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  • 1.
    Bakkman, Linda
    et al.
    Karolinska institutet.
    Fernström, Maria
    Karolinska institutet.
    Loogna, Peter
    Sophiahemmet.
    Rooyackers, Olav
    Brandt, Lena
    Karolinska institutet.
    Lagerros, Ylva Trolle
    Karolinska institutet.
    Reduced respiratory capacity in muscle mitochondria of obese subjects.2010In: Obesity Facts, ISSN 1662-4025, E-ISSN 1662-4033, Vol. 3, no 6, p. 371-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIMS: The extent of weight gain varies among individuals despite equal calorie overconsumption. Furthermore, weight gain is often less than expected from energy excess. This suggests differences in metabolic efficiency and basal metabolism. Since mitochondrial uncoupling accounts for a substantial portion of the basal metabolic rate, we compared skeletal muscle mitochondrial respiration in obese subjects to normal-weight reference groups with various degrees of physical activity.

    METHODS: Muscle biopsies were taken from the vastus lateralis muscle of 9 healthy obese subjects (BMI 40 ± 3). Mitochondria were isolated and analyzed for coupled (state 3) and uncoupled (state 4) respirations as well as mitochondrial efficiency (P/O ratio) using pyruvate as a substrate. Respiratory data were compared to reference groups A, normal-weight untrained (BMI 24 ± 0.7), and B, normal-weight trained (BMI 24 ± 0.6).

    RESULTS: Obese subjects had a decreased respiratory capacity per mitochondrial volume compared to the reference groups: this was evident in state 4 (65% and 35% of reference group A and B, respectively) and state 3 (53% and 29% of A and B, respectively) (p < 0.05).

    CONCLUSION: Obese subjects had a low capacity for fuel oxidation, which may play a role in the predisposition of obesity. However, whether lower mitochondrial capacity is a cause or a consequence of obesity requires further research.

  • 2. Fakhrai-Rad, H
    et al.
    Nikoshkov, A
    Kamel, A
    Fernström, Maria
    Karolinska institutet.
    Zierath, J R
    Norgren, S
    Luthman, H
    Galli, J
    Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats.2000In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 9, no 14, p. 2149-58Article in journal (Refereed)
    Abstract [en]

    Genetic analysis of the diabetic GK rat has revealed several diabetes susceptibility loci. Congenic strains have been established for the major diabetes locus, Niddm1, by transfer of GK alleles onto the genome of the normoglycemic F344 rat. Niddm1 was dissected into two subloci, physically separated in the congenic strains Niddm1b and Niddm1i, each with at least one disease susceptibility gene. Here we have mapped Niddm1b to 1 cM by genetic and pathophysiological characterization of new congenic substrains for the locus. The gene encoding insulin-degrading enzyme (IDE:) was located to this 1 cM region, and the two amino acid substitutions (H18R and A890V) identified in the GK allele reduced insulin-degrading activity by 31% in transfected cells. However, when the H18R and A890V variants were studied separately, no effects were observed, demonstrating a synergistic effect of the two variants on insulin degradation. No effect on insulin degradation was observed in cell lysates, indicating that the effect is coupled to receptor-mediated internalization of insulin. Congenic rats with the IDE: GK allele displayed post-prandial hyperglycemia, reduced lipogenesis in fat cells, blunted insulin-stimulated glucose transmembrane uptake and reduced insulin degradation in isolated muscle. Analysis of additional rat strains demonstrated that the dysfunctional IDE: allele was unique to GK. These data point to an important role for IDE: in the diabetic phenotype in GK.

  • 3.
    Fernberg, Ulrika
    et al.
    Örebro University.
    Fernström, Maria
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology. Örebro University.
    Hurtig-Wennlöf, Anita
    Örebro University.
    Arterial stiffness is associated to cardiorespiratory fitness and body mass index in young Swedish adults: The Lifestyle, Biomarkers, and Atherosclerosis study.2017In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 24, no 17, p. 1809-1818, article id 2047487317720796Article in journal (Refereed)
    Abstract [en]

    Background Early changes in the large muscular arteries are already associated with risk factors as hypertension and obesity in adolescence and young adulthood. The present study examines the association between arterial stiffness measurements, pulse wave velocity and augmentation index and lifestyle-related factors, body composition and cardiorespiratory fitness, in young, healthy, Swedish adults. Design This study used a population-based cross-sectional sample. Methods The 834 participants in the study were self-reported healthy, non-smoking, age 18-25 years. Augmentation index and pulse wave velocity were measured with applanation tonometry. Cardiorespiratory fitness was measured by ergometer bike test to estimate maximal oxygen uptake. Body mass index (kg/m(2)) was calculated and categorised according to classification by the World Health Organisation. Results Young Swedish adults with obesity and low cardiorespiratory fitness have significantly higher pulse wave velocity and augmentation index than non-obese young adults with medium or high cardiorespiratory fitness. The observed U-shaped association between pulse wave velocity and body mass index categories in women indicates that it might be more beneficial to be normal weight than underweight when assessing the arterial stiffness with pulse wave velocity. The highest mean pulse wave velocity was found in overweight/obese individuals with low cardiorespiratory fitness. The lowest mean pulse wave velocity was found in normal weight individuals with high cardiorespiratory fitness. Cardiorespiratory fitness had a stronger effect than body mass index on arterial stiffness in multiple regression analyses. Conclusions The inverse association between cardiorespiratory fitness and arterial stiffness is observed already in young adults. The study result highlights the importance of high cardiorespiratory fitness, but also that underweight individuals may be a possible risk group that needs to be further studied.

