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Cardinale, D. A., Larsen, F. J., Jensen-Urstad, M., Rullman, E., Søndergaard, H., Morales-Alamo, D., . . . Boushel, R. (2019). Muscle mass and inspired oxygen influence oxygen extraction at maximal exercise: role of mitochondrial oxygen affinity.. Acta Physiologica, 225(1), Article ID e13110.
Open this publication in new window or tab >>Muscle mass and inspired oxygen influence oxygen extraction at maximal exercise: role of mitochondrial oxygen affinity.
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2019 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 225, no 1, article id e13110Article in journal (Refereed) Published
Abstract [en]

AIM:We examined the Fick components together with mitochondrial O2 affinity (p50mito ) in defining O2 extraction and O2 uptake during exercise with large and small muscle mass during normoxia (NORM) and hyperoxia (HYPER).

METHODS:Seven individuals performed two incremental exercise tests to exhaustion on a bicycle ergometer (BIKE) and two on a one-legged knee extension ergometer (KE) in NORM or HYPER. Leg blood flow and VO2 were determined by thermodilution and the Fick method. Maximal ADP-stimulated mitochondrial respiration (OXPHOS) and p50mito were measured ex vivo in isolated mitochondria. Mitochondrial excess capacity in the leg was determined from OXPHOS in permeabilized fibers and muscle mass measured with magnetic resonance imaging in relation to peak leg O2 delivery.

RESULTS:The ex vivo p50mito increased from 0.06±0.02 to 0.17±0.04 kPa with varying substrate supply and O2 flux rates from 9.84±2.91 to 16.34±4.07 pmol O2 ·s-1 ·μg-1 respectively. O2 extraction decreased from 83% in BIKE to 67% in KE as a function of a higher O2 delivery, and lower mitochondrial excess capacity. There was a significant relationship between O2 extraction and mitochondrial excess capacity and p50mito that was unrelated to blood flow and mean transit time.

CONCLUSION:O2 extraction varies with mitochondrial respiration rate, p50mito and O2 delivery. Mitochondrial excess capacity maintains a low p50mito which enhances O2 diffusion from microvessels to mitochondria during exercise. This article is protected by copyright. All rights reserved.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
Keywords
OXPHOS, VO2max, Fick method, hyperoxia, mitochondrial p50, muscle O2 diffusion, thermodilution technique
National Category
Sport and Fitness Sciences
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-5287 (URN)10.1111/apha.13110 (DOI)000454605500006 ()29863764 (PubMedID)
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2019-01-18Bibliographically approved
Cardinale, D. A., Larsen, F. J., Schiffer, T. A., Morales-Alamo, D., Ekblom, B., Calbet, J. A., . . . Boushel, R. (2018). Superior Intrinsic Mitochondrial Respiration in Women Than in Men.. Frontiers in Physiology, 9, Article ID 1133.
Open this publication in new window or tab >>Superior Intrinsic Mitochondrial Respiration in Women Than in Men.
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2018 (English)In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1133Article in journal (Refereed) Published
Abstract [en]

Sexual dimorphism is apparent in humans, however, to date no studies have investigated mitochondrial function focusing on intrinsic mitochondrial respiration (i.e., mitochondrial respiration for a given amount of mitochondrial protein) and mitochondrial oxygen affinity (p50mito) in relation to biological sex in human. A skeletal muscle biopsy was donated by nine active women, and ten men matched for maximal oxygen consumption (VO2max) and by nine endurance trained men. Intrinsic mitochondrial respiration, assessed in isolated mitochondria, was higher in women compared to men when activating complex I (CIP) and complex I+II (CI+IIP) (p < 0.05), and was similar to trained men (CIP, p = 0.053; CI+IIP, p = 0.066). Proton leak and p50mito were higher in women compared to men independent of VO2max. In conclusion, significant novel differences in mitochondrial oxidative function, intrinsic mitochondrial respiration and p50mito exist between women and men. These findings may represent an adaptation in the oxygen cascade in women to optimize muscle oxygen uptake to compensate for a lower oxygen delivery during exercise.

