemic O2 extraction was the ratio between the systemic a–v O2 difference and the arterial O2 content. Blood gases, haemoglobin, glucose and lactate concentrations were measured using an ABL700 analyser (Radiometer, Copenhagen, Denmark). Oesophageal temperature was measured with a thermocouple (MOV-A, Ellab, Copenhagen, Denmark) inserted through the nasal passage at a distance equal to one-fourth of the subject's standing height, and HR was measured with a Polar Sports Tester (Polar Electro). In study 1, blood gas variables were corrected for the temperature measured during the non-invasive trials, whereas in study 2 the correction was made from the femoral venous blood temperature. Leg muscle mass was calculated from the whole-body dual-energy X-ray absorptiometry scanning (Prodigy, General Electrics Medical Systems, WI, USA) as lean mass of the region. Quadriceps femoris muscle mass was calculated using the antropomethic method, as described by Anderson & Saltin, 1985.

Statistical analysis

A one-way repeated measures analysis of variance (ANOVA) was performed to test significance within and between the two trials. Following a significant F test, pair-wise differences were identified using Tukey's honestly significant difference (HSD) post hoc procedure. To determine whether exhaustion during the constant maximal exercise was preceded by reductions in Inline graphic, SV and O2 delivery, final values were compared with peak values during exercise using one-way repeated measures ANOVA with Tukey's HSD post hoc procedure. The significance level was set at P < 0.05 and data are means ± s.e.m. unless indicated otherwise.

Results

Performance and maximal O2 uptake

No significant differences in endurance, Inline graphic or peak power were observed between the non-invasive and the invasive experiments. In INC, time to fatigue was 6.45 ± 0.2 and 6.96 ± 0.1 min during the non-invasive and invasive experiments, respectively, accompanied by a similar Inline graphic (4.81 ± 0.12 and 4.75 ± 0.15 l min−1, respectively) and peak power (440 ± 16 and 446 ± 13 W, respectively). Similarly, in CON, time to fatigue was 7.01 ± 0.23 and 6.87 ± 0.50 min during the non-invasive and invasive experiments, respectively, and Inline graphic was 4.82 ± 0.12 versus 4.75 ± 0.13 l min−1. In INC the workload elicited 20 ± 0, 39 ± 0, 59 ± 1, 79 ± 1, 88 ± 15, 93 ± 1 and 100 ± 0% of peak power during the invasive experiment. Oesophageal temperature increased from ∼37.8°C at the onset of exercise to 39.5 ± 0.1 and 39.9 ± 0.1°C in INC and CON, respectively (Fig. 1).

Figure 1. Core temperature during the constant and incremental protocols.

Figure 1

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Oesophageal temperature at rest, during submaximal and maximal exercise, and during 10 min of recovery, in incremental (•) and constant (^) exercise protocols. Data are means ± s.e.m. for 8 subjects.

Systemic haemodynamics, O2 transport and O2 uptake

No differences in systemic haemodynamics, O2 transport or Inline graphic were observed at rest or during the 15 min of submaximal exercise (Fig. 2). In INC, Inline graphic increased linearly to 80% of peak power (r2 = 0.998; P < 0.001) and then plateaued (Figs 2, 3, 4). In CON, Inline graphic increased during the first 1.5 min, reached a peak value of 27.1 ± 1.1 l min−1 after 4.6 ± 0.6 min (range 3–6 min) and then declined 1.9 ± 0.5 l min−1 before exhaustion (P < 0.05). The observed plateau in Inline graphic above 80% of peak power in INC and the drop during CON were due to a fall in SV (20 ± 3 and 27 ± 6 ml beat−1 in INC and CON, respectively), because HR continued to increase to exhaustion (190 ± 2 and 192 ± 2 beats min−1, respectively). In both INC and CON, central venous pressure increased from −3 mmHg at rest to 2–5 mmHg at exhaustion. In INC, MAP increased from 94 ± 4 mmHg at the start of exercise to 136 ± 7 mmHg at exhaustion. In contrast, in CON, MAP stabilized at ∼128 mmHg after 1.5 min. In INC, perfusion pressure increased from 98 ± 3 to 131 ± 6 mmHg at exhaustion accompanying an increase in pulse pressure from 59 ± 4 to 144 ± 4 mmHg. In contrast, perfusion pressure in CON increased from 100 ± 4 to 127 ± 6 mmHg after 3 min and remained stable thereafter. Similarly, pulse pressure increased from 60 ± 3 to 137 ± 4 mmHg after 3 min. In INC, systemic vascular conductance increased to ∼80% of peak power (range 60–90%) and then declined (P < 0.05). In CON, vascular conductance reached a plateau (range 0.75–3 min) and then declined (P < 0.05). No difference in dP/dtmax was observed at peak SV and exhaustion in either INC (2287 ± 96 versus 2419 ± 77 mmHg s−1; P = 0.35) or CON (2119 ± 271 versus 2193 ± 230 mmHg s−1; P = 0.72).

