Hans Søndergaard

Muscle mitochondrial capacity exceeds maximal oxygen delivery in humans

Across a wide range of species and body mass a close matching exists between maximal conductive oxygen delivery and mitochondrial respiratory rate. In this study we investigated in humans how closely in-vivo maximal oxygen consumption (VO(2) max) is matched to state 3 muscle mitochondrial respiration. High resolution respirometry was used to quantify mitochondrial respiration from the biopsies of arm and leg muscles while in-vivo arm and leg VO(2) were determined by the Fick method during leg cycling and arm cranking. We hypothesized that muscle mitochondrial respiratory rate exceeds that of systemic oxygen delivery. The state 3 mitochondrial respiration of the deltoid muscle (4.3±0.4 mmol o(2)kg(-1) min(-1)) was similar to the in-vivo VO(2) during maximal arm cranking (4.7±0.5 mmol O(2) kg(-1) min(-1)) with 6 kg muscle. In contrast, the mitochondrial state 3 of the quadriceps was 6.9±0.5 mmol O(2) kg(-1) min(-1), exceeding the in-vivo leg VO(2) max (5.0±0.2 mmol O(2) kg(-1) min(-1)) during leg cycling with 20 kg muscle (P<0.05). Thus, when half or more of the body muscle mass is engaged during exercise, muscle mitochondrial respiratory capacity surpasses in-vivo VO(2) max. The findings reveal an excess capacity of muscle mitochondrial respiratory rate over O(2) delivery by the circulation in the cascade defining maximal oxidative rate in humans.

Effect of blood haemoglobin concentration on V̇O2,max and cardiovascular function in lowlanders acclimatised to 5260 m

The principal aim of this investigation was to determine the influence of blood haemoglobin concentration ([Hb]) on maximal exercise capacity and maximal O2 consumption (V̇O2,max) in healthy subjects acclimatised to high altitude. Secondarily, we examined the effects of [Hb] on the regulation of cardiac output (CO), blood pressure and muscular blood flow (LBF) during exercise. Eight Danish lowlanders (three females and five males; 24 ± 0.6 years, mean ±s.e.m.) performed submaximal and maximal exercise on a cycle ergometer after 9 weeks at an altitude of 5260 m (Mt Chacaltaya, Bolivia). This was done first with the high [Hb] resulting from acclimatisation and again 2‐4 days later, 1 h after isovolaemic haemodilution with Dextran 70 to near sea level [Hb]. After measurements at maximal exercise while breathing air at each [Hb], subjects were switched to hyperoxia (55 % O2 in N2) and the measurements were repeated, increasing the work rate as tolerated. Hyperoxia increased maximal power output and leg V̇O2,max, showing that breathing ambient air at 5260 m, V̇O2,max is limited by the availability of O2 rather than by muscular oxidative capacity. Altitude increased [Hb] by 36 % from 136 ± 5 to 185 ± 5 g l−1 (P < 0.001), while haemodilution (replacing 1 l of blood with 1 l of 6 % Dextran) lowered [Hb] by 24 % to 142 ± 6 g l−1 (P < 0.001). Haemodilution had no effect on maximal pulmonary or leg V̇O2,max, or power output. Despite higher LBF, leg O2 delivery was reduced and maximal V̇O2 was thus maintained by higher O2 extraction. While CO increased linearly with work rate irrespective of [Hb] or inspired oxygen fraction (FI,O2), both LBF and leg vascular conductance were systematically higher when [Hb] was low. Close and significant relationships were seen between LBF (and CO) and both plasma noradrenaline and K+ concentrations, independently of [Hb] and FI,O2. In summary, under conditions where O2 supply limits maximal exercise, the increase in [Hb] with altitude acclimatisation does not improve maximal exercise capacity or V̇O2,max, and does not alter peak CO. However, LBF and vascular conductance are higher at altitude when [Hb] is lowered to sea level values, with both relating closely to catecholamine and potassium concentrations. This suggests that the lack of effect of [Hb] on V̇O2,max may involve reciprocal changes in LBF via local metabolic control of the muscle vasculature.