  • 4.
    Fernberg, Ulrika
    et al.
    Örebro universitet.
    Fernström, Maria
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology. Örebro universitet.
    Hurtig-Wennlöf, Anita
    Örebro universitet.
    Central and peripheral blood pressure and the association with BMI in young adults – the Lifestyle, Biomarkers, and Atherosclerosis Study2018In: Book of abstracts, Nobel Day’s Festivities 2018, School of Medical Sciences and School of Health Sciences, Örebro University , 2018, p. 10-Conference paper (Other academic)
  • 5.
    Fernström, Maria
    Swedish School of Sport and Health Sciences, GIH.
    Effects of endurance exercise on mitochondrial efficiency, uncoupling and lipid oxidation in human skeletal muscle2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During the last years the importance of muscle mitochondria, and mitochondrial function, not only for performance but also for health has been highlighted. The main function of the mitochondria is to produce ATP by oxidative phosphorylation (coupled respiration). In skeletal muscle a substantial part of the energy is lost in non-coupled reactions, it has been estimated that non-coupled respiration accounts for as much as 20-25% of the total energy expenditure. It is now almost 10 years since the discovery of uncoupling protein 3 (UCP3), but the functional role of UCP3 in non-coupled respiration is not completely understood. The aim of this thesis was to investigate mitochondrial efficiency (P/O ratio), mitochondrial fat oxidation, non-coupled respiration (state 4) and protein expression of UCP3 in response to exercise and training in human skeletal muscle.

    In study I eight healthy subjects endurance trained for 6 weeks and 9 subjects performed one exercise session (75 min). In the cycling efficiency study II, and in the study on mitochondrial lipid oxidation III, 9 healthy trained and 9 healthy untrained men participated. In study IV mitochondrial function and reactive oxygen species (ROS) production was studied in 9 elite athletes after extreme exercise, 24 hours of cycling, running and paddling.

    Endurance training increased whole body oxygen uptake (VO2 peak) by 24% and muscle citrate synthase (CS) activity (marker of mitochondrial volume) by 47% (P< 0.05), but non-coupled respiration and UCP3 adjusted for mitochondrial volume were reduced (P< 0.05). One session of exercise did not affect non-coupled respiration or UCP3.

    Cycling efficiency (expressed as work efficiency) was inversely related to protein expression of UCP3 (r= 0.57) and correlated to type 1 fibers (r= 0.58). Work efficiency was not influenced by training status or correlated to mitochondrial efficiency. UCP3 was 52% higher in the untrained men (P< 0.05). Mitochondrial capacity for fat oxidation was not influenced by training status, but related to fiber type composition. The hypothesis that mitochondrial fat oxidation is related to whole body lipid oxidation during low-intensity exercise was confirmed (r= 0.62).

    Mitochondrial capacity for fat oxidation increased after 24 hours of exercise, whereas mitochondrial efficiency (P/O ratio) decreased. P/O ratio remained reduced also after 28 hours of recovery. Formation of ROS by isolated mitochondria increased after exercise. Non-coupled respiration (state 4), however, decreased and UCP3 tended to be reduced after recovery from ultra-endurance exercise (P= 0.07).

    In conclusion: UCP3 does not follow exercise induced mitochondrial biogenesis. UCP3 is reduced by endurance training and lower in trained men compared with untrained men. Non-coupled respiration, measured in isolated mitochondria was reduced by endurance training and reduced after recovery from ultra-endurance exercise, but similar in trained and untrained men. In these studies UCP3 and non-coupled respiration follow the same pattern but are not correlated. Further studies are needed to understand the complex role of UCP3 in skeletal muscle metabolism.

  • 6.
    Fernström, Maria
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Hög aerob uthållighet förenat med låg risk för hjärt-kärlsjukdom hos svenska unga vuxna2018In: BestPractice, no SeptArticle in journal (Other academic)
  • 7.
    Fernström, Maria
    et al.
    Örebro University.
    Bakkman, Linda
    Karolinska institutet.
    Loogna, Peter
    Sophiahemmet.
    Rooyackers, Olav
    Karolinska institutet.
    Svensson, Madeleine
    Karolinska institutet.
    Jakobsson, Towe
    Karolinska institutet.
    Brandt, Lena
    Örebro University.
    Lagerros, Ylva Trolle
    Karolinska institutet.
    Improved Muscle Mitochondrial Capacity Following Gastric Bypass Surgery in Obese Subjects.2016In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 26, no 7, p. 1391-7Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Weight loss resulting from low-calorie diets is often less than expected. We hypothesized that energy restriction would influence proton leakage and improve mitochondrial efficiency, leading to reduced energy expenditure, partly explaining the difficulties in weight loss maintenance.

    METHODS: Eleven women with a median BMI of 38.5 kg/m(2) (q-range 37-40), and referred to gastric bypass surgery participated. Before surgery, and at 6 months of follow-up, muscle biopsies were collected from the vastus lateralis muscle. Mitochondria were isolated and analyzed for coupled (state 3) and uncoupled (state 4) respiration and mitochondrial capacity (P/O ratio).

    RESULTS: At follow-up, the participants had a median BMI of 29.6 kg/m(2) (28.3-32.0). State 3 increased from 20.6 (17.9-28.9) to 34.9 nmol O2/min/U citrate synthase (CS) (27.0-49.0), p = 0.01, while state 4 increased from 2.8 (1.8-4.2) to 4.2 nmol O2/min/U CS (3.1-6.1), although not statistically significant. The P/O ratio increased from 2.7 (2.5-2.8) to 3.2 (3.0-3.4), p = 0.02, indicating improved mitochondrial efficiency.