Figure 2. Central haemodynamics during the constant and incremental protocols.

Figure 2

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Cardiac output, heart rate, stroke volume, central venous and arterial pressure, systemic vascular conductance, arterial O2 content, systemic O2 delivery, a–v O2 difference and Inline graphic at rest, during submaximal and maximal exercise, and during 10 min of recovery, in incremental (•) and constant load (^) exercise. Data are means ± s.e.m. for 8 subjects, except arterial and central venous pressures and systemic vascular conductance for which data represent 7 subjects. * Lower than the value after 22 min when cycling at 80% of peak power, P < 0.05. ‡ Lower than the peak values observed after 20–24 min of constant load maximal cycling, P < 0.05.

Figure 3. Central haemodynamics during incremental exercise to exhaustion.

Figure 3

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Cardiac output, heart rate, stroke volume, arterial (•) and central venous (▾) pressure, systemic vascular conductance, arterial O2 content, systemic O2 delivery, systemic a–v O2 difference, systemic O2 extraction and pulmonary Inline graphic during incremental exercise to exhaustion plotted against the relative increase in power output. Data are means ± s.e.m. for 8 subjects. * Lower than 80% of peak power, P < 0.05.

Figure 4. Relationship between cardiac output and systemic Inline graphic during incremental exercise to exhaustion.

Figure 4

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Cardiac output, stroke volume and systemic O2 delivery plotted against the increases in Inline graphic during incremental exercise. The plateau in cardiac output was due to a concomitant decline in stroke volume. Data are means ± s.e.m. for 8 subjects. * Lower than the stroke volume value observed at a systematic Inline graphic of 3.9 L min−1 when cycling at 80% of peak power, P < 0.05.

In both INC and CON, there was an increase in haemoglobin concentration, resulting in an elevated arterial O2 content, despite declining arterial O2 tension and saturation (Tables 1 and 2; Fig. 2). In INC, systemic O2 delivery increased linearly to 80% of peak power (r2 = 0.998; P < 0.001) and then levelled off (Figs 2, 3, 4). In CON, systemic O2 delivery increased to reach a maximal value of 5.7 ± 0.2 l min−1 after 4.4 ± 0.4 min (range 3–5 min) and then declined 0.35 ± 0.08 l min−1 before exhaustion (P < 0.05). During both INC and CON, systemic a–v O2 difference and O2 extraction increased until exhaustion. At exhaustion in INC and CON, systemic O2 extraction was 84 ± 2% and 87 ± 1%, respectively. In INC, Inline graphic increased linearly to exhaustion and therefore Inline graphic was reached during the last ∼0.5 min (r2 = 0.998; P < 0.001; Fig. 3). In CON, Inline graphic was reached within 4–6 min, maintained for 2.0 ± 0.3 min, but declined 0.14 ± 0.05 l min−1 before exhaustion (P < 0.05).

Table 1.

