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  • 1. Amundsen, Brage Høyem
    et al.
    Ericsson, Madelene
    Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
    Seland, John Georg
    Pavlin, Tina
    Ellingsen, Øyvind
    Brekken, Christian
    A comparison of retrospectively self-gated magnetic resonance imaging and high-frequency echocardiography for characterization of left ventricular function in mice.2011In: Laboratory animals, ISSN 1758-1117, Vol. 45, no 1, p. 31-37Article in journal (Refereed)
    Abstract [en]

    Non-invasive imaging methods like echocardiography and magnetic resonance imaging (MRI) are very valuable in longitudinal follow-up studies of cardiac function in small animals. To be able to compare results from studies using different methods, and explain possible differences, it is important to know the agreement between these methods. As both self-gated high-field MRI and high-frequency echocardiography (hf-echo) M-mode are potential methods for evaluation of left ventricular (LV) function in healthy mice, our aim was to assess the agreement between these two methods. Fifteen healthy female C57BL/6J mice underwent both self-gated MRI and hf-echo during the same session of light isoflurane anaesthesia. LV dimensions were estimated offline, and agreement between the methods and reproducibility for the two methods assessed using Bland-Altman methods. In summary, hf-echo M-mode had better inter-observer repeatability than self-gated MRI for all measured parameters. Compared with hf-echo, systolic posterior wall thicknesses were significantly higher when measured by MRI, while diastolic anterior wall thicknesses were found to be significantly smaller. MRI measurements of diastolic LV diameter were also higher using MRI, resulting in larger fractional shortening values compared with the values obtained by hf-echo. In conclusion, hf-echo M-mode is easy to apply, has high temporal and spatial resolution, and good reproducibility. Self-gated MRI might be advantageous in cases of abnormal LV geometry and heterogeneous regional myocardial function, especially with improvements in spatial resolution. The moderate agreement between the methods must be taken into account when comparing studies using the two modalities.

  • 2. Andersen, Sonja
    et al.
    Ericsson, Madelene
    Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim.
    Dai, Hong Yan
    Peña-Diaz, Javier
    Slupphaug, Geir
    Nilsen, Hilde
    Aarset, Harald
    Krokan, Hans E
    Monoclonal B-cell hyperplasia and leukocyte imbalance precede development of B-cell malignancies in uracil-DNA glycosylase deficient mice2005In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 4, no 12, p. 1432-1441Article in journal (Refereed)
    Abstract [en]

    Ung-deficient mice have reduced class switch recombination, skewed somatic hypermutation, lymphatic hyperplasia and a 22-fold increased risk of developing B-cell lymphomas. We find that lymphomas are of follicular (FL) and diffuse large B-cell type (DLBCL). All FLs and 75% of the DLBCLs were monoclonal while 25% were biclonal. Monoclonality was also observed in hyperplasia, and could represent an early stage of lymphoma development. Lymphoid hyperplasia occurs very early in otherwise healthy Ung-deficient mice, observed as a significant increase of splenic B-cells. Furthermore, loss of Ung also causes a significant reduction of T-helper cells, and 50% of the young Ung(-/-) mice investigated have no detectable NK/NKT-cell population in their spleen. The immunological imbalance is confirmed in experiments with spleen cells where the production of the cytokines interferon gamma, interleukin 6 and interleukin 2 is clearly different in wild type and in Ung-deficient mice. This suggests that Ung-proteins, directly or indirectly, have important functions in the immune system, not only in the process of antibody maturation, but also for production and functions of immunologically important cell types. The immunological imbalances shown here in the Ung-deficient mice may be central in the development of lymphomas in a background of generalised lymphoid hyperplasia.

