| 1. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 2. |
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| 3. |
- Siebenmann, C, et al.
(författare)
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Hemoglobin mass and intravascular volume kinetics during and after exposure to 3,454-m altitude
- 2015
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 119:10, s. 1194-1201
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Tidskriftsartikel (refereegranskat)abstract
- Siebenmann C, Cathomen A, Hug M, Keiser S, Lundby AK, Hilty MP, Goetze JP, Rasmussen P, Lundby C. Hemoglobin mass and intravascular volume kinetics during and after exposure to 3,454 m altitude. J Appl Physiol 119: 1194-1201, 2015. First published March 6, 2015; doi:10.1152/japplphysiol.01121.2014.-High altitude (HA) exposure facilitates a rapid contraction of plasma volume (PV) and a slower occurring expansion of hemoglobin mass (Hbmass). The kinetics of the Hbmass expansion has never been examined by multiple repeated measurements, and this was our primary study aim. The second aim was to investigate the mechanisms mediating the PV contraction. Nine healthy, normally trained sea-level (SL) residents (8 males, 1 female) sojourned for 28 days at 3,454 m. Hbmass was measured and PV was estimated by carbon monoxide rebreathing at SL, on every 4th day at HA, and 1 and 2 wk upon return to SL. Four weeks at HA increased Hbmass by 5.26% (range 2.5-11.1%; P < 0.001). The individual Hbmass increases commenced with up to 12 days of delay and reached a maximal rate of 4.04±1.02 g/day after 14.9±5.2 days. The probability for Hbmass to plateau increased steeply after 20-24 days. Upon return to SL Hbmass decayed by-2.46 ± 2.3 g/day, reaching values similar to baseline after 2 wk. PV, aldosterone concentration, and renin activity were reduced at HA (P < 0.001) while the total circulating protein mass remained unaffected. In summary, the Hbmass response to HA exposure followed a sigmoidal pattern with a delayed onset and a plateau after ∼3 wk. The decay rate of Hbmass upon descent to SL did not indicate major changes in the rate of erythrolysis. Moreover, our data support that PV contraction at HA is regulated by the renin-angiotensin-aldosterone axis and not by changes in oncotic pressure. © 2015 The American Physiological Society.
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| 4. |
- Calbet, José A L, et al.
(författare)
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Limitations to oxygen transport and utilisation during sprint exercise in humans : evidence for a functional reserve in muscle O2 diffusing capacity.
- 2015
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Ingår i: Journal of Physiology. - 0022-3751 .- 1469-7793. ; 593:20, s. 4649-4664
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Tidskriftsartikel (refereegranskat)abstract
- KEY POINTS SUMMARY: Severe acute hypoxia reduces sprint performance. Muscle VO2 during sprint exercise in normoxia is not limited by O2 delivery, O2 off-loading from haemoglobin or structure-dependent diffusion constraints in the skeletal muscle of young healthy men. A large functional reserve in muscle O2 diffusing capacity exists and remains available at exhaustion during exercise in normoxia, which is recruited during exercise in hypoxia. During whole-body incremental exercise to exhaustion in severe hypoxia leg VO2 is primarily dependent on convective O2 delivery and less limited by diffusion constraints than previously thought. The kinetics of O2 off-loading from haemoglobin does not limit VO2 peak in hypoxia. Our results indicate that the limitation to VO2 during short sprints resides in mechanisms regulating mitochondrial respiration.ABSTRACT: To determine the contribution of convective and diffusive limitations to VO2 peak during exercise in humans oxygen transport and haemodynamics were measured in eleven men (22 ± 2 years) during incremental (IE) and 30-s all-out sprints (Wingate test, WgT), in normoxia (Nx, PI O2 :143 mmHg) and hypoxia (Hyp, PI O2 :73 mmHg). Carboxyhaemoglobin (COHb) was increased to 6-7% before both WgTs to left-shift the oxyhaemoglobin dissociation curve. Leg VO2 was measured by the Fick method, and leg blood flow (BF) with thermodilution and muscle O2 diffusing capacity (DMO2 ) was calculated. In the WgT mean power output, leg BF, leg O2 delivery and leg VO2 were 7, 5, 28 and 23% lower in Hyp than Nx (P < 0.05), however, peak WgT DMO2 was higher in hypoxia (51.5 ± 9.7) than Nx (20.5 ± 3.0 ml min(-1) mmHg(-1) , P < 0.05). Despite a similar PaO2 (33.3 ± 2.4 and 34.1 ± 3.3 mmHg), mean capillary PO2 (16.7 ± 1.2 and 17.1 ± 1.6 mmHg), and peak perfusion during IE and WgT in Hyp, DMO2 and leg VO2 were 12 and 14% higher during WgT than IE in Hyp (both, P < 0.05). DMO2 was apparently insensitive to COHb (COHb: 0.7 vs 7%, in IE Hyp and WgT Hyp). At exhaustion, the Y equilibration index was well above 1.0 in both conditions, reflecting greater convective than diffusive limitation to the O2 transfer both in Nx and Hyp. In conclusion, muscle VO2 during sprint exercise is not limited by O2 delivery, the O2 off-loading from haemoglobin or structure-dependent diffusion constraints in the skeletal muscle. These findings reveal a remarkable functional reserve in muscle O2 diffusing capacity. This article is protected by copyright. All rights reserved.