Blood variables at rest, during incremental exercise to exhaustion, and after 10 min of recovery

Incremental exercise (% peak power)
Rest 20% 40% 60% 80% 90% 95% 100% 10 min recovery
Haemoglobin (g l−1)
 a 150 ± 4 153 ± 3 155 ± 3 156 ± 2* 157 ± 2* 158 ± 3* 160 ± 3* 162 ± 3* 156 ± 3*
 v 151 ± 4 151 ± 4 152 ± 4 153 ± 4 158 ± 3* 159 ± 3* 161 ± 4* 163 ± 4* 154 ± 3
PO2 (mmHg)
 a 120 ± 4 101 ± 2* 95 ± 2* 92 ± 4* 91 ± 3* 93 ± 3* 96 ± 3* 102 ± 3* 118 ± 2
 v 40 ± 2 30 ± 2* 26 ± 1* 22 ± 1* 21 ± 1* 20 ± 1* 20 ± 1* 21 ± 1* 48 ± 2*
O2 saturation (%)
 a 98.8 ± 0.1 98.0 ± 0.1 97.5 ± 0.2* 97.1 ± 0.3* 96.6 ± 0.3* 96.2 ± 0.3* 95.4 ± 0.5* 95.0 ± 0.5* 97.3 ± 0.2*
 v 71.3 ± 2.3 50.4 ± 2.7* 37.6 ± 3.0* 30.4 ± 2.1* 25.6 ± 2.1* 20.9 ± 1.8* 17.2 ± 1.7* 14.8 ± 1.5* 69.8 ± 1.2
O2 content (ml l−1)
 a 202 ± 5 203 ± 4 205 ± 3 205 ± 3 206 ± 3 206 ± 3 208 ± 4 210 ± 4* 207 ± 4
 v 146 ± 7 103 ± 7* 78 ± 7* 63 ± 5* 55 ± 5* 45 ± 4* 38 ± 4* 33 ± 4* 146 ± 5
PCO2 (mmHg)
 a 41 ± 1 42 ± 1 42 ± 1 42 ± 0 42 ± 1 41 ± 1 39 ± 1 37 ± 1* 33 ± 1*
 v 50 ± 1 53 ± 1 56 ± 1 61 ± 1* 70 ± 1* 77 ± 2* 83 ± 2* 87 ± 3* 43 ± 1*
pH
 a 7.40 ± 0.01 7.40 ± 0.00 7.39 ± 0.00 7.38 ± 0.01 7.36 ± 0.01* 7.32 ± 0.01* 7.26 ± 0.01* 7.20 ± 0.01* 7.19 ± 0.01*
 v 7.35 ± 0.01 7.35 ± 0.00 7.33 ± 0.01 7.30 ± 0.01* 7.24 ± 0.01* 7.17 ± 0.01* 7.10 ± 0.01* 7.03 ± 0.01* 7.16 ± 0.01*
Lactate (mmol l−1)
 a 1.0 ± 0.1 1.0 ± 0.1 1.3 ± 0.1 2.0 ± 0.2 4.2 ± 0.3* 7.7 ± 0.3* 11.9 ± 0.4* 16.4 ± 0.7* 14.3 ± 0.6*
 v 1.0 ± 0.1 1.0 ± 0.1 1.7 ± 0.4 2.4 ± 0.4 4.3 ± 0.3* 8.0 ± 0.4* 12.1 ± 0.5* 16.8 ± 0.8* 13.7 ± 0.8*
Glucose (mmol l−1)
 a 5.3 ± 0.3 5.3 ± 0.3 5.3 ± 0.3 5.4 ± 0.3 5.3 ± 0.3 5.2 ± 0.3 5.2 ± 0.3 5.0 ± 0.3 6.2 ± 0.2*
 v 5.2 ± 0.3 5.2 ± 0.3 5.2 ± 0.3 5.2 ± 0.3 5.3 ± 0.3 5.2 ± 0.3 5.1 ± 0.3 4.9 ± 0.3 6.1 ± 0.2*
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Values are means ± s.e.m. for 8 subjects. a, arterial. v, right atrium.

*

Different from rest, P < 0.05. PO2,PCO2 and pH values were corrected for changes in blood temperature.

Table 2.