  • 3. Berg, Kirsti
    et al.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Lindgren, Mikael
    Gustafsson, Håkan
    A High Precision Method for Quantitative Measurements of Reactive Oxygen Species in Frozen Biopsies2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e90964-Article in journal (Refereed)
    Abstract [en]

    Objective: An electron paramagnetic resonance (EPR) technique using the spin probe cyclic hydroxylamine 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) was introduced as a versatile method for high precision quantification of reactive oxygen species, including the superoxide radical in frozen biological samples such as cell suspensions, blood or biopsies. Materials and Methods: Loss of measurement precision and accuracy due to variations in sample size and shape were minimized by assembling the sample in a well-defined volume. Measurement was carried out at low temperature (150 K) using a nitrogen flow Dewar. The signal intensity was measured from the EPR 1st derivative amplitude, and related to a sample, 3-carboxy-proxyl (CPN) with known spin concentration. Results: The absolute spin concentration could be quantified with a precision and accuracy better than +/- 10 mu M (k = 1). The spin concentration of samples stored at -80 degrees C could be reproduced after 6 months of storage well within the same error estimate. Conclusion: The absolute spin concentration in wet biological samples such as biopsies, water solutions and cell cultures could be quantified with higher precision and accuracy than normally achievable using common techniques such as flat cells, tissue cells and various capillary tubes. In addition; biological samples could be collected and stored for future incubation with spin probe, and also further stored up to at least six months before EPR analysis, without loss of signal intensity. This opens for the possibility to store and transport incubated biological samples with known accuracy of the spin concentration over time.

  • 4. Berg, Kirsti
    et al.
    Langaas, Mette
    Ericsson, Madelene
    Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
    Pleym, Hilde
    Basu, Samar
    Nordrum, Ivar Skjåk
    Vitale, Nicola
    Haaverstad, Rune
    Acetylsalicylic acid treatment until surgery reduces oxidative stress and inflammation in patients undergoing coronary artery bypass grafting2013In: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 43, no 6, p. 1154-1163Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Acetylsalicylic acid (ASA) is a cornerstone in the treatment of coronary artery disease (CAD) due to its antiplatelet effect. Cessation of aspirin before coronary artery bypass grafting (CABG) is often recommended to avoid bleeding, but the practice is controversial because it is suggested to worsen the underlying CAD. The aims of the present prospective, randomized study were to assess if ASA administration until the day before CABG decreases the oxidative load through a reduction of inflammation and myocardial damage, compared with patients with preoperative discontinuation of ASA. METHODS: Twenty patients scheduled for CABG were randomly assigned to either routine ASA-treatment (160 mg daily) until the time of surgery (ASA), or to ASA-withdrawal 7 days before surgery (No-ASA). Blood-samples were taken from a radial artery and coronary sinus, during and after surgery and analysed for 8-iso-prostaglandin (PG) F(2α); a major F(2)-isoprostane, high-sensitivity C-reactive protein (hs-CRP), cytokines and troponin T. Left ventricle Tru-Cut biopsies were taken from viable myocardium close to the left anterior descending artery just after connection to cardiopulmonary bypass, and before cardioplegia were established for gene analysis (Illumina HT-12) and immunohistochemistry (CD45). RESULTS: 8-Iso-PGF(2α) at baseline (t(1)) were 111 (277) pmol/l and 221 (490) pmol/l for ASA and No-ASA, respectively (P = 0.065). Area under the curve showed a significantly lower level in plasma concentration of 8-iso-PGF(2α) and hsCRP in the ASA group compared with the No-ASA group with (158 pM vs 297 pM, P = 0.035) and hsCRP (8.4 mg/l vs 10.1 mg/l, P = 0.013). All cytokines increased during surgery, but no significant differences between the two groups were observed. Nine genes (10 transcripts) were found with a false discovery rate (FDR) <0.1 between the ASA and No-ASA groups. CONCLUSIONS: Continued ASA treatment until the time of CABG reduced oxidative and inflammatory responses. Also, a likely beneficial effect upon myocardial injury was noticed. Although none of the genes known to be involved in oxidative stress or inflammation took a different expression in myocardial tissue, the genetic analysis showed interesting differences in the mRNA level. Further research in this field is necessary to understand the role of the genes.

  • 5.
    Caraballo, Remi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, Mikael
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tran, Nam Phuong Nguyen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kindahl, Tomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Uppsala, Sweden.
    Saar, Valeria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Artursson, Per
    Uppsala, Sweden.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo2015In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, p. 191-209Article in journal (Refereed)
    Abstract [en]

    The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo. 2015 The Authors. Published by Elsevier Masson SAS.