The re-establishment of the normal blood lactate response to exercise in humans after prolonged acclimatization to altitude

1 One to five weeks of chronic exposure to hypoxia has been shown to reduce peak blood lactate concentration compared to acute exposure to hypoxia during exercise, the high altitude ‘lactate paradox’. However, we hypothesize that a sufficiently long exposure to hypoxia would result in a blood lactate and net lactate release from the active leg to an extent similar to that observed in acute hypoxia, independent of work intensity. 2 Six Danish lowlanders (25–26 years) were studied during graded incremental bicycle exercise under four conditions: at sea level breathing either ambient air (0 m normoxia) or a low‐oxygen gas mixture (10 % O2 in N2, 0 m acute hypoxia) and after 9 weeks of acclimatization to 5260 m breathing either ambient air (5260 m chronic hypoxia) or a normoxic gas mixture (47 % O2 in N2, 5260 m acute normoxia). In addition, one‐leg knee‐extensor exercise was performed during 5260 m chronic hypoxia and 5260 m acute normoxia. 3 During incremental bicycle exercise, the arterial lactate concentrations were similar at sub‐maximal work at 0 m acute hypoxia and 5260 m chronic hypoxia but higher compared to both 0 m normoxia and 5260 m acute normoxia. However, peak lactate concentration was similar under all conditions (10.0 ± 1.3, 10.7 ± 2.0, 10.9 ± 2.3 and 11.0 ± 1.0 mmol l−1) at 0 m normoxia, 0 m acute hypoxia, 5260 m chronic hypoxia and 5260 m acute normoxia, respectively. Despite a similar lactate concentration at sub‐maximal and maximal workload, the net lactate release from the leg was lower during 0 m acute hypoxia (peak 8.4 ± 1.6 mmol min−1) than at 5260 m chronic hypoxia (peak 12.8 ± 2.2 mmol min−1). The same was observed for 0 m normoxia (peak 8.9 ± 2.0 mmol min−1) compared to 5260 m acute normoxia (peak 12.6 ± 3.6 mmol min−1). Exercise after acclimatization with a small muscle mass (one‐leg knee‐extensor) elicited similar lactate concentrations (peak 4.4 ± 0.2 vs. 3.9 ± 0.3 mmol l−1) and net lactate release (peak 16.4 ± 1.8 vs. 14.3 mmol l−1) from the active leg at 5260 m chronic hypoxia and 5260 m acute normoxia. 4 In conclusion, in lowlanders acclimatized for 9 weeks to an altitude of 5260 m, the arterial lactate concentration was similar at 0 m acute hypoxia and 5260 m chronic hypoxia. The net lactate release from the active leg was higher at 5260 m chronic hypoxia compared to 0 m acute hypoxia, implying an enhanced lactate utilization with prolonged acclimatization to altitude. The present study clearly shows the absence of a lactate paradox in lowlanders sufficiently acclimatized to altitude.

Body dimensions, exercise capacity and physical activity level of adolescent Nandi boys in western Kenya

The aim of this study was to characterize untrained Nandi boys (mean age 16.6 years) from a town (n = 11) and from a rural area (n = 19) in western Kenya (altitude ˜2000 m.a.s.l.) in regard to their body dimensions, oxygen uptake and physical activity level. The town boys had a mean maximal oxygen uptake (VO2max) of 50 (range: 45–60) mL kg−1 min−1, whereas the village boys reached a value of 55 (37−63) mL kg−1 min−1 ( p<0.01) in VO2max. The running economy, determined as the oxygen cost at a given running speed, was 221 mL kg−1 km−1 (597 mL kg−0.75 km−1) for town as well as for village boys. The body mass index (BMI) was very low for town as well as for village boys (18.6 vs 18.4 kg m−2). The daily mean time spent working in the field during secondary school and doing sports were significantly higher in village boys compared to town boys (working in the field: 44.2 (0–128) vs 1.3 (0–11) min, p<0.01; sports: 32.0 (11–72) vs 12.8 (0–35) min, p<0.01, respectively). A positive correlation between the daily time spent doing sports and VO2max was found when pooling the data from the town and the village boys (R = 0.55, p<0.01). It is concluded that the body dimensions of adolescent Nandi town and village boys corresponds well with findings in Kenyan elite runners. They are very slender with relatively long legs. In addition, the VO2max of the village boys was higher than that of the town boys, which is probably due to a higher physical activity level of the village boys during secondary school.