Blood variables at rest, during constant load maximal exercise, and after 10 min of recovery

Constant load exercise (min)
Rest 0.8 1.5 3 4 5 6.9 ± 0.5 10 min recovery
Haemoglobin (g l−1)
 a 151 ± 3 155 ± 3 159 ± 3* 160 ± 4* 165 ± 3* 166 ± 3* 169 ± 3* 158 ± 4*
 v 155 ± 3 158 ± 3 161 ± 4 163 ± 3 165 ± 3* 166 ± 3* 165 ± 3* 157 ± 5
PO2 (mmHg)
 a 118 ± 4 91 ± 4* 91 ± 3* 92 ± 4* 94 ± 4* 96 ± 4* 101 ± 4* 117 ± 3
 v 40 ± 1 22 ± 1* 20 ± 1* 20 ± 1* 20 ± 1* 20 ± 1* 20 ± 1* 49 ± 2*
O2 saturation (%)
 a 98.8 ± 0.2 97.1 ± 0.5 96.6 ± 0.3* 96.1 ± 0.6* 94.7 ± 0.6* 94.3 ± 0.9* 93.0 ± 1.0* 96.9 ± 0.4*
 v 70.8 ± 2.4 31.7 ± 2.8* 22.9 ± 2.3* 18.7 ± 1.7* 16.6 ± 1.6* 15.1 ± 1.8* 12.5 ± 1.2* 68.8 ± 1.3
O2 content (ml l−1)
 a 204 ± 4 205 ± 4 209 ± 5 209 ± 6 213 ± 4* 213 ± 4* 213 ± 4* 209 ± 5
 v 149 ± 7 68 ± 7* 50 ± 6* 42 ± 4* 37 ± 4* 34 ± 4* 29 ± 3* 146 ± 5
PCO2 (mmHg)
 a 41 ± 1 41 ± 1 41 ± 1 38 ± 1 37 ± 1 36 ± 1* 34 ± 1* 33 ± 1*
 v 51 ± 1 58 ± 2* 71 ± 2* 76 ± 2* 78 ± 2* 79 ± 2* 82 ± 3* 43 ± 1*
pH
 a 7.41 ± 0.01 7.39 ± 0.01 7.35 ± 0.01 7.27 ± 0.01* 7.23 ± 0.01* 7.20 ± 0.01* 7.12 ± 0.02* 7.17 ± 0.03*
 v 7.35 ± 0.00 7.32 ± 0.01 7.22 ± 0.01* 7.13 ± 0.01* 7.09 ± 0.01* 7.06 ± 0.01* 7.00 ± 0.02* 7.14 ± 0.03*
Lactate (mmol l−1)
 a 1.1 ± 0.1 1.9 ± 0.2 5.3 ± 0.4* 10.8 ± 0.6* 13.7 ± 0.8* 16.0 ± 0.9* 19.0 ± 1.1* 13.8 ± 1.2*
 v 1.0 ± 0.1 2.2 ± 0.2 5.4 ± 0.5* 10.8 ± 0.6* 13.4 ± 0.7* 15.6 ± 0.9* 18.6 ± 1.1* 13.6 ± 1.2*
Glucose (mmol l−1)
 a 5.4 ± 0.2 5.3 ± 0.2 5.4 ± 0.2 5.3 ± 0.3 5.2 ± 0.3 5.2 ± 0.3 5.3 ± 0.2 7.3 ± 0.3*
 v 5.3 ± 0.2 5.3 ± 0.2 5.3 ± 0.2 5.3 ± 0.2 5.2 ± 0.3 5.2 ± 0.2 5.2 ± 0.2 7.2 ± 0.3*
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Values are means ± s.e.m. for 8 subjects. a, arterial. v, right atrium.

*

Different from rest, P < 0.05. PO2, PCO2 and pH values were corrected for changes in blood temperature.