  • 6.
    Ericsson, Madelene
    et al.
    Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, and Department of Medical Imaging, St. Olavs Hospital, Olav Kyrres gate 9, NO-7489 Trondheim, Norway.
    Andersson, Kristin B
    Amundsen, Brage H
    Torp, Sverre H
    Sjaastad, Ivar
    Christensen, Geir
    Sejersted, Ole M
    Ellingsen, Øyvind
    High-intensity exercise training in mice with cardiomyocyte-specific disruption of Serca22010In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 108, no 5, p. 1311-1320Article in journal (Refereed)
    Abstract [en]

    Several lines of evidence indicate that the sarco(endo)plasmic reticulum ATPase type 2 (SERCA2) is essential for maintaining myocardial calcium handling and cardiac pump function. Hence, a reduction in SERCA2 abundance is expected to reduce work performance and maximal oxygen uptake (VO2max) and to limit the response to exercise training. To test this hypothesis, we compared VO2max and exercise capacity in mice with cardiac disruption of Serca2 (SERCA2 KO) with control mice (SERCA2 FF). We also determined whether the effects on VO2max and exercise capacity could be modified by high-intensity aerobic exercise training. Treadmill running at 85-90% of VO2max started 2 wk after Serca2 gene disruption and continued for 4 wk. VO2max and maximal running speed were measured weekly in a metabolic chamber. Cardiac function was assessed by echocardiography during light anesthesia. In sedentary SERCA2 KO mice, the aerobic capacity was reduced by 50% and running speed by 28%, whereas trained SERCA2 KO mice were able to maintain maximal running speed despite a 36% decrease in VO2max. In SERCA2 FF mice, both VO2max and maximal running speed increased by training, while no changes occurred in the sedentary group. Left ventricle dimensions remained unchanged by training in both genotypes. In contrast, training induced right ventricle hypertrophy in SERCA2 KO mice. In conclusion, the SERCA2 protein is essential for sustaining cardiac pump function and exercise capacity. Nevertheless, SERCA2 KO mice were able to maintain maximal running speed in response to exercise training despite a large decrease in VO2max.

  • 7.
    Ericsson, Madelene
    et al.
    Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
    Sjåland, Cecilie
    Andersson, Kristin B
    Sjaastad, Ivar
    Christensen, Geir
    Sejersted, Ole M
    Ellingsen, Øyvind
    Exercise training before cardiac-specific Serca2 disruption attenuates the decline in cardiac function in mice2010In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 109, no 6, p. 1749-1755Article in journal (Refereed)
    Abstract [en]

    In the heart, function of the sarco(endo)plasmic Ca(2+)-ATPase (SERCA2) is closely linked to contractility, cardiac function, and aerobic fitness. SERCA2 function can be increased by high-intensity interval training, whereas reduced SERCA2 abundance is associated with impaired cardiac function. The working hypothesis was, therefore, that exercise training before cardiomyocyte-specific disruption of the Serca2 gene would delay the onset of cardiac dysfunction in mice. Before Serca2 gene disruption by tamoxifen, untreated SERCA2 knockout mice (Serca2(flox/flox) Tg-αMHC-MerCreMer; S2KO), and SERCA2 FF control mice (Serca2(flox/flox), S2FF) were exercise trained by high-intensity interval treadmill running for 6 wk. Both genotypes responded to training, with comparable increases in maximal oxygen uptake (Vo(2max); 17%), left ventricle weight (15%), and maximal running speed (40%). After exercise training, cardiac-specific Serca2 gene disruption was induced in both exercise trained and sedentary S2KO mice. In trained S2KO, cardiac function decreased less rapidly than in sedentary S2KO. Vo(2max) remained higher in trained S2KO the first 15 days after gene disruption. Six weeks after Serca2 disruption, cardiac output was higher in trained compared with sedentary S2KO mice. An exercise-training program attenuates the decline in cardiac performance induced by acute cardiac Serca2 gene disruption, indicating that mechanisms other than SERCA2 contribute to the favorable effect of exercise training.

