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Gnaiger E.,Innsbruck Medical University | Boushel R.,The Copenhagen Muscle Research Center | Boushel R.,University of British Columbia | Sondergaard H.,The Copenhagen Muscle Research Center | And 13 more authors.
Scandinavian Journal of Medicine and Science in Sports | Year: 2015

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. © 2015 John Wiley & Sons A/S.


PubMed | Innsbruck Medical University, University of Zaragoza, National Serum Institute, University of Las Palmas de Gran Canaria and 4 more.
Type: | Journal: Scandinavian journal of medicine & science in sports | Year: 2015

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 42days of acclimation to exercise, approaching the higher level of the Inuit hunters. A common pattern emerges of mitochondrial acclimatization and evolutionary adaptation in humans athigh 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.


Jacobs R.A.,University of Zürich | Boushel R.,University of Zürich | Boushel R.,The Copenhagen Muscle Research Center | Wright-Paradis C.,University of Zürich | And 6 more authors.
Experimental Physiology | Year: 2013

New Findings: • What is the central question of this study? Are the enzymatic alterations in human skeletal muscle observed following 9-11 days of exposure to high altitude reflected in mitochondrial function? • What is the main finding and its importance? The main findings of this study are that the capacity fat oxidation, individualized respiration capacity through mitochondrial complex I and II, and electron coupling efficiency are not greatly affected by 9-11 days of exposure to high altitude. The importance of this data is that high altitude exposure failed to affect integrated measures of mitochondrial functional capacity in skeletal muscle despite significant decrements to enzyme concentrations involved in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Studies regarding mitochondrial modifications in human skeletal muscle following acclimatization to high altitude are conflicting, and these inconsistencies may be due to the prevalence of representing mitochondrial function through static and isolated measurements of specific mitochondrial characteristics. The aim of this study, therefore, was to investigate mitochondrial function in response to high-altitude acclimatization through measurements of respiratory control in the vastus lateralis muscle. Skeletal muscle biopsies were obtained from 10 lowland natives prior to and again after a total of 9-11 days of exposure to 4559 m. High-resolution respirometry was performed on the muscle samples to compare respiratory chain function and respiratory capacities. Respirometric analysis revealed that mitochondrial function was largely unaffected, because high-altitude exposure did not affect the capacity for fat oxidation or individualized respiration capacity through either complex I or complex II. Respiratory chain function remained unaltered, because neither coupling nor respiratory control changed in response to hypoxic exposure. High-altitude acclimatization did, however, show a tendency (P= 0.059) to limit mass-specific maximal oxidative phosphorylation capacity. These data suggest that 9-11 days of exposure to high altitude do not markedly modify integrated measures of mitochondrial functional capacity in skeletal muscle despite significant decrements in the concentrations of enzymes involved in the tricarboxylic acid cycle and oxidative phosphorylation. © 2012 The Authors. Experimental Physiology © 2012 The Physiological Society.


Boushel R.,The Copenhagen Muscle Research Center | Boushel R.,The Swedish School of Sport and Health Sciences | Ara I.,The Copenhagen Muscle Research Center | Ara I.,University of Castilla - La Mancha | And 12 more authors.
Acta Physiologica | Year: 2014

Aim: 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. Methods: In nine healthy volunteers (seven males, two females), haemodynamic and metabolic responses to incremental arm cycling were measured by the Fick method and biopsy of the deltoid and triceps muscles before and after 42 days of skiing for 6 h day-1 at 60% max heart rate. Results: Peak pulmonary VO2 during arm crank was unchanged after training (2.38 ± 0.19 vs. 2.18 ± 0.2 L min-1 pre-training) yet arm VO2 (1.04 ± 0.08 vs. 0.83 ± 0.1 L min1, P < 0.05) and power output (137 ± 9 vs. 114 ± 10 Watts) were increased along with a higher arm blood flow (7.9 ± 0.5 vs. 6.8 ± 0.6 L min-1, P < 0.05) and expanded muscle capillary volume (76 ± 7 vs. 62 ± 4 mL, P < 0.05). Muscle O2 diffusion capacity (16.2 ± 1 vs. 12.5 ± 0.9 mL min-1 mHg-1, P < 0.05) and O2 extraction (68 ± 1 vs. 62 ± 1%, P < 0.05) were enhanced at a similar mean capillary transit time (569 ± 43 vs. 564 ± 31 ms) and P50 (35.8 ± 0.7 vs. 35 ± 0.8), whereas mitochondrial O2 flux capacity was unchanged (147 ± 6 mL kg min-1 vs. 146 ± 8 mL kg min-1). Conclusion: The mechanisms underlying the increase in peak arm VO2 with prolonged low-intensity training in previously untrained subjects are an increased convective O2 delivery specifically to the muscles of the arm combined with a larger capillary-muscle surface area that enhance diffusional O2 conductance, with no apparent role of mitochondrial respiratory capacity. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.


Boushel R.,The Copenhagen Muscle Research Center | Boushel R.,University of British Columbia | Gnaiger E.,Innsbruck Medical University | Larsen F.J.,The Swedish School of Sport and Health Sciences | And 13 more authors.
Scandinavian Journal of Medicine and Science in Sports | Year: 2015

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. © 2015 John Wiley & Sons A/S.