Leg haemodynamics, O2 transport and O2 uptake

The rate of increase in LBF and O2 delivery during incremental exercise was attenuated at intensities above 50% of peak power, reaching a plateau at 73–88% (Fig. 5). The levelling off in LBF, associated with a plateau in leg vascular conductance, attenuated the increase in leg Inline graphic (8.8 ± 0.5 versus 11.9 ± 0.7 ml W−1 min−1 at exhaustion compared to 50% peak power, respectively; P = 0.003), despite increasing O2 extraction. At the systemic level, Inline graphic reached a plateau at ∼80% peak power leading to the blunting of the rate of increase in O2 delivery per litre of Inline graphic (Fig. 6). In contrast to incremental cycling, LBF, O2 delivery and leg Inline graphic increased linearly from rest to exhaustion during one-legged knee-extensor exercise (r2 = 0.994–0.999; P < 0.0002), thereby allowing the maintenance of constant LBF, leg O2 delivery and leg Inline graphic per unit of work (slopes = 75.6, 16.3 and 13.4 ml W−1 min−1, respectively). As depicted in Fig. 7, LBF and leg Inline graphic were higher during maximal cycling compared to knee-extensor exercise. However, leg Inline graphic was lower during cycle compared to knee-extensor exercise when expressed per unit of work (8.8 ± 0.5 versus 12.2 ± 0.6 ml W−1 min−1, respectively; P < 0.01) or estimated active muscle mass (175 ± 9 versus 443 ± 34 ml kg−1 min−1, respectively; P < 0.01) due largely to the lower blood flow.

Figure 5. Leg haemodynamics during incremental exercise to exhaustion.

Figure 5

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Leg blood flow, mean arterial pressure, leg vascular conductance, leg O2 delivery, leg a–v O2 difference and leg Inline graphic during incremental exercise to exhaustion plotted against the relative increase in power. Data are means ± s.e.m. for 10 subjects.

Figure 6. Relationship between blood flow, vascular conductance and O2 delivery and Inline graphic.

Figure 6

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Cardiac output and 2-legged blood flow, systemic and 2-legged vascular conductance, and systemic and 2-legged O2 delivery plotted against the increases in Inline graphic during incremental exercise to exhaustion. Data are means ± s.e.m. for 6 subjects.

Figure 7. Quadriceps muscle perfusion and Inline graphic during maximal knee-extensor and cycling exercise.

Figure 7

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Maximal values for leg blood flow and Inline graphic during maximal knee-extensor and cycling exercise expressed as absolute values (A), in relation to peak power (B; 103 ± 4 and 225 ± 10 W, respectively), and in relation to the estimated active muscle mass (C), assuming that all quadriceps muscles (2.9 kg) and all leg muscles (11.4 kg) were recruited during maximal knee-extensor and cycling exercise, respectively. Data are means ± s.e.m. for 10 subjects. * Different from knee-extensor exercise, P < 0.05.

Discussion

This study employed two-legged cycling and one-legged knee-extension as exercise models for investigating whether O2 transport poses a limitation to aerobic power and capacity in humans. The key observations were: (1) during incremental cycling, Inline graphic, LBF and O2 delivery reached a plateau at intensities below Inline graphic, accompanying a decline in SV and increases in central venous pressure and MAP, (2) with a blunted LBF, leg Inline graphic per unit of work declined despite the increasing O2 extraction, (3) when LBF increased linearly during knee-extensor exercise, Inline graphic per unit of work was unaltered, (4) during constant load cycling, SV, Inline graphic, and systemic O2 delivery and Inline graphic dropped before exhaustion, despite increasing or stable central venous pressure, MAP and O2 extraction, and (5) the impaired O2 supply during cycling was due to a fall in SV, as both the arterial O2 content and HR continued to increase. These results indicate that an inability of the circulatory system to sustain a linear increase in O2 delivery to the locomotor limb muscles markedly restrains aerobic power. Moreover, the impaired SV and O2 delivery during cycling together with the higher muscle Inline graphic with unrestricted circulation during knee-extensor exercise support a preponderant central limitation to aerobic power and capacity in humans.