  • 8.
    Ericsson, Madelene
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Sjödin, Anna
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Burén, Jonas
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Försämrad hjärtfunktion efter fyra veckors intag av lågkolhydrat/högfettkost hos möss: Kan vi lära av translationell forskning?2017In: Svensk kardiologi, ISSN 1400-5816, no 1, p. 33-35Article in journal (Other (popular science, discussion, etc.))
  • 9.
    Hellström, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Faraz, Mahmood
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Anderson, Fredrick
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm/Gotland, Stockholm, Sweden.
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice2016In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 310, no 11, p. R1045-R1052Article in journal (Refereed)
    Abstract [en]

    Genetic factors confer risk for cardiovascular disease. Recently, large genome-wide population studies have shown associations between genomic loci close to LRIG3 and heart failure and plasma high-density lipoprotein (HDL) cholesterol level. Here, we ablated Lrig3 in mice and investigated the importance of Lrig3 for heart function and plasma lipid levels. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze Lrig3 expression in the hearts of wild-type and Lrig3-deficient mice. In addition, molecular, physiological, and functional parameters such as organ weights, heart rate, blood pressure, heart structure and function, gene expression in the heart, and plasma insulin, glucose, and lipid levels were evaluated. The Lrig3-deficient mice were smaller than the wild-type mice but otherwise appeared grossly normal. Lrig3 was expressed at detectable but relatively low levels in adult mouse hearts. At 9 mo of age, ad libitum-fed Lrig3-deficient mice had lower insulin levels than wildtype mice. At 12 mo of age, Lrig3-deficient mice exhibited increased blood pressure, and the Lrig3-deficient female mice displayed signs of cardiac hypertrophy as assessed by echocardiography, heart-to-body weight ratio, and expression of the cardiac hypertrophy marker gene Nppa. Additionally, Lrig3-deficient mice had reduced plasma HDL cholesterol and free glycerol. These findings in mice complement the human epidemiological results and suggest that Lrig3 may influence heart function and plasma lipid levels in mice and humans.

  • 10. Jönsson, Sofia
    et al.
    Becirovic-Agic, Mediha
    Isackson, Henrik
    Tveitarås, Maria K.
    Skogstrand, Trude
    Narfström, Fredrik
    Karlsen, Tine, V
    Lidén, Åsa
    Leh, Sabine
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Reed, Rolf K.
    Hultström, Michael
    Angiotensin II and salt-induced decompensation in Balb/CJ mice is aggravated by fluid retention related to low oxidative stress2019In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 5, p. F914-F933Article in journal (Refereed)
    Abstract [en]

    Balb/CJ mice are more sensitive to treatment with angiotensin II (ANG II) and high-salt diet compared with C57BL/6J mice. Together with higher mortality, they develop edema, signs of heart failure, and acute kidney injury. The aim of the present study was to identify differences in renal gene regulation that may affect kidney function and fluid balance, which could contribute to decompensation in Balb/CJ mice after ANG II + salt treatment. Male Balb/CJ and C57BL/6J mice were divided into the following five different treatment groups: control, ANG II, salt, ANG II + salt. and ANG II + salt + N-acetylcysteine. Gene expression microarrays were used to explore differential gene expression after treatment and between the strains. Published data from the Mouse Genome Database were used to identify the associated genomic differences. The glomerular filtration rate (GFR) was measured using inulin clearance, and fluid balance was measured using metabolic cages. Gene ontology enrichment analysis of gene expression microarrays identified glutathione transferase (antioxidant system) as highly enriched among differentially expressed genes. Balb/CJ mice had similar GFR compared with C57BL/6J mice but excreted less Na+ and water, although net fluid and electrolyte balance did not differ, suggesting that Balb/CJ mice may be inherently more prone to decompensation. Interestingly, C57BL/6J mice had higher urinary oxidative stress despite their relative protection from decompensation. In addition, treatment with the antioxidant N-acetylcysteine decreased oxidative stress in C57BL/6J mice, reduced urine excretion, and increased mortality. Balb/CJ mice are more sensitive than C57BL/6J to ANG II + salt, in part mediated by lower oxidative stress, which favors fluid and Na+ retention.