    CONCLUSIONS: Six months after gastric bypass surgery, the mitochondrial capacity for coupled, i.e., ATP-generating, respiration increased, and the P/O ratio improved. Uncoupled respiration was not enhanced to the same extent. This could partly explain the decreased basal metabolism and the reduced inclination for weight loss during energy restriction.

  • 8.
    Fernström, Maria
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Bakkman, Linda
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Tonkonogi, Michail
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Shabalina, Irina
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Rozhdestvenskaya, Z
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Mattsson, C. Mikael
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Björn Ekblom's research group.
    Enqvist, Jonas K
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Björn Ekblom's research group.
    Ekblom, Björn
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Björn Ekblom's research group.
    Sahlin, Kent
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Reduced efficiency, but increased fat oxidation, in mitochondria from human skeletal muscle after 24-h ultraendurance exercise.2007In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 102, no 5, p. 1844-1849Article in journal (Refereed)
    Abstract [en]

    The hypothesis that ultraendurance exercise influences muscle mitochondrial function has been investigated. Athletes in ultraendurance performance performed running, kayaking, and cycling at 60% of their peak O(2) consumption for 24 h. Muscle biopsies were taken preexercise (Pre-Ex), postexercise (Post-Ex), and after 28 h of recovery (Rec). Respiration was analyzed in isolated mitochondria during state 3 (coupled to ATP synthesis) and state 4 (noncoupled respiration), with fatty acids alone [palmitoyl carnitine (PC)] or together with pyruvate (Pyr). Electron transport chain activity was measured with NADH in permeabilized mitochondria. State 3 respiration with PC increased Post-Ex by 39 and 41% (P < 0.05) when related to mitochondrial protein and to electron transport chain activity, respectively. State 3 respiration with Pyr was not changed (P > 0.05). State 4 respiration with PC increased Post-Ex but was lower than Pre-Ex at Rec (P < 0.05 vs. Pre-Ex). Mitochondrial efficiency [amount of added ADP divided by oxygen consumed during state 3 (P/O ratio)] decreased Post-Ex by 9 and 6% (P < 0.05) with PC and PC + Pyr, respectively. P/O ratio remained reduced at Rec. Muscle uncoupling protein 3, measured with Western blotting, was not changed Post-Ex but tended to decrease at Rec (P = 0.07 vs. Pre-Ex). In conclusion, extreme endurance exercise decreases mitochondrial efficiency. This will increase oxygen demand and may partly explain the observed elevation in whole body oxygen consumption during standardized exercise (+13%). The increased mitochondrial capacity for PC oxidation indicates plasticity in substrate oxidation at the mitochondrial level, which may be of advantage during prolonged exercise.

  • 9.
    Fernström, Maria
    et al.
    Örebro University.
    Fernberg, Ulrika
    Örebro University.
    Eliason, Gabriella
    Örebro University.
    Hurtig-Wennlöf, Anita
    Örebro University.
    Aerobic fitness is associated with low cardiovascular disease risk: the impact of lifestyle on early risk factors for atherosclerosis in young healthy Swedish individuals - the Lifestyle, Biomarker, and Atherosclerosis study.2017In: Vascular Health and Risk Management, ISSN 1176-6344, E-ISSN 1178-2048, Vol. 13, p. 91-99Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The progression of cardiovascular disease (CVD) and atherosclerosis is slow and develops over decades. In the cross-sectional Swedish Lifestyle, Biomarker, and Atherosclerosis study, 834 young, self-reported healthy adults aged 18.0-25.9 years have been studied to identify early risk factors for atherosclerosis.

    PURPOSE: The aims of this study were to 1) assess selected cardiometabolic biomarkers, carotid intima-media thickness (cIMT) as a marker of subclinical atherosclerosis, and lifestyle-related indicators (food habits, handgrip strength, and oxygen uptake, VO2 max); 2) analyze the associations between cIMT and lifestyle factors; and 3) identify subjects at risk of CVD using a risk score and to compare the characteristics of subjects with and without risk of CVD.

    METHOD: Blood samples were taken in a fasting state, and food habits were reported through a questionnaire. cIMT was measured by ultrasound, and VO2 max was measured by ergometer bike test. The risk score was calculated according to Wildman.

    RESULT: cIMT (mean ± standard deviation) was 0.50±0.06 mm, and VO2 max values were 37.8±8.5 and 42.9±9.9 mL/kg/min, in women and men, respectively. No correlation was found between aerobic fitness expressed as VO2 max (mL/kg/min) and cIMT. Using Wildman's definition, 12% of the subjects were classified as being at risk of CVD, and 15% had homeostasis model assessment of insulin resistance. A total of 35% of women and 25% of men had lower high-density lipoprotein cholesterol than recommended. Food habits did not differ between those at risk and those not at risk. However, aerobic fitness measured as VO2 max (mL/kg/min) differed; 47% of the subjects at risk had low aerobic fitness compared to 23% of the nonrisk subjects (P<0.001).

    CONCLUSION: High aerobic fitness is associated with low CVD risk in Swedish young adults. The high prevalence of young adults observed with unfavorable levels of high-density lipoprotein cholesterol and homeostasis model assessment of insulin resistance raises concerns about future CVD risk.