Munch G.D.W.,The Copenhagen Muscle Research Center | Munch G.D.W.,Rigshospitalet | Svendsen J.H.,Copenhagen University | Damsgaard R.,The Copenhagen Muscle Research Center | And 5 more authors.
Journal of Physiology | Year: 2014

In humans, maximal aerobic power (V̇O2 max ) is associated with a plateau in cardiac output (Q̇), but the mechanisms regulating the interplay between maximal heart rate (HRmax) and stroke volume (SV) are unclear. To evaluate the effect of tachycardia and elevations in HRmax on cardiovascular function and capacity during maximal exercise in healthy humans, 12 young male cyclists performed incremental cycling and one-legged knee-extensor exercise (KEE) to exhaustion with and without right atrial pacing to increase HR. During control cycling, Q̇ and leg blood flow increased up to 85% of maximal workload (WLmax) and remained unchanged until exhaustion. SV initially increased, plateaued and then decreased before exhaustion (P < 0.05) despite an increase in right atrial pressure (RAP) and a tendency (P = 0.056) for a reduction in left ventricular transmural filling pressure (LVFP). Atrial pacing increased HRmax from 184 ± 2 to 206 ± 3 beats min-1 (P < 0.05), but Q̇ remained similar to the control condition at all intensities because of a lower SV and LVFP (P < 0.05). No differences in arterial pressure, peripheral haemodynamics, catecholamines or V̇O2 were observed, but pacing increased the rate pressure product and RAP (P < 0.05). Atrial pacing had a similar effect on haemodynamics during KEE, except that pacing decreased RAP. In conclusion, the human heart can be paced to a higher HR than observed during maximal exercise, suggesting that HRmax and myocardial work capacity do not limit V̇O2 max in healthy individuals. A limited left ventricular filling and possibly altered contractility reduce SV during atrial pacing, whereas a plateau in LVFP appears to restrict Q̇ close to V̇O2 max. © 2013 The Physiological Society.


Boushel R.,The Copenhagen Muscle Research Center | Boushel R.,Copenhagen University | Gnaiger E.,Innsbruck Medical University | Calbet J.A.L.,The Copenhagen Muscle Research Center | And 7 more authors.
Mitochondrion | Year: 2011

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 (VO2 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 VO2 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±0.4mmolo2kg-1min-1) was similar to the in-vivo VO2 during maximal arm cranking (4.7±0.5mmolO2kg-1min-1) with 6kg muscle. In contrast, the mitochondrial state 3 of the quadriceps was 6.9±0.5mmolO2kg-1min-1, exceeding the in-vivo leg VO2 max (5.0±0.2mmolO2kg-1min-1) during leg cycling with 20kg 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 VO2 max. The findings reveal an excess capacity of muscle mitochondrial respiratory rate over O2 delivery by the circulation in the cascade defining maximal oxidative rate in humans. © 2010 Elsevier B.V. and Mitochondria Research Society.


Boushel R.,Copenhagen University | Boushel R.,The Copenhagen Muscle Research Center | Fuentes T.,University of Las Palmas de Gran Canaria | Hellsten Y.,Copenhagen University | And 2 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2012

Nitric oxide (NO) and prostaglandins (PG) together play a role in regulating blood flow during exercise. NO also regulates mitochondrial oxygen consumption through competitive binding to cytochrome-c oxidase. Indomethacin uncouples and inhibits the electron transport chain in a concentration-dependent manner, and thus, inhibition of NO and PG synthesis may regulate both muscle oxygen delivery and utilization. The purpose of this study was to examine the independent and combined effects of NO and PG synthesis blockade (L-NMMA and indomethacin, respectively) on mitochondrial respiration in human muscle following knee extension exercise (KEE). Specifically, this study examined the physiological effect of NO, and the pharmacological effect of indomethacin, on muscle mitochondrial function. Consistent with their mechanism of action, we hypothesized that inhibition of nitric oxide synthase (NOS) and PG synthesis would have opposite effects on muscle mitochondrial respiration. Mitochondrial respiration was measured ex vivo by high-resolution respirometry in saponin-permeabilized fibers following 6 min KEE in control (CON; n = 8), arterial infusion of N G-monomethyl-L-arginine (L-NMMA; n = 4) and Indo (n = 4) followed by combined inhibition of NOS and PG synthesis (L-NMMA + Indo, n = 8). ADP-stimulated state 3 respiration (OXPHOS) with substrates for complex I (glutamate, malate) was reduced 50% by Indo. State 3 O 2 flux with complex I and II substrates was reduced less with both Indo (20%) and L-NMMA + Indo (15%) compared with CON. The results indicate that indomethacin reduces state 3 mitochondrial respiration primarily at complex I of the respiratory chain, while blockade of NOS by L-NMMA counteracts the inhibition by Indo. This effect on muscle mitochondria, in concert with a reduction of blood flow accounts for in vivo changes in muscle O 2 consumption during combined blockade of NOS and PG synthesis. © 2012 the American Physiological Society.


PubMed | The Copenhagen Muscle Research Center, The Swedish School of Sport and Health Sciences and Innsbruck Medical University
Type: | Journal: Scandinavian journal of medicine & science in sports | Year: 2015

We recently reported the circulatory and muscle oxidative capacities of the arm after prolonged low-intensity skiing in the arctic (Boushel etal., 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 42days of skiing at 60% HR max.Peak pulmonary VO2 (3.520.18L.min(-1) pre vs 3.520.19 post) and VO2 across the leg (2.80.4L.min(-1) pre vs 3.00.2 post) were unchanged after the ski journey. Peak leg O2 delivery (3.60.2L.min(-1) pre vs 3.80.4 post), O2 extraction (821% pre vs 831 post), and muscle capillaries per mm(2) (57617 pre vs 61228 post) were also unchanged; however, leg musclemitochondrial OXPHOS capacity was reduced (903pmol.sec(-1) .mg(-1) pre vs 702 post, P<0.05) as was citrate synthase activity (403mol.min(-1) .g(-1) pre vs 343 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.

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