  • 11.
    Larsson, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Caraballo, Rémi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Lookene, Aivar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Tallinn University of Technology, Department of Chemistry, Tallinn, Estonia.
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo2014In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 450, no 2, p. 1063-1069Article in journal (Refereed)
    Abstract [en]

    Patients at increased cardiovascular risk commonly display high levels of plasma triglycerides (TGs) levels, elevated LDL cholesterol, small dense LDL particles and low levels of HDL-cholesterol. Many remain at high risk even after successful statin therapy, presumably because TG levels remain high. Lipoprotein lipase (LPL) maintains TG homeostasis in blood by hydrolysis of TG-rich lipoproteins. Efficient clearance of TGs is accompanied by increased levels of HDL-cholesterol and decreased levels of small dense LDL. Given the central role of LPL in lipid metabolism we sought to find small molecules that could increase LPL activity and serve as starting points for drug development efforts against cardiovascular disease. Using a small molecule screening approach we have identified small molecules that can protect LPL from inactivation by the controller protein angiopoietin-like protein 4 during incubations in vitro. One of the selected compounds, 50F10, was directly shown to preserve the active homodimer structure of LPL, as demonstrated by heparin-Sepharose chromatography. This compound tended to reduce fasting TG levels in normal rats. On injection to hypertriglyceridemic apolipoprotein A-V deficient mice the compound ameliorated the postprandial response after an olive oil gavage. This compound is a potential lead compound for the development of drugs that could reduce the residual risk associated with elevated TGs in dyslipidemia.

  • 12. Mosti, M P
    et al.
    Stunes, A K
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Pullisaar, H
    Reseland, J E
    Shabestari, M
    Eriksen, E F
    Syversen, U
    Effects of the peroxisome proliferator-activated receptor (PPAR)-δ agonist GW501516 on bone and muscle in ovariectomized rats2014In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 155, no 6, p. 2178-2189Article in journal (Refereed)
    Abstract [en]

    Estrogen deficiency promotes bone loss and skeletal muscle dysfunction. Peroxisome proliferator-activated receptors (PPARs) have 3 subtypes (α, δ, and γ). PPARγ agonists induce bone loss, whereas PPARα agonists increase bone mass. Although PPARδ agonists are known to influence skeletal muscle metabolism, the skeletal effects are unsettled. This study investigated the musculoskeletal effects of the PPARδ agonist GW501516 in ovariectomized (OVX) rats. Female Sprague Dawley rats, 12 weeks of age, were allocated to a sham-operated group and 3 OVX groups; high-dose GW501516 (OVX-GW5), low-dose GW501516 (OVX-GW1), and a control group (OVX-CTR), respectively (n = 12 per group). Animals received GW501516 or vehicle (methylcellulose) daily for 4 months by gavage. Bone mineral density (BMD) was assessed by dual x-ray absorptiometry at the femur, spine, and whole body. Bone microarchitecture at the proximal tibia was assessed by microcomputed tomography, and dynamic histomorphometry was performed. Quadriceps muscle morphology and the relative expression of mitochondrial proteins were analyzed. Bone metabolism markers and metabolic markers were measured in plasma. After 4 months, the OVX-GW5 group displayed lower femoral BMD than OVX-CTR. Trabecular separation was higher in the GW-treated groups, compared with OVX-CTR. The OVX-GW5 group also exhibited lower cortical area fraction and a higher structure model index than OVX-CTR. These effects coincided with impaired bone formation in both GW groups. The OVX-GW5 group displayed elevated triglyceride levels and reduced adiponectin levels, whereas no effects on muscle morphology or mitochondrial gene expression appeared. In summary, the PPARδ agonist GW501516 negatively affected bone properties in OVX rats, whereas no effects were detected in skeletal muscle.