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| 5. |
- Jacobs, Robert A., et al.
(författare)
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Twenty-eight days of exposure to 3,454 m increases mitochondrial volume density in human skeletal muscle
- 2015
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Ingår i: Journal of Physiology. - : Blackwell Publishing. - 0022-3751 .- 1469-7793. ; 594:5, s. 1151-1166
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Tidskriftsartikel (refereegranskat)abstract
- The role of hypoxia on skeletal muscle mitochondria is controversial. Studies superimposing exercise training with hypoxic exposure demonstrate an increase in skeletal muscle mitochondrial volume density (MitoVD ) over equivalent normoxic training. In contrast, a reduction in both skeletal muscle mass and MitoVD have been reported following mountaineering expeditions. These observations may however be confounded by negative energy balance, which may obscure the results. Accordingly we sought to examine the effects of high altitude hypoxic exposure on mitochondrial characteristics, with emphasis on MitoVD , while minimizing changes in energy balance. For this purpose, skeletal muscle biopsies were obtained from 9 lowlanders at sea level (Pre) and following 7 (7 Days) and 28 (28 Days) days of exposure to 3454 m. Maximal ergometer power output, whole-body weight and composition, leg lean mass, and skeletal muscle fibre area all remained unchanged following the altitude exposure. Transmission electron microscopy determined intermyofibrillar (IMF) MitoVD was augmented (P = 0.028) by 11.5 ± 9.2% from Pre (5.05 ± 0.9%) to Day 28 (5.61 ± 0.04%). On the contrary, there was no change in subsarcolemmal (SS) MitoVD . As a result total MitoVD (IMF + SS) was increased (P = 0.031) from 6.20 ± 1.5% at Pre to 6.62 ± 1.4% on Day 28 (7.8 ± 9.3%). At the same time no changes in mass-specific respiratory capacities, mitochondrial protein or antioxidant content were found. This study demonstrates that skeletal muscle MitoVD may increase with 28 days acclimation to 3454 m.
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| 6. |
- Lundby, A. K. M., et al.
(författare)
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Kidney-synthesized erythropoietin is the main source for the hypoxia-induced increase in plasma erythropoietin in adult humans
- 2014
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 114:6, s. 1107-1111
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Tidskriftsartikel (refereegranskat)abstract
- Erythropoietin (EPO) is mainly synthesized within renal peritubular fibroblasts, and also other tissues such as the liver possess the ability. However, to what extent non-kidney produced EPO contributes to the hypoxia-induced increase in circulating EPO in adult humans remains unclear. We aimed to quantify this by assessing the distribution of EPO glycoforms which are characterized by posttranslational glycosylation patterns specific to the synthesizing cell. The analysis was performed on samples obtained in seven healthy volunteers before, during and after 1 month of sojourn at 3,454 m altitude. Umbilical cord (UC) plasma served as control. As expected a peak (p < 0.05) in urine (2.3 +/- A 0.5-fold) and plasma (3.3 +/- A 0.5-fold) EPO was observed on day 1 of high-altitude exposure, and thereafter the concentration decreased for the urine sample obtained after 26 days at altitude, but remained elevated (p < 0.05) by 1.5 +/- A 0.2-fold above the initial sea level value for the plasma sample. The EPO glycoform heterogeneity, in the urine samples collected at altitude, did not differ from values at sea level, but were markedly lower (p < 0.05) than the mean percent migrated isoform (PMI) for the umbilical cord samples. Our studies demonstrate (1) UC samples express a different glycoform distribution as compared to adult humans and hence illustrates the ability to synthesis EPO in non-kidney cells during fetal development (2) as expected hypoxia augments circulating EPO in adults and the predominant source here for remains being kidney derived.