  • 10.
    Fernström, Maria
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Sahlin, Kent
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Mogensen, M
    Bagger, M
    Pedersen, PK
    The potential for mitochondrial fat oxidation in human skeletal muscle influences whole body fat oxidation during low-intensity exercise2007In: American journal of physiology. Endocrinology and metabolism, ISSN 0193-1849, Vol. 292, no 1, p. E223-30Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate fatty acid (FA) oxidation in isolated mitochondrial vesicles (mit) and its relation to training status, fiber type composition, and whole body FA oxidation. Trained (Vo(2 peak) 60.7 +/- 1.6, n = 8) and untrained subjects (39.5 +/- 2.0 ml.min(-1).kg(-1), n = 5) cycled at 40, 80, and 120 W, and whole body relative FA oxidation was assessed from respiratory exchange ratio (RER). Mit were isolated from muscle biopsies, and maximal ADP stimulated respiration was measured with carbohydrate-derived substrate [pyruvate + malate (Pyr)] and FA-derived substrate [palmitoyl-l-carnitine + malate (PC)]. Fiber type composition was determined from analysis of myosin heavy-chain (MHC) composition. The rate of mit oxidation was lower with PC than with Pyr, and the ratio between PC and Pyr oxidation (MFO) varied greatly between subjects (49-93%). MFO was significantly correlated to muscle fiber type distribution, i.e., %MHC I (r = 0.62, P = 0.03), but was not different between trained (62 +/- 5%) and untrained subjects (72 +/- 2%). MFO was correlated to RER during submaximal exercise at 80 (r = -0.62, P = 0.02) and 120 W (r = -0.71, P = 0.007) and interpolated 35% Vo(2 peak) (r = -0.74, P = 0.004). ADP sensitivity of mit respiration was significantly higher with PC than with Pyr. It is concluded that MFO is influenced by fiber type composition but not by training status. The inverse correlation between RER and MFO implies that intrinsic mit characteristics are of importance for whole body FA oxidation during low-intensity exercise. The higher ADP sensitivity with PC than that with Pyr may influence fuel utilization at low rate of respiration.

  • 11.
    Fernström, Maria
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Shabalina, Irina
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Bakkman, Linda
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Tonkonogi, Michail
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Mattsson, C. Mikael
    Swedish School of Sport and Health Sciences, GIH.
    Enqvist, Jonas
    Swedish School of Sport and Health Sciences, GIH.
    Ekblom, Björn
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Björn Ekblom's research group.
    Sahlin, Kent
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Skeletal muscle mitochondrial function and ROS production in response to extreme endurance exercise in athletes.2006In: 14 European bioenergetic conference, Moscow, Russia, 22-27 July, 2006, 2006Conference paper (Other academic)
    Abstract [en]

    Although it is well known that endurance exercise induces oxidative stress (1) there is no evidence of deteriorated mitochondrial function after 1-2 hours intensive exercise (2). However, the effects of extreme endurance exercise on mitochondrial function and mitochondrial ROS production have not been investigated previously. Nine healthy well-trained men (age 27.1 ± 0.87 (mean ± SE), BMI 24.2 ± 0.64 and VO2 peak 62.5 ± 1.78 ml/kg. min) performed 24 hours exercise, consisting of equal parts running, cycling and paddling. Muscle biopsies were taken from vastus lateralis pre-exercise (PreEx), immediately post-exercise (PostEx) and after 28 hours of recovery (PostEx-28). Mitochondria were isolated and mitochondrial respiration was analyzed with palmitoyl-carnitine (PC) and pyruvate (Pyr). Mitochondrial H2O2 release was measured with the Amplex Red-horseradish peroxide method. The reaction was initiated by addition of succinate with following addition of antimycin A (reversed electron flow). UCP3 protein expression, evaluated with western blot technique, was not changed by exercise. Both state 3 (Pyr and PC) and state 4 (PC) rates of oxygen consumption (estimated per maximal ETC-activity) were increased PostEx (+29%, +11% and +18%). State 3 remained elevated PostEx-28, whereas state 4 (Pyr) decreased below that at PreEx (-18%). Mitochondrial efficiency (P/O) decreased PostEx (Pyr -8.9%, PC -6.1%) and remained reduced PostEx-28. The relative substrate oxidation (state 3 PC/Pyr) increased after exercise PreEx: (0.71 ± 0.06 vs. PostEx (0.90 ±0.04) and (0.77 ±0.06) PostEx-28. Mitochondrial H2O2 release (succinate) increased dramatically after exercise (+189 ± 64%). Treatment with Antimycin A resulted in a twofold-increased rate of mitochondrial H2O2 release PreEx but a decreased rate in PostEx samples. The exercise-induced changes in mitochondrial ROS production was totally abolished PostEx-28. In conclusion extreme endurance exercise decreases mitochondrial efficiency and increases mitochondrial ROS production. Both of these changes would increase the oxygen demand during exercise. Relative fatty acid oxidation as measured in isolated mitochondria increased after exercise indicating that the capacity to oxidize fat is improved during prolonged exercise.

    1. Mastaloudis, A., S.W. Leonard, and M.G. Traber, Oxidative stress in athletes during extreme endurance exercise. Free Radic Biol Med, 2001. 31(7): p. 911-22.

    2. Tonkonogi, M., et al., Mitochondrial function and antioxidative defence in human muscle: effects of endurance training and oxidative stress. J Physiol, 2000. 528 Pt 2: p. 379-88.