  • 13. Mosti, Mats Peder
    et al.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Erben, Reinhold G.
    Schüler, Christiane
    Syversen, Unni
    Stunes, Astrid Kamilla
    The PPARα Agonist Fenofibrate Improves the Musculoskeletal Effects of Exercise in Ovariectomized Rats2016In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 157, no 10, p. 3924-3934Article in journal (Refereed)
    Abstract [en]

    The musculoskeletal effects of exercise are attenuated by estrogen deficiency. The peroxisome proliferator-activated receptor-α agonist fenofibrate exerts beneficial effects in bone and muscle. We therefore examined whether fenofibrate could enhance the musculoskeletal training response during estrogen deficiency. We investigated the combined effects of 8 weeks of fenofibrate and jumping exercise in ovariectomized (OVX) Sprague Dawley rats. Female rats were allocated to a sham-operated group and four OVX groups; fenofibrate (OVX-Fen), exercise (OVX-Ex), combined fenofibrate and exercise (OVX-FenEx), and a control group (OVX-Ctr) (n = 12/group). Fenofibrate (90 mg/kg/d) or methylcellulose was given by gavage. The combination of exercise and fenofibrate resulted in enhanced femoral bone mineral density (BMD) and improved bone microarchitecture compared with fenofibrate alone as well as increased trabecular BMD compared with OVX-Ctr. These effects were not seen in the OVX-Ex group. Femoral BMD was normalized in both exercise groups relative to sham and increased more in all intervention groups compared with OVX-Ctr. A higher plasma level of the bone formation marker type 1 collagen amino propeptide was observed in the OVX-Fen and OVX-FenEx groups compared with controls. Lean mass and soleus muscle weight were higher in the OVX-FenEx group than in the OVX-Ctr group, which coincided with lower mRNA levels of Atrogin1. These results suggest that peroxisome proliferator-activated receptor-α activation improves the musculoskeletal effects of exercise during estrogen deficiency.

  • 14.
    Nilsson, Jessica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Joibari, Masoumeh Motamedi
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Anderson, Fredrick
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nilsson, Stefan K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Sjödin, Anna
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Burén, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice2016In: Nutrition & Metabolism, ISSN 1743-7075, E-ISSN 1743-7075, Vol. 13, article id 79Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Excess body fat is a major health issue and a risk factor for the development of numerous chronic diseases. Low-carbohydrate diets like the Atkins Diet are popular for rapid weight loss, but the long-term consequences remain the subject of debate. The Scandinavian low-carbohydrate high-fat (LCHF) diet, which has been popular in Scandinavian countries for about a decade, has very low carbohydrate content (~5 E %) but is rich in fat and includes a high proportion of saturated fatty acids. Here we investigated the metabolic and physiological consequences of a diet with a macronutrient composition similar to the Scandinavian LCHF diet and its effects on the organs, tissues, and metabolism of weight stable mice.

    METHODS: Female C57BL/6J mice were iso-energetically pair-fed for 4 weeks with standard chow or a LCHF diet. We measured body composition using echo MRI and the aerobic capacity before and after 2 and 4 weeks on diet. Cardiac function was assessed by echocardiography before and after 4 weeks on diet. The metabolic rate was measured by indirect calorimetry the fourth week of the diet. Mice were sacrificed after 4 weeks and the organ weight, triglyceride levels, and blood chemistry were analyzed, and the expression of key ketogenic, metabolic, hormonal, and inflammation genes were measured in the heart, liver, and adipose tissue depots of the mice using real-time PCR.

    RESULTS: The increase in body weight of mice fed a LCHF diet was similar to that in controls. However, while control mice maintained their body composition throughout the study, LCHF mice gained fat mass at the expense of lean mass after 2 weeks. The LCHF diet increased cardiac triglyceride content, impaired cardiac function, and reduced aerobic capacity. It also induced pronounced alterations in gene expression and substrate metabolism, indicating a unique metabolic state.

    CONCLUSIONS: Pair-fed mice eating LCHF increased their percentage of body fat at the expense of lean mass already after 2 weeks, and after 4 weeks the function of the heart deteriorated. These findings highlight the urgent need to investigate the effects of a LCHF diet on health parameters in humans.

  • 15.
    Nilsson, Stefan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Anderson, Fredrick
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Larsson, Mikael
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Makoveychuk, Elena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Lookene, Aivar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Heeren, Joerg
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL42012In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1821, no 10, p. 1370-1378Article in journal (Refereed)
    Abstract [en]

    Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate.