During incremental cycling exercise, Inline graphic and systemic O2 delivery increased linearly to ∼80% of peak power but levelled off thereafter. Similarly, the initial linear increase in LBF and O2 delivery was attenuated at intensities above 50% of peak power, reaching a plateau at 73–88%. The tight 1: 1 relationship between systemic and locomotor limb O2 delivery versus Inline graphic at low and moderate exercise intensities was therefore blunted at intensities above ∼80% of peak power. This novel finding refutes the theory that O2 delivery is linearly related to Inline graphic from rest to Inline graphic. This concept is based on linear regression analysis of: (1) Inline graphic data that were not normalized (Asmussen & Nielsen, 1952; Chapman et al. 1960; Bevegård et al. 1963; Åstrand et al. 1964; Saltin, 1964; Grimsby et al. 1966), (2) haemodynamic data from longitudinal studies on human subjects undergoing changes in physical activity levels (Saltin et al. 1968), (3) cross-sectional data from subjects with different training status with the focus of the analysis on whether Inline graphic could explain the differences in Inline graphic between well-trained and sedentary people (Ekblom & Hermansen, 1968; Ekblom, 1968), and (4) haemodynamic data in untrained humans who might have failed to attain maximal levels of exertion (Poliner et al. 1980; Higginbotham et al. 1986). Although these studies collectively documented a tight relationship between Inline graphic and Inline graphic over a wide range of aerobic capacities, they provide neither insight into the relationship between systemic O2 delivery and Inline graphic close to maximal exercise, nor specific information on the contribution of locomotor limb muscle O2 transport to Inline graphic. The present findings in healthy trained subjects show that systemic and locomotor limb blood flow and O2 delivery are linearly related to Inline graphic up to 50–90% of Inline graphic, levelling off before Inline graphic is reached. The critical consequence of the plateau in locomotor limb O2 delivery is the attenuation in the rate of rise in Inline graphic despite increasing O2 extraction.

Restrictions in systemic and locomotor limb muscle O2 transport pose a more important limitation to Inline graphic and maximal endurance capacity than suspected. In the exercising legs, Inline graphic per unit of work declined from 11.9 ± 0.7 ml W−1 min−1 at 50% peak power to 8.8 ± 0.5 ml W−1 min−1 at exhaustion, suggesting that the concomitant exponential rise in leg lactate release accompanied a suppression in skeletal muscle aerobic ATP production. The estimate that leg O2 delivery and Inline graphic would have been ∼52% higher (i.e. both ∼1 l min−1) during cycling exercise if LBF increased linearly until exhaustion, illustrates the magnitude of the blunting of LBF and its effect on locomotor muscle Inline graphic. Limitations in diffusive O2 transport from the muscle capillary to the mitochondrial cytochrome and/or oxidative capacity of mitochondria could also be restricting muscle Inline graphic based on the observation that leg O2 extraction is not maximal at exhaustion (Roca et al. 1989). Yet, an increase in leg O2 extraction from the measured value of 87% to a hypothetical 100% would only increase leg Inline graphic by 16% (i.e. ∼0.3 l min−1), although this is an overestimation given that ∼20% of the leg consists of non-muscle tissues with lower O2 extraction than contracting muscle.

A critical question is whether the leg muscles can indeed increase Inline graphic above the levels observed during maximal cycling exercise. An approach to answer this question is to determine whether quadriceps Inline graphic is elevated when systemic O2 transport is not limiting during maximal one-legged knee-extensor exercise (Andersen & Saltin, 1985). In contrast to cycling and in agreement with published reports (Andersen & Saltin, 1985; Richardson et al. 1993), leg Inline graphic increased linearly during knee-extensor exercise to exhaustion in parallel with the rise in LBF. Leg Inline graphic per unit of work at fatigue was therefore higher during knee-extensor than cycling exercise (Fig. 7). Moreover, assuming that the quadriceps femoris and all leg muscles are active during knee-extensor and cycling exercise, we estimated that Inline graphic per kilogram of muscle was 3-fold higher during knee-extensor than cycling exercise (Richardson & Saltin 1998). Despite the uncertainty of the assumption, it is clear that the quadriceps muscles as the only muscles generating power during knee-extensor exercise, are consuming more O2 (i.e. 1.3 l min−1; 103 W; ∼2.9 kg) than they are as mere contributors to power generation during cycling (i.e. 2.0 l min−1; 225 W; ∼11.4 kg). Collectively, these observations reveal that during maximal whole body exercise: (1) locomotor muscle Inline graphic and exercise endurance could be improved if blood flow increased linearly, (2) the rates of mitochondrial oxidation and O2 transport from capillary to mitochondrial cytochrome are not maximal, and (3) convective O2 transport to contracting skeletal muscle fibres is severely restricted owing to the lower blood flow.