  • 12.
    Fernström, Maria
    et al.
    Karolinska institutet.
    Song, Xiao Mei
    Karolinska institutet.
    Galuska, Dana
    Karolinska institutet.
    Fiedler, Maj
    Pharmacia & UpJohn.
    Rincon, Jorge
    Karolinska institutet.
    Ryder, Jeffrey W
    Karolinska institutet.
    Liang, Yin
    Pharmacia & UpJohn.
    Krook, Anna
    Karolinska institutet.
    Zierath, Juleen R
    Karolinska institutet.
    AICAR-treatment improves glucose homeostasis in ob/ob mice2000In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 50, no Suppl 1, p. 396-396Article in journal (Refereed)
  • 13.
    Fernström, Maria
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Tonkonogi, Michail
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Sahlin, Kent
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle.2004In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 554, p. 755-763Article in journal (Refereed)
    Abstract [en]

    Mitochondrial proteins such as uncoupling protein 3 (UCP3) and adenine nucleotide translocase (ANT) may mediate back-leakage of protons and serve as uncouplers of oxidative phosphorylation. We hypothesized that UCP3 and ANT increase after prolonged exercise and/or endurance training, resulting in increased uncoupled respiration (UCR). Subjects were investigated with muscle biopsies before and after acute exercise (75 min of cycling at 70% of .VO2peak) or 6 weeks endurance training. Mitochondria were isolated and respiration measured in the absence (UCR or state 4) and presence of ADP (coupled respiration or state 3). Protein expression of UCP3 and ANT was measured with Western blotting. After endurance training, .VO2peak, citrate synthase activity (CS), state 3 respiration and ANT increased by 24, 47, 40 and 95%, respectively (all P < 0.05), whereas UCP3 remained unchanged. When expressed per unit of CS (a marker of mitochondrial volume) UCP3 and UCR decreased by 54% and 18%(P < 0.05). CS increased by 43% after acute exercise and remained elevated after 3 h of recovery (P < 0.05), whereas the other muscle parameters remained unchanged. An intriguing finding was that acute exercise reversibly enhanced the capacity of mitochondria to accumulate Ca2+(P < 0.05) before opening of permeability transition pores. In conclusion, UCP3 protein and UCR decrease after endurance training when related to mitochondrial volume. These changes may prevent excessive basal thermogenesis. Acute exercise enhances mitochondrial resistance to Ca2+ overload but does not influence UCR or protein expression of UCP3 and ANT. The increased Ca2+ resistance may prevent mitochondrial degradation and the mechanism needs to be further explored.

  • 14.
    Fiedler, Maj
    et al.
    Pharmacia.
    Liang, Yin
    Pharmacia.
    Song, Xiao Mei
    Karolinska institutet.
    Fernström, Maria
    Karolinska institutet.
    Zierath, Juleen R
    Karolinska institutet.
    Selén, Göran
    Pharmacia.
    Klingström, Gunnel
    Pharmacia.
    Sakariassen, Kjell S
    Pharmacia.
    AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) ameliorates hyperglycemia and hyperinsulinemia in type 2 diabetic mice2000In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 50, no Suppl 1, p. 397-397Article in journal (Refereed)
  • 15. Hey-Mogensen, M
    et al.
    Højlund, K
    Vind, B F
    Wang, Li
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Dela, F
    Beck-Nielsen, H
    Fernström, Maria
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Sahlin, Kent
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Effect of physical training on mitochondrial respiration and reactive oxygen species release in skeletal muscle in patients with obesity and type 2 diabetes.2010In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 53, no 9, p. 1976-85Article in journal (Refereed)
    Abstract [en]

    AIM/HYPOTHESIS: Studies have suggested a link between insulin resistance and mitochondrial dysfunction in skeletal muscles. Our primary aim was to investigate the effect of aerobic training on mitochondrial respiration and mitochondrial reactive oxygen species (ROS) release in skeletal muscle of obese participants with and without type 2 diabetes. METHODS: Type 2 diabetic men (n = 13) and control (n = 14) participants matched for age, BMI and physical activity completed 10 weeks of aerobic training. Pre- and post-training muscle biopsies were obtained before a euglycaemic-hyperinsulinaemic clamp and used for measurement of respiratory function and ROS release in isolated mitochondria. RESULTS: Training significantly increased insulin sensitivity, maximal oxygen consumption and muscle mitochondrial respiration with no difference between groups. When expressed in relation to a marker of mitochondrial density (intrinsic mitochondrial respiration), training resulted in increased mitochondrial ADP-stimulated respiration (with NADH-generating substrates) and decreased respiration without ADP. Intrinsic mitochondrial respiration was not different between groups despite lower insulin sensitivity in type 2 diabetic participants. Mitochondrial ROS release tended to be higher in participants with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Aerobic training improves muscle respiration and intrinsic mitochondrial respiration in untrained obese participants with and without type 2 diabetes. These adaptations demonstrate an increased metabolic fitness, but do not seem to be directly related to training-induced changes in insulin sensitivity.

  • 16. Hjeltnes, N
    et al.
    Fernström, Maria
    Karolinska institutet.
    Zierath, J R
    Krook, A
    Regulation of UCP2 and UCP3 by muscle disuse and physical activity in tetraplegic subjects.1999In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 42, no 7, p. 826-30Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The regulation of uncoupling protein 2 and uncoupling protein 3 gene expression in skeletal muscle has recently been the focus of intense interest. Our aim was to determine expression of uncoupling protein 2 and 3 in skeletal muscle from tetraplegic subjects, a condition representing profound muscle inactivity. Thereafter we determined whether exercise training would modify expression of these genes in skeletal muscle.

    METHODS: mRNA expression of uncoupling protein 2 and 3 was determined using quantitative reverse transcription-polymerase chain-reaction.

    RESULTS: Expression of uncoupling protein 2 and 3 mRNA was increased in skeletal muscle from tetraplegic compared with able-bodied subjects (3.7-fold p < 0.01 and 4.1-fold, p < 0.05, respectively). A subgroup of four tetraplegic subjects underwent an 8-week exercise programme consisting of electrically-stimulated leg cycling (ESLC, 7 ESLC sessions/week). This training protocol leads to increases in whole body insulin-stimulated glucose uptake and expression of genes involved in glucose metabolism in skeletal muscle from tetraplegic subjects. After ESLC training, uncoupling protein 2 expression was reduced by 62% and was similar to that in able-bodied people. Similarly, ESLC training was associated with a reduction of uncoupling protein 3 expression in skeletal muscle from three of four tetraplegic subjects, however, post-exercise levels remained increased compared with able-bodied subjects.