Keywords
OXPHOS, endurance performance, mitochondria, mitochondrial function, sexual dimorphism, skeletal muscle
National Category
Sport and Fitness Sciences
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-5407 (URN)10.3389/fphys.2018.01133 (DOI)000441955000001 ()30174617 (PubMedID)
Available from: 2018-09-04 Created: 2018-09-04 Last updated: 2018-10-17Bibliographically approved
Manselin, T. A., Södergård, O., Larsen, F. J. & Lindholm, P. (2017). Aerobic efficiency is associated with the improvement in maximal power output during acute hyperoxia.. Physiological Reports, 5(2), Article ID e13119.
Open this publication in new window or tab >>Aerobic efficiency is associated with the improvement in maximal power output during acute hyperoxia.
2017 (English)In: Physiological Reports, E-ISSN 2051-817X, Vol. 5, no 2, article id e13119Article in journal (Refereed) Published
Abstract [en]

This study investigated the relationship between aerobic efficiency during cycling exercise and the increase in physical performance with acute hyperoxic exposure (FiO2 ~31%) (HOX) and also tested the hypothesis that fat oxidation could be increased by acute hyperoxia. Fourteen males and four females were recruited for two sessions, where they exercised for 2 × 10 min at 100 W to determine efficiency. HOX and normoxia (NOX) were administered randomly on both occasions to account for differences in nitrogen exchange. Thereafter, a progressive ramp test was performed to determine VO2max and maximal power output (Wmax). After 30 min rest, workload was set to 80% of maximal power output (Wmax) for a time to exhaustion test (TTE). At 100W gross efficiency was reduced from 19.4% during NOX to 18.9% during HOX (P ≤ 0.0001). HOX increased fat oxidation at 100 W by 52% from 3.41 kcal min(-1) to 5.17 kcal min(-1) (P ≤ 0.0001) with a corresponding reduction in carbohydrate oxidation. Wmax increased by 2.4% from 388.8 (±82.1) during NOX to 397.8 (±83.5) during HOX (P ≤ 0.0001). SaO2 was higher in HOX both at the end of the maximal exercise test and TTE. Subjects with a high level of efficiency in NOX had a larger improvement in Wmax with HOX, in agreement with the hypothesis that an optimum level of efficiency exists that maximizes power production. No association between mitochondrial excess capacity and endurance performance was found; increases in oxygen supply seemed to increase maximal aerobic power production and maintain/increase endurance capacity at the same relative workload.

National Category
Physiology
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-4764 (URN)10.14814/phy2.13119 (DOI)000393855700011 ()28108650 (PubMedID)
Available from: 2017-02-01 Created: 2017-02-01 Last updated: 2018-01-13
Montenegro, M. F., Sundqvist, M. L., Larsen, F. J., Zhuge, Z., Carlström, M., Weitzberg, E. & Lundberg, J. O. (2017). Blood Pressure-Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor.. Hypertension, 69(1), 23-31
Open this publication in new window or tab >>Blood Pressure-Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor.
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2017 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 69, no 1, p. 23-31Article in journal (Refereed) Published
Abstract [en]

Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure. The mechanisms for nitrite bioactivation are unclear, but recent studies in rodents suggest that gastric acidity may influence the systemic effects of this anion. In a randomized, double-blind, placebo-controlled crossover study, we tested the effects of a proton pump inhibitor on the acute cardiovascular effects of nitrite. Fifteen healthy nonsmoking, normotensive subjects, aged 19 to 39 years, were pretreated with placebo or esomeprazole (3×40 mg) before ingesting sodium nitrite (0.3 mg kg(-1)), followed by blood pressure monitoring. Nitrite reduced systolic blood pressure by a maximum of 6±1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect. Peak plasma nitrite, nitrate, and nitroso species levels after nitrite ingestion were similar in both interventions. In 8 healthy volunteers, we then infused increasing doses of sodium nitrite (1, 10, and 30 nmol kg(-1) min(-1)) intravenously. Interestingly, although plasma nitrite peaked at similar levels as with orally ingested nitrite (≈1.8 µmol/L), no changes in blood pressure were observed. In rodents, esomeprazole did not affect the blood pressure response to the NO donor, DEA NONOate, or vascular relaxation to nitroprusside and acetylcholine, demonstrating an intact downstream NO-signaling pathway. We conclude that the acute blood pressure-lowering effect of nitrite requires an acidic gastric environment. Future studies will reveal if the cardiovascular complications associated with the use of proton pump inhibitors are linked to interference with the nitrate-nitrite-NO pathway.