During incremental cycling, Inline graphic and LBF plateaued at ∼80% peak power in parallel to a marked blunting of systemic and leg vascular conductance, indicating an enhanced sympathetic vasoconstrictor activity. This agrees with the plateau in LBF at high cycling intensities in humans (Knight et al. 1992; Rosenmeier et al. 2004) and the plateau in Inline graphic and skeletal muscle blood flow before exhaustion in miniature swine running on a treadmill (Armstrong et al. 1987), but contrasts with the linear increase in LBF during one-legged knee-extensor exercise in humans when the systemic circulation is not compromised (Andersen & Saltin, 1985; Richardson et al. 1993). It therefore seems that during exercise with a large muscle mass, reflexes signalling the plateau in Inline graphic override the local vasodilatory stimuli responsible for the partial or full linear increase in LBF with incremental cycling and knee-extensor exercise, respectively. In support of this, a human study showed that the blunting of LBF and vascular conductance at high cycling intensities is associated with an exponential rise in circulating noradrenaline outstripping the increase of the vasodilator ATP (Rosenmeier et al. 2004). It is likely that the upper body limb and postural muscles as well as the heart and respiratory muscles become more active, thereby contributing to the linear increase in systemic Inline graphic above 80% peak power. This scenario implies that the upper body muscles and organs are competing with the exercising legs for the available Inline graphic (Harms et al. 1997, 1998). However, the redistribution of blood flow to upper body muscles and organs ought to be small as the plateau in Inline graphic accounts for the majority of the LBF response. On the other hand, perfusion pressure did not reduce LBF as MAP increased until exhaustion. Consequently, the suppression in blood flow to the exercising legs during cycling appears to be, for the most part, the result of the blunted Inline graphic and the overriding sympathetic vasoconstrictor activity to the muscle microvasculature (Pawelczyk et al. 1992).

The similar maximal haemodynamic responses and blunting of O2 transport before exhaustion during INC and CON provide further insight into the limits of cardiovascular regulation in exercising humans. Even though Inline graphic was maintained over a longer period during constant load cycling, both types of maximal exercise were characterized by essentially the same peak Inline graphic (27 and 28 l min−1 for INC and CON, respectively), HR (190 and 192 beats min−1), MAP (129 and 136 mmHg), systemic O2 delivery (5.7 and 5.8 l min−1), systemic O2 extraction (84 and 87%) and Inline graphic (4.8 l min−1). This indicates that the limits of the cardiovascular system and a true Inline graphic were reached during both types of cycling. Five decades ago, Mitchell et al. (1958) provided data on the determinants of Inline graphic. Arguing in favour of a limiting Inline graphic, they found a lower Inline graphic during supramaximal compared to maximal exercise (18.2 versus 21.0 l min−1, respectively), but Inline graphic was the same (2.81 versus 2.87 l min−1; n = 6) because of the widening of the systemic a–v O2 difference. Our study extends previous work by simultaneously looking at the dynamics of the central and exercising limb circulations, allowing an assessment of the contribution of the locomotor muscle to Inline graphic. Because LBF and Inline graphic are impaired during maximal constant load cycling (González-Alonso & Calbet, 2003), we surmise that the locomotor skeletal muscles are the main tissue accounting for the restrictions in peripheral blood flow and O2 delivery during INC and CON.