    CONCLUSION/INTERPRETATION: Tetraplegia is associated with increased mRNA expression of uncoupling protein 2 and 3 in skeletal muscle. Exercise training leads to normalisation of uncoupling protein 2 expression in tetraplegic subjects. Muscle disuse and physical activity appear to be powerful regulators of uncoupling protein 2 and 3 expression in human skeletal muscle.

  • 17. Iaia, F Marcello
    et al.
    Hellsten, Ylva
    Nielsen, Jens Jung
    Fernström, Maria
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Sahlin, Kent
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Bangsbo, Jens
    Four weeks of speed endurance training reduces energy expenditure during exercise and maintains muscle oxidative capacity despite a reduction in training volume.2009In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 106, no 1, p. 73-80Article in journal (Refereed)
    Abstract [en]

    We studied the effect of an alteration from regular endurance to speed endurance training on muscle oxidative capacity, capillarization, as well as energy expenditure during submaximal exercise and its relationship to mitochondrial uncoupling protein 3 (UCP3) in humans. Seventeen endurance-trained runners were assigned to either a speed endurance training (SET; n = 9) or a control (Con; n = 8) group. For a 4-wk intervention (IT) period, SET replaced the ordinary training ( approximately 45 km/wk) with frequent high-intensity sessions each consisting of 8-12 30-s sprint runs separated by 3 min of rest (5.7 +/- 0.1 km/wk) with additional 9.9 +/- 0.3 km/wk at low running speed, whereas Con continued the endurance training. After the IT period, oxygen uptake was 6.6, 7.6, 5.7, and 6.4% lower (P < 0.05) at running speeds of 11, 13, 14.5, and 16 km/h, respectively, in SET, whereas remained the same in Con. No changes in blood lactate during submaximal running were observed. After the IT period, the protein expression of skeletal muscle UCP3 tended to be higher in SET (34 +/- 6 vs. 47 +/- 7 arbitrary units; P = 0.06). Activity of muscle citrate synthase and 3-hydroxyacyl-CoA dehydrogenase, as well as maximal oxygen uptake and 10-km performance time, remained unaltered in both groups. In SET, the capillary-to-fiber ratio was the same before and after the IT period. The present study showed that speed endurance training reduces energy expenditure during submaximal exercise, which is not mediated by lowered mitochondrial UCP3 expression. Furthermore, speed endurance training can maintain muscle oxidative capacity, capillarization, and endurance performance in already trained individuals despite significant reduction in the amount of training.

  • 18.
    Lindkvist, Madelene
    et al.
    Örebro university.
    Fernberg, Ulrika
    Örebro university.
    Ljungberg, Liza U
    Örebro university.
    Fälker, Knut
    Örebro university.
    Fernström, Maria
    Örebro university.
    Hurtig-Wennlöf, Anita
    Örebro university.
    Grenegård, Magnus
    Örebro university.
    Individual variations in platelet reactivity towards ADP, epinephrine, collagen and nitric oxide, and the association to arterial function in young, healthy adults.2019In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 174, p. 5-12, article id S0049-3848(18)30647-9Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Platelet aggregation and secretion can be induced by a large number of endogenous activators, such as collagen, adenosine diphosphate (ADP) and epinephrine. Conversely, the blood vessel endothelium constitutively release platelet inhibitors including nitric oxide (NO) and prostacyclin. NO and prostacyclin are also well-known vasodilators and contribute to alterations in local blood flow and systemic blood pressure.

    MATERIALS AND METHODS: In this study we investigated individual variations in platelet reactivity and arterial functions including blood pressure and flow-mediated vasodilation (FMD) in 43 young, healthy individuals participating in the Lifestyle, Biomarkers and Atherosclerosis (LBA) study. Platelet aggregation and dense granule secretion were measured simultaneously by light transmission and luminescence. FMD was measured with ultrasound.

    RESULTS: The platelet function assay showed inter-individual differences in platelet reactivity. Specifically, a sub-group of individuals had platelets with an increased response to low concentrations of ADP and epinephrine, but not collagen. When the NO-donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) was combined with high doses of these platelet activators, the results indicated for sub-groups of NO-sensitive and NO-insensitive platelets. The individuals with NO-sensitive platelets in response to SNAP in combination with collagen had a higher capacity of FMD of the arteria brachialis.

    CONCLUSIONS: Platelet reactivity towards ADP, epinephrine and NO differs between young, healthy individuals. Some individuals have a more effective response towards NO, both in the aspect of platelet inhibition ex vivo, as well as vasodilation in vivo.