  • 16.
    Nyrén, Rakel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Makoveichuk, Elena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Malla, Sandhya
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Kersten, Sander
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Lipoprotein lipase in mouse kidney: effects of nutritional status and high-fat diet2019In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 3, p. F558-F571Article in journal (Refereed)
    Abstract [en]

    Activity of lipoprotein lipase (LPL) is high in mouse kidney, but the reason is poorly understood. The aim was to characterize localization, regulation, and function of LPL in kidney of C57BL/6J mice. We found LPL mainly in proximal tubules, localized inside the tubular epithelial cells, under all conditions studied. In fed mice, some LPL, colocalized with the endothelial markers CD31 and GPIHBP1 and could be removed by perfusion with heparin. indicating a vascular location. The role of angiopoietin-like protein 4 (ANGPTL4) for nutritional modulation of LPL activity was studied in wild-type and Angptl4(-/-) mice. In Angptl4(-/-) mice, kidney LPL activity remained high in fasted animals, indicating that ANGPTL4 is involved in suppression of LPL activity on fasting, like in adipose tissue. The amount of ANGPTL4 protein in kidney was low, and the protein appeared smaller in size, compared with ANGPTL4 in heart and adipose tissue. To study the influence of obesity, mice were challenged with high-fat diet for 22 wk, and LPL was studied after an overnight fast compared with fasted mice given food for 3 h. High-fat diet caused blunting of the normal adaptation of LPL activity to feeding/fasting in adipose tissue, but in kidneys this adaptation was lost only in male mice. LPL activity increases to high levels in mouse kidney after feeding, but as no difference in uptake of chylomicron triglycerides in kidneys is found between fasted and fed states, our data confinn that LPL appears to have a minor role for lipid uptake in this organ.

  • 17. Recirovic-Agic, Mediha
    et al.
    Jönsson, Sofia
    Tveitarås, Maria K.
    Skogstrand, Trude
    Karlsen, Tine, V
    Lidén, Åsa
    Leh, Sabine
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Reed, Rolf K.
    Hultstrom, Michael
    Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome2019In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 316, no 5, p. R563-R570Article in journal (Refereed)
    Abstract [en]

    The genetic background of a mouse strain determines its susceptibility to disease. C57BL/6J and Balb/CJ are two widely used inbred mouse strains that we found react dramatically differently to angiotensin II and high-salt diet (ANG II + Salt). Balb/CJ show increased mortality associated with anuria and edema formation while C57BL/6J develop arterial hypertension but do not decompensate and die. Clinical symptoms of heart failure in Balb/CJ mice gave the hypothesis that ANG II + Salt impairs cardiac function and induces cardiac remodeling in male Balb/CJ but not in male C57BL/6J mice. To test this hypothesis, we measured cardiac function using echocardiography before treatment and every day for 7 days during treatment with ANG II + Salt. Interestingly, pulsed wave Doppler of pulmonary artery flow indicated increased pulmonary vascular resistance and right ventricle systolic pressure in Balb/CJ mice, already 24 h after ANG II + Salt treatment was started. In addition, Balb/CJ mice showed abnormal diastolic filling indicated by reduced early and late filling and increased isovolumic relaxation time. Furthermore, Balb/CJ exhibited lower cardiac output compared with C57BL/6J even though they retained more sodium and water, as assessed using metabolic cages. Left posterior wall thickness increased during ANG II + Salt treatment but did not differ between the strains. In conclusion, ANG II + Salt treatment causes early restriction of pulmonary flow and reduced left ventricular filling and cardiac output in Balb/CJ, which results in fluid retention and peripheral edema. This makes Balb/CJ a potential model to study the adaptive capacity of the heart for identifying new disease mechanisms and drug targets.

  • 18.
    Signoret, Carine
    et al.
    Linnaeus Centre HEAD, Swedish Institute for Disability Research, Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
    Ng, Elaine
    Linnaeus Centre HEAD, Swedish Institute for Disability Research, Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
    Da Silva, Stéphanie
    Department of Clinical and Experimental Medicine, Division of Surgery, Faculty of Health Sciences, Linköping University, County Council of Östergötland, Linköping, Sweden.
    Tack, Ayco
    Department of Ecology, Environment and Plant Sciences, Stockholm University, Stockholm, Sweden.
    Voss, Ulrikke
    Department of Experimental Medical Sciences, Future Faculty, Lund University, Lund, Sweden.
    Lidö, Helga H.
    Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Patthey, Cedric
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Hadrevi, Jenny
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Balachandran, Chanchal
    Department of Management and Engineering (IEI), The Institute for Analytical Sociology, Linköping University, Linköping, Sweden.
    Well-being of early-career researchers: insights from a Swedish survey2019In: Higher Education Policy, ISSN 0952-8733, E-ISSN 1740-3863, Vol. 32, no 2, p. 273-296Article in journal (Refereed)
    Abstract [en]