National Category
Physiology
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-4638 (URN)10.1161/HYPERTENSIONAHA.116.08081 (DOI)27802417 (PubMedID)
Available from: 2016-11-14 Created: 2016-11-14 Last updated: 2018-01-13Bibliographically approved
Schiffer, T. A., Peleli, M., Sundqvist, M. L., Ekblom, B., Lundberg, J. O., Weitzberg, E. & Larsen, F. J. (2016). Control of Human Energy Expenditure by Cytochrome C Oxidase Subunit IV-2.. American Journal of Physiology - Cell Physiology, 311(3), C452-C461
Open this publication in new window or tab >>Control of Human Energy Expenditure by Cytochrome C Oxidase Subunit IV-2.
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2016 (English)In: American Journal of Physiology - Cell Physiology, ISSN 0363-6143, E-ISSN 1522-1563, Vol. 311, no 3, p. C452-C461Article in journal (Refereed) Published
Abstract [en]

Resting metabolic rate (RMR) in human shows pronounced individual variations, but the underlying molecular mechanism remains elusive. Cytochrome C oxidase (COX) plays a key role in control of metabolic rate and recent studies of the subunit 4 isoform 2 (COX IV-2) indicate involvement in the cellular response to hypoxia and oxidative stress. We evaluated whether the COX subunit IV isoform composition may explain the pronounced individual variations in resting metabolic rate (RMR). RMR was determined in healthy humans by indirect calorimetry and correlated to levels of COX IV-2 and COX IV-1 in Vastus Lateralis. Over expression and knock down of the COX IV isoforms were performed in primary myotubes followed by evaluation of the cell respiration and production of reactive oxygen species. Here we show that COX IV-2 protein is constitutively expressed in human skeletal muscle and strongly correlated to RMR. Primary human myotubes overexpressing COX IV-2 displayed markedly (>60%) lower respiration, reduced (>50%) cellular H2O2 production, higher resistance towards both oxidative stress and severe hypoxia compared to control cells. These results suggest an important role of isoform COX IV-2 in the control of energy expenditure, hypoxic tolerance and mitochondrial ROS homeostasis in humans.

National Category
Physiology
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-4521 (URN)10.1152/ajpcell.00099.2016 (DOI)000384749700010 ()27486093 (PubMedID)
Available from: 2016-08-08 Created: 2016-08-08 Last updated: 2018-01-10Bibliographically approved
Larsen, F. J., Schiffer, T. A., Ørtenblad, N., Zinner, C., Morales-Alamo, D., Willis, S. J., . . . Boushel, R. (2016). High-intensity sprint training inhibits mitochondrial respiration through aconitase inactivation.. The FASEB Journal, 30(1), 417-427
Open this publication in new window or tab >>High-intensity sprint training inhibits mitochondrial respiration through aconitase inactivation.
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2016 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 30, no 1, p. 417-427Article in journal (Refereed) Published
Abstract [en]

Intense exercise training is a powerful stimulus that activates mitochondrial biogenesis pathways and thus increases mitochondrial density and oxidative capacity. Moderate levels of reactive oxygen species (ROS) during exercise are considered vital in the adaptive response, but high ROS production is a serious threat to cellular homeostasis. Although biochemical markers of the transition from adaptive to maladaptive ROS stress are lacking, it is likely mediated by redox sensitive enzymes involved in oxidative metabolism. One potential enzyme mediating such redox sensitivity is the citric acid cycle enzyme aconitase. In this study, we examined biopsy specimens of vastus lateralis and triceps brachii in healthy volunteers, together with primary human myotubes. An intense exercise regimen inactivated aconitase by 55-72%, resulting in inhibition of mitochondrial respiration by 50-65%. In the vastus, the mitochondrial dysfunction was compensated for by a 15-72% increase in mitochondrial proteins, whereas H2O2 emission was unchanged. In parallel with the inactivation of aconitase, the intermediary metabolite citrate accumulated and played an integral part in cellular protection against oxidative stress. In contrast, the triceps failed to increase mitochondrial density, and citrate did not accumulate. Instead, mitochondrial H2O2 emission was decreased to 40% of the pretraining levels, together with a 6-fold increase in protein abundance of catalase. In this study, a novel mitochondrial stress response was highlighted where accumulation of citrate acted to preserve the redox status of the cell during periods of intense exercise.-Larsen, F. J., Schiffer, T. A., Ørtenblad, N., Zinner, C., Morales-Alamo, D., Willis, S. J., Calbet, J. A., Holmberg, H.-C., Boushel, R. High-intensity sprint training inhibits mitochondrial respiration through aconitase inactivation.