Low-intensity training increases peak arm VO2 by enhancing both convective and diffusive O2 delivery

It is an ongoing discussion the extent to which oxygen delivery and oxygen extraction contribute to an increased muscle oxygen uptake during dynamic exercise. It has been proposed that local muscle factors including the capillary bed and mitochondrial oxidative capacity play a large role in prolonged low‐intensity training of a small muscle group when the cardiac output capacity is not directly limiting. The purpose of this study was to investigate the relative roles of circulatory and muscle metabolic mechanisms by which prolonged low‐intensity exercise training alters regional muscle VO2.

Central and peripheral hemodynamics in exercising humans: leg vs arm exercise.

In humans, arm exercise is known to elicit larger increases in arterial blood pressure (BP) than leg exercise. However, the precise regulation of regional vascular conductances (VC) for the distribution of cardiac output with exercise intensity remains unknown. Hemodynamic responses were assessed during incremental upright arm cranking (AC) and leg pedalling (LP) to exhaustion (Wmax) in nine males. Systemic VC, peak cardiac output (Qpeak) (indocyanine green) and stroke volume (SV) were 18%, 23%, and 20% lower during AC than LP. The mean BP, the rate‐pressure product and the associated myocardial oxygen demand were 22%, 12%, and 14% higher, respectively, during maximal AC than LP. Trunk VC was reduced to similar values at Wmax. At Wmax, muscle mass‐normalized VC and fractional O2 extraction were lower in the arm than the leg muscles. However, this was compensated for during AC by raising perfusion pressure to increase O2 delivery, allowing a similar peak VO2 per kg of muscle mass in both extremities. In summary, despite a lower Qpeak during arm cranking the cardiovascular strain is much higher than during leg pedalling. The adjustments of regional conductances during incremental exercise to exhaustion depend mostly on the relative intensity of exercise and are limb‐specific.

Training response of adolescent Kenyan town and village boys to endurance running

To investigate the response to endurance training on physiological characteristics, 10 Nandi town boys and 14 Nandi village boys 16.5 and 16.6 years of age, respectively, from western Kenya performed 12 weeks of running training. The study was performed at altitude (∼2000 m.a.s.l. ∼595 mm Hg). Training heart rate and speed were registered during every training session throughout the entire training period. While town and village boys trained at similar heart rates (172.1 vs. 172.5 beats min−1), the training speed of the town boys was 9% lower compared with the village boys (12.4 vs. 13.6 km h−1, P<0.001). Significant increases in VO2max were observed in the town boys (from 50.3 to 55.6 mL kg−1 min−1, P<0.001) and in village boys (from 56.0 to 59.1 mL kg−1 min−1, P<0.002). Significant decreases in submaximal heart rate (from 172.4 to 160.3 beats min−1 (P<0.005)), blood lactate (from 2.7 to 1.4 mmol L−1 (P<0.005)) and ammonia concentration (from 102.0 to 71.4 μmol L−1 (P<0.01)) at 9.9 km h−1 were observed in the town boys, while similar decreases in heart rate (from 170.2 to 159.2 beats min−1 (P<0.001)), blood lactate (from 2.4 to 1.4 mmol L−1 (P<0.001)) and ammonia concentration (from 102.5 to 72.7 lmol L−1 (P<0.001)) at 10.9 km h−1 were observed in the village boys. The oxygen cost of running was decreased from 221.5 to 211.5 mL kg−1 km−1 (P<0.03) in the town boys and from 220.1 to 207.2 mL kg−1 km−1 (P<0.01) in the village boys. The 5000 m performance time of the town boys was significantly greater than that of the village boys (20.25 vs. 18.42 min (P=0.01)). It is concluded that no difference was observed in trainability with respect to VO2max, running economy, submaximal heart rate, and submaximal blood lactate and ammonia concentration between Kenyan Nandi town and village boys. The higher performance level of the village boys was likely due to a higher VO2max of these boys.

Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and Caucasians in the arctic winter

During evolution, mitochondrial DNA haplogroups of arctic populations may have been selected for lower coupling of mitochondrial respiration to ATP production in favor of higher heat production. We show that mitochondrial coupling in skeletal muscle of traditional and westernized Inuit habituating northern Greenland is identical to Danes of western Europe haplogroups. Biochemical coupling efficiency was preserved across variations in diet, muscle fiber type, and uncoupling protein‐3 content. Mitochondrial phenotype displayed plasticity in relation to lifestyle and environment. Untrained Inuit and Danes had identical capacities to oxidize fat substrate in arm muscle, which increased in Danes during the 42 days of acclimation to exercise, approaching the higher level of the Inuit hunters. A common pattern emerges of mitochondrial acclimatization and evolutionary adaptation in humans at high latitude and high altitude where economy of locomotion may be optimized by preservation of biochemical coupling efficiency at modest mitochondrial density, when submaximum performance is uncoupled from VO2max and maximum capacities of oxidative phosphorylation.

Blood temperature and perfusion to exercising and non‐exercising human limbs

What is the central question of this study? Temperature‐sensitive mechanisms are thought to contribute to blood‐flow regulation, but the relationship between exercising and non‐exercising limb perfusion and blood temperature is not established. What is the main finding and its importance? The close coupling among perfusion, blood temperature and aerobic metabolism in exercising and non‐exercising extremities across different exercise modalities and activity levels and the tight association between limb vasodilatation and increases in plasma ATP suggest that both temperature‐ and metabolism‐sensitive mechanisms are important for the control of human limb perfusion, possibly by activating ATP release from the erythrocytes.

Maintained peak leg and pulmonary VO2 despite substantial reduction in muscle mitochondrial capacity

We recently reported the circulatory and muscle oxidative capacities of the arm after prolonged low‐intensity skiing in the arctic (Boushel et al., 2014). In the present study, leg VO2 was measured by the Fick method during leg cycling while muscle mitochondrial capacity was examined on a biopsy of the vastus lateralis in healthy volunteers (7 male, 2 female) before and after 42 days of skiing at 60% HR max. Peak pulmonary VO2 (3.52 ± 0.18 L.min−1 pre vs 3.52 ± 0.19 post) and VO2 across the leg (2.8 ± 0.4L.min−1 pre vs 3.0 ± 0.2 post) were unchanged after the ski journey. Peak leg O2 delivery (3.6 ± 0.2 L.min−1 pre vs 3.8 ± 0.4 post), O2 extraction (82 ± 1% pre vs 83 ± 1 post), and muscle capillaries per mm2 (576 ± 17 pre vs 612 ± 28 post) were also unchanged; however, leg muscle mitochondrial OXPHOS capacity was reduced (90 ± 3 pmol.sec−1.mg−1 pre vs 70 ± 2 post, P < 0.05) as was citrate synthase activity (40 ± 3 μmol.min−1.g−1 pre vs 34 ± 3 vs P < 0.05). These findings indicate that peak muscle VO2 can be sustained with a substantial reduction in mitochondrial OXPHOS capacity. This is achieved at a similar O2 delivery and a higher relative ADP‐stimulated mitochondrial respiration at a higher mitochondrial p50. These findings support the concept that muscle mitochondrial respiration is submaximal at VO2max, and that mitochondrial volume can be downregulated by chronic energy demand.