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| 7. |
- Lundby, Carsten, et al.
(författare)
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Physiological, biochemical, anthropometric, and biomechanical influences on exercise economy in humans
- 2017
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Ingår i: Scandinavian Journal of Medicine & Science in Sports. - : Wiley. - 0905-7188. ; 27:12, s. 1627-1637
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Tidskriftsartikel (refereegranskat)abstract
- Interindividual variation in running and cycling exercise economy (EE) remains unexplained although studied for more than a century. This study is the first to comprehensively evaluate the importance of biochemical, structural, physiological, anthropometric, and biomechanical influences on running and cycling EE within a single study. In 22 healthy males (VO(2)max range 45.5-72.1mLmin-1kg-1), no factor related to skeletal muscle structure (% slow-twitch fiber content, number of capillaries per fiber), mitochondrial properties (volume density, oxidative capacity, or mitochondrial efficiency), or protein content (UCP3 and MFN2 expression) explained variation in cycling and running EE among subjects. In contrast, biomechanical variables related to vertical displacement correlated well with running EE, but were not significant when taking body weight into account. Thus, running EE and body weight were correlated (R-2=.94; P<.001), but was lower for cycling EE (R-2=.23; P<.023). To separate biomechanical determinants of running EE, we contrasted individual running and cycling EE considering that during cycle ergometer exercise, the biomechanical influence on EE would be small because of the fixed movement pattern. Differences in cycling and running exercise protocols, for example, related to biomechanics, play however only a secondary role in determining EE. There was no evidence for an impact of structural or functional skeletal muscle variables on EE. Body weight was the main determinant of EE explaining 94% of variance in running EE, although more than 50% of the variability of cycling EE remains unexplained.
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| 8. |
- Montero, D., et al.
(författare)
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Sexual dimorphism of substrate utilization: Differences in skeletal muscle mitochondrial volume density and function
- 2018
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Ingår i: Experimental Physiology. - : Wiley. - 0958-0670. ; 103:6, s. 851-859
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Tidskriftsartikel (refereegranskat)abstract
- Fat oxidation during exercise is greater in females than in males. We sought to determine whether sex differences in substrate metabolism are paralleled by distinct skeletal muscle mitochondrial volume density and oxidative capacity. Whole-body substrate (fat and carbohydrate) utilization during submaximal treadmill running was assessed, and skeletal muscle biopsies were taken to determine mitochondrial volume density and function in healthy young females (n=12) and males (n=12) matched by aerobic exercise capacity and exercise performance. Females presented a lower respiratory exchange ratio (0.87 +/- 0.04 versus 0.91 +/- 0.04, P=0.023) and whole-body carbohydrate oxidation (27.8 +/- 8.3 versus 35.8 +/- 6.5mgkg(-1)min(-1), P=0.027), whereas fat oxidation was higher (8.7 +/- 2.8 versus 5.9 +/- 2.6mgkg(-1)min(-1), P=0.034) during submaximal exercise compared with males. In skeletal muscle biopsies, females demonstrated augmented mitochondrial volume density (7.51 +/- 1.77 versus 5.90 +/- 1.72%, P=0.035) and oxidative capacity for fatty acid [36.6 +/- 12.8 versus 24.5 +/- 7.3pmol O(2)s(-1)(mg wet weight)(-1), P=0.009] and lactate [71.1 +/- 24.4 versus 53.2 +/- 14.6pmol O(2)s(-1)(mg wet weight)(-1), P=0.040]. No sex differences in respiratory exchange ratio, whole-body fat oxidation and skeletal muscle variables were detected when adjusted for anthropometric variables including body mass or leg mass, which were lower in females. In conclusion, female prioritization of fat over carbohydrate oxidation during exercise is underpinned by augmented body size-related mitochondrial volume density, fatty acid and lactate oxidative capacity in skeletal muscle fibres.