National Category
Sport and Fitness Sciences
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-4184 (URN)10.1096/fj.15-276857 (DOI)26452378 (PubMedID)
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2017-12-01Bibliographically approved
Zinner, C., Morales-Alamo, D., Ørtenblad, N., Larsen, F. J., Schiffer, T. A., Willis, S. J., . . . Holmberg, H.-C. (2016). The Physiological Mechanisms of Performance Enhancement with Sprint Interval Training Differ between the Upper and Lower Extremities in Humans.. Frontiers in Physiology, 7, Article ID 426.
Open this publication in new window or tab >>The Physiological Mechanisms of Performance Enhancement with Sprint Interval Training Differ between the Upper and Lower Extremities in Humans.
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2016 (English)In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, article id 426Article in journal (Refereed) Published
Abstract [en]

To elucidate the mechanisms underlying the differences in adaptation of arm and leg muscles to sprint training, over a period of 11 days 16 untrained men performed six sessions of 4-6 × 30-s all-out sprints (SIT) with the legs and arms, separately, with a 1-h interval of recovery. Limb-specific VO2peak, sprint performance (two 30-s Wingate tests with 4-min recovery), muscle efficiency and time-trial performance (TT, 5-min all-out) were assessed and biopsies from the m. vastus lateralis and m. triceps brachii taken before and after training. VO2peak and Wmax increased 3-11% after training, with a more pronounced change in the arms (P < 0.05). Gross efficiency improved for the arms (+8.8%, P < 0.05), but not the legs (-0.6%). Wingate peak and mean power outputs improved similarly for the arms and legs, as did TT performance. After training, VO2 during the two Wingate tests was increased by 52 and 6% for the arms and legs, respectively (P < 0.001). In the case of the arms, VO2 was higher during the first than second Wingate test (64 vs. 44%, P < 0.05). During the TT, relative exercise intensity, HR, VO2, VCO2, VE, and Vt were all lower during arm-cranking than leg-pedaling, and oxidation of fat was minimal, remaining so after training. Despite the higher relative intensity, fat oxidation was 70% greater during leg-pedaling (P = 0.017). The aerobic energy contribution in the legs was larger than for the arms during the Wingate tests, although VO2 for the arms was enhanced more by training, reducing the O2 deficit after SIT. The levels of muscle glycogen, as well as the myosin heavy chain composition were unchanged in both cases, while the activities of 3-hydroxyacyl-CoA-dehydrogenase and citrate synthase were elevated only in the legs and capillarization enhanced in both limbs. Multiple regression analysis demonstrated that the variables that predict TT performance differ for the arms and legs. The primary mechanism of adaptation to SIT by both the arms and legs is enhancement of aerobic energy production. However, with their higher proportion of fast muscle fibers, the arms exhibit greater plasticity.

National Category
Sport and Fitness Sciences
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-4611 (URN)10.3389/fphys.2016.00426 (DOI)000384362100001 ()27746738 (PubMedID)
Available from: 2016-10-24 Created: 2016-10-24 Last updated: 2017-11-29
Boushel, R., Gnaiger, E., Larsen, F. J., Helge, J. W., González-Alonso, J., Ara, I., . . . Calbet, J. A. (2015). Maintained peak leg and pulmonary VO2 despite substantial reduction in muscle mitochondrial capacity.. Scandinavian Journal of Medicine and Science in Sports, 25(Suppl 4), 135-143
Open this publication in new window or tab >>Maintained peak leg and pulmonary VO2 despite substantial reduction in muscle mitochondrial capacity.
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2015 (English)In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 25, no Suppl 4, p. 135-143Article in journal (Refereed) Published
Abstract [en]

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 mm(2) (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.