  • 19. Mogensen, Martin
    et al.
    Bagger, Malene
    Pedersen, Preben
    Fernstrom, Maria
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Sahlin, Kent
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Cycling efficiency in humans is related to low UCP3 content and to type I fibres but not to mitochondrial efficiency2006In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 571, no 3, p. 669-681Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the hypothesis that cycling efficiency in vivo is related to mitochondrial efficiency measured in vitro and to investigate the effect of training status on these parameters. Nine endurance trained and nine untrained male subjects ( , respectively) completed an incremental submaximal efficiency test for determination of cycling efficiency (gross efficiency, work efficiency (WE) and delta efficiency). Muscle biopsies were taken from m. vastus lateralis and analysed for mitochondrial respiration, mitochondrial efficiency (MEff; i.e. P/O ratio), UCP3 protein content and fibre type composition (% MHC I). MEff was determined in isolated mitochondria during maximal (state 3) and submaximal (constant rate of ADP infusion) rates of respiration with pyruvate. The rates of mitochondrial respiration and oxidative phosphorylation per muscle mass were about 40% higher in trained subjects but were not different when expressed per unit citrate synthase (CS) activity (a marker of mitochondrial density). Training status had no influence on WE (trained 28.0 +/- 0.5, untrained 27.7 +/- 0.8%, N.S.). Muscle UCP3 was 52% higher in untrained subjects, when expressed per muscle mass (P < 0.05 versus trained). WE was inversely correlated to UCP3 (r=-0.57, P < 0.05) and positively correlated to percentage MHC I (r= 0.58, P < 0.05). MEff was lower (P < 0.05) at submaximal respiration rates (2.39 +/- 0.01 at 50% ) than at state 3 (2.48 +/- 0.01) but was neither influenced by training status nor correlated to cycling efficiency. In conclusion cycling efficiency was not influenced by training status and not correlated to MEff, but was related to type I fibres and inversely related to UCP3. The inverse correlation between WE and UCP3 indicates that extrinsic factors may influence UCP3 activity and thus MEff in vivo.

  • 20.
    Sahlin, Kent
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll. Karolinska institutet.
    Fernström, Maria
    Karolinska institutet.
    Svensson, Michael
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences. Karolinska institutet.
    Tonkonogi, Michail
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences. Karolinska institutet.
    No evidence of an intracellular lactate shuttle in rat skeletal muscle.2002In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 541, no Pt 2, p. 569-74Article in journal (Refereed)
    Abstract [en]

    The concerted view is that cytosolic pyruvate is transferred into mitochondria and after oxidative decarboxylation further metabolized in the tricarboxylic acid cycle. Recently this view has been challenged. Based on experimental evidence from rat skeletal muscle it has been concluded that mitochondria predominantly oxidize lactate in vivo and that this constitutes part of an 'intracellular lactate shuttle'. This view appears to be gaining acceptance in the scientific community and due to its conceptual importance, confirmation by independent experiments is required. We have repeated the experiments in mitochondria isolated from rat soleus muscle. Contrary to the previously published findings we cannot find any mitochondrial respiration with lactate. Analysis of lactate dehydrogenase (LDH) by spectrophotometry demonstrated that the activity in the mitochondrial fraction was only 0.7 % of total activity. However, even when external LDH was added to mitochondria, there were no signs of respiration with lactate. In the presence of conditions where lactate is converted to pyruvate (external additions of both LDH and NAD(+)), mitochondrial oxygen consumption increased. Furthermore, we provide theoretical evidence that direct mitochondrial lactate oxidation is energetically unlikely. Based on the present data we conclude that direct mitochondrial lactate oxidation does not occur in skeletal muscle. The presence of an 'intracellular lactate shuttle' can therefore be questioned.

  • 21.
    Sahlin, Kent
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Shabalina, Irina G
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology. Stockholm University.
    Mattsson, C Mikael
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Björn Ekblom's research group.
    Bakkman, Linda
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology. Karolinska Institutet.
    Fernström, Maria
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology. Karolinska Institutet.
    Rozhdestvenskaya, Zinaida
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology.
    Enqvist, Jonas K
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Björn Ekblom's research group.
    Nedergaard, Jan
    Stockholm University.
    Ekblom, Björn T
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Björn Ekblom's research group.
    Tonkonogi, Michail
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology. University of Dalarna.
    Ultra-endurance exercise increases the production of reactive oxygen species in isolated mitochondria from human skeletal muscle.2010In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 108, no 4, p. 780-787Article in journal (Refereed)
    Abstract [en]

    Exercise-induced oxidative stress is important for the muscular adaptation to training but may also cause muscle damage. We hypothesized that prolonged exercise would increase mitochondrial production of reactive oxygen species (ROS) measured in vitro and that this correlates with oxidative damage. Eight male athletes (24-32 years) performed ultra-endurance exercise (kayaking/running/cycling) with an average work intensity of 55% VO2peak for 24 h. Muscle biopsies were taken from vastus lateralis before exercise, immediately after exercise and after 28 h of recovery. The production of H2O2 was measured fluorometrically in isolated mitochondria with the Amplex red and peroxidase system. Succinate-supported mitochondrial H2O2 production was significantly increased after exercise (73% higher, P=0.025) but restored to the initial level at recovery. Plasma level of free fatty acids (FFA) increased 4-fold and exceeded 1.2 mmol l(-1) during the last 6 h of exercise. Plasma FFA at the end of exercise was significantly correlated to mitochondrial ROS production (r=0.74, P<0.05). Mitochondrial content of 4-hydroxy-nonenal-adducts (a marker of oxidative damage) was increased only after recovery and was not correlated with mitochondrial ROS production. Total thiol-group level and glutathione peroxidase activity were elevated after recovery. In conclusion: ultra-endurance exercise increases ROS production in isolated mitochondria but this is reversed after 28 h recovery. Mitochondrial ROS production was not correlated with oxidative damage of mitochondrial proteins, which was increased at recovery but not immediately after exercise. Key words: antioxidative defence, fatty acids, oxidative stress.

  • 22.
    Sahlin, Kent
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Tonkonogi, Michail
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Fernström, Maria
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    The leaky mitochondrion.2004In: Physiology News, Vol. 56, p. 27-28Article in journal (Other academic)
  • 23. Song, X M
    et al.
    Fiedler, M
    Galuska, D
    Ryder, J W
    Fernström, Maria
    Karolinska institutet.
    Chibalin, A V
    Wallberg-Henriksson, H
    Zierath, J R
    5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice.2002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, no 1, p. 56-65Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The 5'AMP-activated protein kinase is an important mediator of muscle contraction-induced glucose transport and a target for pharmacological treatment of Type II (non-insulin-dependent) diabetes mellitus. The 5'AMP-activated protein kinase can be activated by 5-aminoimidazole-4-carboxamide ribonucleoside. We hypothesised that 5-aminoimidazole-4-carboxamide ribonucleoside treatment could restore glucose homeostasis in ob/ob mice.