    Several studies have documented the importance of optimal work situation and the general well-being of early-career researchers (ECRs) for enhancing the academic performance of universities. Yet, most studies focused on specific categories of ECRs, or on specific academic disciplines as well as on specific outcomes. With this study, we recognize the need for a broader sample encompassing different categories of ECRs across academic disciplines. In a national survey of Swedish universities, the National Junior Faculty of Sweden (NJF) collected data from ECRs in order to study the influence of work situation and well-being on perceived scientific environment. We observed that work situation and well-being are interdependent and jointly influence each other in shaping the conditions for ideal scientific environment. Importantly, we employ structural equation model (SEM) analysis to account for the endogenous relationship between work situation and personal well-being in predicting perceived scientific environment. Results from SEM indicate that support from the university, work time management, job clarity, contract length and quality of life satisfaction were related to the perceived possibility of conducting the best science. Our research also highlighted individual differences across demographic factors and contract length in the perceived work situation and the possibility of conducting the best science.

  • 19. Sjåland, Cecilie
    et al.
    Lunde, Per Kristian
    Swift, Fredrik
    Munkvik, Morten
    Ericsson, Madelene
    Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
    Lunde, Marianne
    Boye, Sigurd
    Christensen, Geir
    Ellingsen, Øyvind
    Sejersted, Ole M
    Andersson, Kristin B
    Slowed relaxation and preserved maximal force in soleus muscles of mice with targeted disruption of the Serca2 gene in skeletal muscle2011In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 589, no Pt 24, p. 6139-6155Article in journal (Refereed)
    Abstract [en]

    Sarcoplasmic reticulum Ca(2+) ATPases (SERCAs) play a major role in muscle contractility by pumping Ca(2+) from the cytosol into the sarcoplasmic reticulum (SR) Ca(2+) store, allowing muscle relaxation and refilling of the SR with releasable Ca(2+). Decreased SERCA function has been shown to result in impaired muscle function and disease in human and animal models. In this study, we present a new mouse model with targeted disruption of the Serca2 gene in skeletal muscle (skKO) to investigate the functional consequences of reduced SERCA2 expression in skeletal muscle. SkKO mice were viable and basic muscle structure was intact. SERCA2 abundance was reduced in multiple muscles, and by as much as 95% in soleus muscle, having the highest content of slow-twitch fibres (40%). The Ca(2+) uptake rate was significantly reduced in SR vesicles in total homogenates. We did not find any compensatory increase in SERCA1 or SERCA3 abundance, or altered expression of several other Ca(2+)-handling proteins. Ultrastructural analysis revealed generally well-preserved muscle morphology, but a reduced volume of the longitudinal SR. In contracting soleus muscle in vitro preparations, skKO muscles were able to fully relax, but with a significantly slowed relaxation time compared to controls. Surprisingly, the maximal force and contraction rate were preserved, suggesting that skKO slow-twitch fibres may be able to contribute to the total muscle force despite loss of SERCA2 protein. Thus it is possible that SERCA-independent mechanisms can contribute to muscle contractile function.

  • 20.
    Steneberg, Pär
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lindahl, Emma
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Dahl, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lidh, Emmelie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Straseviciene, Jurate
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Backlund, Fredrik
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Kjellkvist, Elisabet
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Berggren, Eva
    Lundberg, Ingela
    Bergqvist, Ingela
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Eriksson, Björn
    Linde, Kajsa
    Westman, Jacob
    Edlund, Thomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Betagenon AB, Umeå, Sweden.
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients2018In: JCI INSIGHT, ISSN 2379-3708, Vol. 3, no 12, article id e99114Article in journal (Refereed)
    Abstract [en]

    AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced beta cell stress, and promoted beta cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro-and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

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