National Category
Sport and Fitness Sciences
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-4220 (URN)10.1111/sms.12613 (DOI)000365322300024 ()26589127 (PubMedID)
Available from: 2015-11-23 Created: 2015-11-23 Last updated: 2017-12-01Bibliographically approved
Mattsson, C. M., Larsen, F. & Holmberg, H. C. (2014). Den nödvändiga distansträningen. Svensk Idrottsforskning: Organ för Centrum för Idrottsforskning, 23(3), 8-13
Open this publication in new window or tab >>Den nödvändiga distansträningen
2014 (Swedish)In: Svensk Idrottsforskning: Organ för Centrum för Idrottsforskning, ISSN 1103-4629, Vol. 23, no 3, p. 8-13Article in journal (Other academic) Published
Abstract [sv]

Korta och intensiva intervallpass är ett trendigt sätt att förbättra sin kondition. Men för att bli en bra löpare, längdåkare eller cyklist måste man träna många långa pass i ett lägre tempo. Forskning har visat att högintensiv intervallträning är tidseffektiv och ger bra effekt på många parametrar som är viktiga för konditionsidrottare. Tanken att ersätta nötandet i spåret med kort och snabb träning kan därför låta lockande. Men fullt så enkelt är det inte. Idrottsfysiologerna Mikael Mattsson, Filip Larsen och H-C Holmberg har studerat den forskning som finns om distansträning. Den visar att det inte går att komma runt den lågintensiva träningen om man vill bli en riktigt bra löpare, orienterare, längdskidåkare eller cyklist. På maraton finns till exempel ett nästan linjärt förhållande mellan träningsmängd och prestation. Ju fler mil löparen tränar i veckan desto bättre blir tiden. Kanske räcker det med att studera hur eliten tränar för att förstå distansträningens betydelse. Visserligen är den intensiva intervallträningen viktig även för dem, särskilt inför viktiga tävlingar. Men upp till 90 procent av den totala träningstiden eller minst 3-4 timmar per dag ägnar de åt mer lågintensiva pass.

Keywords
Idrottsträning
National Category
Sport and Fitness Sciences
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-3475 (URN)
Available from: 2014-10-06 Created: 2014-10-06 Last updated: 2017-12-05
Larsen, F. J., Schiffer, T. A., Ekblom, B., Mattsson, M. P., Checa, A., Wheelock, C. E., . . . Weitzberg, E. (2014). Dietary nitrate reduces resting metabolic rate: a randomized, crossover study in humans.. American Journal of Clinical Nutrition, 99(4), 843-50
Open this publication in new window or tab >>Dietary nitrate reduces resting metabolic rate: a randomized, crossover study in humans.
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2014 (English)In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 99, no 4, p. 843-50Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Nitrate, which is an inorganic anion abundant in vegetables, increases the efficiency of isolated human mitochondria. Such an effect might be reflected in changes in the resting metabolic rate (RMR) and formation of reactive oxygen species. The bioactivation of nitrate involves its active accumulation in saliva followed by a sequential reduction to nitrite, nitric oxide, and other reactive nitrogen species.

OBJECTIVE: We studied effects of inorganic nitrate, in amounts that represented a diet rich in vegetables, on the RMR in healthy volunteers.

DESIGN: In a randomized, double-blind, crossover study, we measured the RMR by using indirect calorimetry in 13 healthy volunteers after a 3-d dietary intervention with sodium nitrate (NaNO3) or a placebo (NaCl). The nitrate dose (0.1 mmol · kg(-1) · d(-1)) corresponded to the amount in 200-300 g spinach, beetroot, lettuce, or other vegetable that was rich in nitrate. Effects of direct nitrite exposure on cell respiration were studied in cultured human primary myotubes.

RESULTS: The RMR was 4.2% lower after nitrate compared with placebo administration, and the change correlated strongly to the degree of nitrate accumulation in saliva (r(2) = 0.71). The thyroid hormone status, insulin sensitivity, glucose uptake, plasma concentration of isoprostanes, and total antioxidant capacity were unaffected by nitrate. The administration of nitrite to human primary myotubes acutely inhibited respiration.

CONCLUSIONS: Dietary inorganic nitrate reduces the RMR. This effect may have implications for the regulation of metabolic function in health and disease.

National Category
Nutrition and Dietetics
Research subject
Medicine/Technology
Identifiers
urn:nbn:se:gih:diva-3271 (URN)10.3945/ajcn.113.079491 (DOI)24500154 (PubMedID)
Available from: 2014-03-31 Created: 2014-03-31 Last updated: 2017-12-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1343-8656

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