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| 9. |
- Bonne, T. C., et al.
(författare)
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Phlebotomy eliminates the maximal cardiac output response to six weeks of exercise training
- 2014
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Ingår i: American Journal of Physiology-Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 306:10, s. R752-R760
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Tidskriftsartikel (refereegranskat)abstract
- With this study we tested the hypothesis that 6 wk of endurance training increases maximal cardiac output (Q(max)) relatively more by elevating blood volume (BV) than by inducing structural and functional changes within the heart. Nine healthy but untrained volunteers (Vo(2max) 47 +/- 5 ml.min(-1).kg(-1)) underwent supervised training (60 min; 4 times weekly at 65% Vo(2max) for 6 wk), and Q(max) was determined by inert gas rebreathing during cycle ergometer exercise before and after the training period. After the training period, blood volume (determined in duplicates by CO rebreathing) was reestablished to pretraining values by phlebotomy and Q(max) was quantified again. Resting echography revealed no structural heart adaptations as a consequence of the training intervention. After the training period, plasma volume (PV), red blood cell volume (RBCV), and BV increased (P < 0.05) by 147 +/- 168 (5 +/- 5%), 235 +/- 64 (10 +/- 3%), and 382 +/- 204 ml (7 +/- 4%), respectively. Vo(2max) was augmented (P < 0.05) by 10 +/- 7% after the training period and decreased (P < 0.05) by 8 +/- 7% with phlebotomy. Concomitantly, Q(max) was increased (P < 0.05) from 18.9 +/- 2.1 to 20.4 +/- 2.3 l/min (9 +/- 6%) as a consequence of the training intervention, and after normalization of BV by phlebotomy Q(max) returned to pretraining values (18.1 +/- 2.5 l/min; 12 +/- 5% reversal). Thus the exercise training-induced increase in BV is the main mechanism increasing Q(max) after 6 wk of endurance training in previously untrained subjects.
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| 10. |
- Calbet, J.A.L., et al.
(författare)
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Chronic hypoxia increases arterial blood pressure and reduces adenosine and ATP induced vasodilatation in skeletal muscle in healthy humans
- 2014
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 211:4, s. 574-584
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine the role played by adenosine, ATP and chemoreflex activation on the regulation of vascular conductance in chronic hypoxia. Methods: The vascular conductance response to low and high doses of adenosine and ATP was assessed in ten healthy men. Vasodilators were infused into the femoral artery at sea level and then after 8-12 days of residence at 4559 m above sea level. At sea level, the infusions were carried out while the subjects breathed room air, acute hypoxia (FIO2 = 0.11) and hyperoxia (FIO2 = 1); and at altitude (FIO2 = 0.21 and 1). Skeletal muscle P2Y2 receptor protein expression was determined in muscle biopsies after 4 weeks at 3454 m by Western blot. Results: At altitude, mean arterial blood pressure was 13% higher (91 ± 2 vs. 102 ± 3 mmHg, P < 0.05) than at sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower at altitude than at sea level (P < 0.05). At altitude, the high doses of adenosine and ATP reduced mean arterial blood pressure by 9-12%, independently of FIO2. The change in vascular conductance in response to ATP was lower at altitude than at sea level by 24 and 38%, during the low and high ATP doses respectively (P < 0.05), and by 22% during the infusion with high adenosine doses. Hyperoxic breathing did not modify the response to vasodilators at sea level or at altitude. P2Y2 receptor expression remained unchanged with altitude residence. Conclusions: Short-term residence at altitude increases arterial blood pressure and reduces the vasodilatory responses to adenosine and ATP. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
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