Within the central circulation, the impaired O2 supply was associated with a fall in SV (20–27 ml beat−1), as both arterial O2 content and HR continued to increase. This is congruent with reports during constant and incremental exercise showing a decline in SV (Keul et al. 1981; Higginbotham et al. 1986; Spina et al. 1992; Seals et al. 1994; Proctor et al. 1998; McCole et al. 1999; González-Alonso & Calbet, 2003; González-Alonso et al. 2004), but contrasts with the bulk of studies using incremental exercise showing either a plateau or an increase in SV with continuously increasing Inline graphic from moderate to peak exercise (Åstrand et al. 1964; Poliner et al. 1980; Rubal et al. 1986; Spina et al. 1992; Gledhill et al. 1994; Seals et al. 1994; Fleg et al. 1994; Proctor et al. 1998). Differences in exercise protocols, levels of exertion, exercise mode, sex, age and training status might account for the discrepancy in the SV responses.

The decline in SV described here could be attributed to alterations in cardiac preload, left ventricular afterload and/or left ventricular contractility (Rowell, 1974; Poliner et al. 1980; Higginbotham et al. 1986). However, a decline in preload does not seem to be a factor because in both trials central venous pressure continued to increase until exhaustion. Enhanced afterload might not be an important factor either, since SV increased early in exercise in parallel with increases in systolic blood pressure and MAP in both INC and CON and declined to a greater extent during CON when systolic blood pressure and MAP were maintained. Lastly, a depression in left ventricular contractility reducing SV is at odds with the finding that dP/dtmax at peak SV and at exhaustion were not different. The rate–pressure product of HR and MAP increased until exhaustion in both maximal tests, indicating that myocardial O2 demand was rising when SV declined. In this setting, an increase in myocardial Inline graphic can only occur by an increase in O2 delivery provided by augmented coronary blood flow because the O2 extraction reserve is minimal. The impaired circulation and aerobic energy turnover in skeletal muscle raises the daunting possibility that alterations in cardiac metabolism contribute to the SV decline.

Alternatively, the observation that SV declined at a HR of 170–180 beats min−1 during both INC and CON raises the possibility that severe tachycardia reduces SV. Studies in humans and dogs manipulating HR by pacing the heart demonstrate that severe tachycardia leads to disproportional reductions in diastolic filling time and left ventricular end-diastolic volume which compromise SV and Inline graphic (Templeton et al. 1972; Weisfeldt et al. 1978; Parke & Case, 1979; Sheriff et al. 1993). Consistent with the increase in core temperature to 39–40°C, human studies demonstrate that hyperthermia-induced tachycardia reduces SV during exercise (Fritzsche et al. 1999; González-Alonso et al. 1997, 1999, 2000a) and that blunting core hyperthermia and HR restores most of the fall in Inline graphic evoked by heat stress (Nybo et al. 2001). Although studies independently altering HR and directly examining cardiac circulation, metabolism and function are required to determine the mechanism, it seems that the decline in SV during maximal exercise is related, at least in part, to the restriction in left ventricular filling time and left ventricular end-diastolic volume that accompanies severe tachycardia and hyperthermia.

In summary, the present findings in trained humans show that systemic and locomotor limb O2 delivery does not increase linearly from rest to Inline graphic, but plateaus at intensities below Inline graphic, resulting in the blunting of locomotor limb Inline graphic despite the increasing O2 extraction. Similarly, systemic O2 delivery and Inline graphic decline during constant load cycling despite the increasing O2 extraction. In both types of maximal exercise, the impaired systemic O2 delivery was associated with a decline in SV. The attenuation in LBF blunting leg O2 delivery and Inline graphic during incremental cycling appears to be largely related to the plateau in Inline graphic and an enhanced muscle sympathetic vasoconstrictor activity. In contrast to two-legged cycling, LBF and Inline graphic increased until volitional exhaustion during one-legged knee-extensor exercise when O2 transport was not limited. Collectively, these findings support the hypothesis that restrictions in O2 supply to locomotor limb muscles impose a limitation to aerobic power and capacity in humans.

Acknowledgments

We give special thanks to the volunteer subjects for their enthusiasm. We also thank Peter Nissen, Troels Munch and Jacob Mørkeberg for the excellent technical assistance. This study was supported by the Gatorade Sports Science Institute and the Novo Nordisk Foundation. J.G.-A. and N.H.S. were supported by The Copenhagen Hospital System.

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