    METHODS: Lean and ob/ob mice were given 5-aminoimidazole-4-carboxamide ribonucleoside (1 mg.g body wt(-1).day(-1) s.c) or 0.9 % NaCl (vehicle) for 1-7 days.

    RESULTS: Short-term 5-aminoimidazole-4-carboxamide ribonucleoside treatment normalised glucose concentrations in ob/ob mice within 1 h, with effects persisting over 4 h. After 1 week of daily injections, 5-aminoimidazole-4-carboxamide ribonucleoside treatment corrected hyperglycaemia, improved glucose tolerance, and increased GLUT4 and hexokinase II protein expression in skeletal muscle, but had deleterious effects on plasma non-esterified fatty acids and triglycerides. Treatment with 5-aminoimidazole-4-carboxamide ribonucleoside increased liver glycogen in fasted and fed ob/ob mice and muscle glycogen in fasted, but not fed ob/ob and lean mice. Defects in insulin-stimulated phosphatidylinositol 3-kinase and glucose transport in skeletal muscle from ob/ob mice were not corrected by 5-aminoimidazole-4-carboxamide ribonucleoside treatment. While ex vivo insulin-stimulated glucose transport was reduced in isolated muscle from ob/ob mice, the 5-aminoimidazole-4-carboxamide ribonucleoside stimulated response was normal.

    CONCLUSION/INTERPRETATION: The 5-aminoimidazole-4-carboxamide ribonucleoside mediated improvements in glucose homeostasis in ob/ob mice can be explained by effects in skeletal muscle and liver. Due to the apparently deleterious effects of 5-aminoimidazole-4-carboxamide ribonucleoside on the blood lipid profile, strategies to develop tissue-specific and pathway-specific activators of 5'AMP-activated protein kinase should be considered in order to improve glucose homeostasis.

  • 24.
    Tonkonogi, Michail
    et al.
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Fernström, Maria
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences.
    Walsh, Brandon
    Ji, Li Li
    Rooyackers, Olav
    Hammarqvist, Folke
    Wernerman, Jan
    Sahlin, Kent
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology, Research group for Mitokondriell funktion och metabolisk kontroll.
    Reduced oxidative power but unchanged antioxidative capacity in skeletal muscle from aged humans.2003In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 446, no 2, p. 261-9Article in journal (Refereed)
    Abstract [en]

    The hypothesis that the aging process is associated with mitochondrial dysfunction and oxidative stress has been investigated in human skeletal muscle. Muscle biopsy samples were taken from seven old male subjects [OS; 75 (range 61-86) years] and eight young male subjects [YS; 25 (22-31) years]. Oxidative function was measured both in permeabilised muscle fibres and isolated mitochondria. Despite matching the degree of physical activity, OS had a lower training status than YS as judged from pulmonary maximal O(2) consumption ( Vdot;O(2)max, -36%) and handgrip strength (-20%). Both maximal respiration and creatine-stimulated respiration were reduced in muscle fibres from OS (-32 and -34%, respectively). In contrast, respiration in isolated mitochondria was similar in OS and YS. The discrepancy might be explained by a biased harvest of "healthy" mitochondria and/or disruption of structural components during the process of isolation. Cytochrome C oxidase was reduced (-40%, P<0.01), whereas UCP3 protein tended to be elevated in OS ( P=0.09). Generation of reactive oxygen species by isolated mitochondria and measures of antioxidative defence (muscle content of glutathione, glutathione redox status, antioxidative enzymes activity) were not significantly different between OS and YS. It is concluded that aging is associated with mitochondrial dysfunction, which appears to be unrelated to reduced physical activity. The hypothesis of increased oxidative stress in aged muscle could not be confirmed in this study.

  • 25. Tsuchida, Hiroki
    et al.
    Björnholm, Marie
    Fernström, Maria
    Karolinska institutet.
    Galuska, Dana
    Johansson, Per
    Wallberg-Henriksson, Harriet
    Zierath, Juleen R
    Lake, Staffan
    Krook, Anna
    Gene expression of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in skeletal muscle from type 2 diabetic subjects.2002In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 445, no 1, p. 25-31Article in journal (Refereed)
    Abstract [en]

    The gene of the p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase gives rise to several splice variants. We hypothesized that the expression of p85alpha splice variants may be altered in skeletal muscle from subjects with type 2 diabetes mellitus. Skeletal muscle biopsies were obtained from nine type 2 diabetic and eight healthy men, matched for age, body mass index (BMI) and physical fitness. PI 3-kinase activity in skeletal muscle following in vitro insulin stimulation was reduced in subjects with type 2 diabetes. p85alpha mRNA was elevated fourfold in type 2 diabetic as compared to healthy control subjects ( P<0.05). p85alpha mRNA abundance was positively correlated with plasma insulin concentration ( P<0.01) and serum glucose concentration ( P<0.01). Despite this, protein levels of p85alpha, p55alpha, and the novel human p50alpha were not altered in type 2 diabetic subjects. Thus, although gene expression of full-length p85alpha is increased in skeletal muscle from type 2 diabetics, this is not reflected by increased protein levels. Therefore, defects in PI 3-kinase activity are likely due to impaired activation of the enzyme rather than changes in protein expression of the isoforms of the regulatory subunit.

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