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Sökning: WFRF:(Wojtaszewski Jørgen)

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  • Treebak, Jonas T, et al. (författare)
  • AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits.
  • 2006
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 55:7, s. 2051-2058
  • Tidskriftsartikel (refereegranskat)abstract
    • AMP-activated protein kinase (AMPK) is a heterotrimeric protein that regulates glucose transport mediated by cellular stress or pharmacological agonists such as 5-aminoimidazole-4-carboxamide 1 beta-D-ribonucleoside (AICAR). AS160, a Rab GTPase-activating protein, provides a mechanism linking AMPK signaling to glucose uptake. We show that AICAR increases AMPK, acetyl-CoA carboxylase, and AS160 phosphorylation by insulin-independent mechanisms in isolated skeletal muscle. Recombinant AMPK heterotrimeric complexes (alpha 1 beta 1 gamma l and alpha 2 beta 2 gamma 1) phosphorylate AS160 in a cell-free assay. In mice deficient in AMPK signaling (alpha 2 AMPK knockout [KO], alpha 2 AMPK kinase dead [KD], and gamma 3 AMPK KO), AICAR effects on AS160 phosphorylation were severely blunted, highlighting that complexes containing alpha 2 and gamma 3 are necessary for AICAR-stimulated AS160 phosphorylation in intact skeletal muscle. Contraction-mediated AS160 phosphorylation was also impaired in alpha 2 AMPK KO and KD but not gamma 3 AMPK KO mice. Our results implicate AS160 as a downstream target of AMPK.
  • Broholm, Christa, et al. (författare)
  • Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men
  • 2020
  • Ingår i: Endocrine Research. - : Taylor & Francis. - 0743-5800. ; 45:1, s. 58-71
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Being born with low birth weight (LBW) is a risk factor for muscle insulin resistance and type 2 diabetes (T2D), which may be mediated by epigenetic mechanisms programmed by the intrauterine environment. Epigenetic mechanisms exert their prime effects in developing cells. We hypothesized that muscle insulin resistance in LBW subjects may be due to early differential epigenomic and transcriptomic alterations in their immature muscle progenitor cells. Results: Muscle progenitor cells were obtained from 23 healthy young adult men born at term with LBW, and 15 BMI-matched normal birth weight (NBW) controls. The cells were subsequently cultured and differentiated into myotubes. DNA and RNA were harvested before and after differentiation for genome-wide DNA methylation and RNA expression measurements. After correcting for multiple comparisons (q ≤ 0.05), 56 CpG sites were found to be significantly, differentially methylated in myoblasts from LBW compared with NBW men, of which the top five gene-annotated CpG sites (SKI, ARMCX3, NR5A2, NEUROG, ESRRG) previously have been associated to regulation of cholesterol, fatty acid and glucose metabolism and muscle development or hypertrophy. LBW men displayed markedly decreased myotube gene expression levels of the AMPK-repressing tyrosine kinase gene FYN and the histone deacetylase gene HDAC7. Silencing of FYN and HDAC7 was associated with impaired myotube formation, which for HDAC7 reduced muscle glucose uptake. Conclusions: The data provides evidence of impaired muscle development predisposing LBW individuals to T2D is linked to and potentially caused by distinct DNA methylation and transcriptional changes including down regulation of HDAC7 and FYN in their immature myoblast stem cells.
  • Davegårdh, Cajsa, et al. (författare)
  • Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects
  • 2017
  • Ingår i: BMC Medicine. - : BioMed Central (BMC). - 1741-7015. ; 15:1, s. 1-27
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Human skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects. Methods: We used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model. Results: We observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects. Conclusions: Our study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.
  • Friedrichsen, Martin, et al. (författare)
  • Dissociation between Skeletal Muscle Inhibitor-{kappa}B Kinase/Nuclear Factor-{kappa}B Pathway Activity and Insulin Sensitivity in Nondiabetic Twins.
  • 2010
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 1945-7197. ; 95:1, s. 414-421
  • Tidskriftsartikel (refereegranskat)abstract
    • Context: Several studies suggest a link between increased activity of the inflammatory inhibitor-kappaB kinase/nuclear factor-kappaB (IKK/NF-kappaB) pathway in skeletal muscle and insulin resistance. Objective: We aimed to study the regulation of skeletal muscle IKK/NF-kappaB pathway activity as well as the association with glucose metabolism and skeletal muscle insulin signaling. Methods: The study population included a metabolically well-characterized cohort of young and elderly predominantly nondiabetic twins (n = 181). Inhibitor-kappaBbeta (IkappaBbeta) protein levels are negatively associated with IKK/NF-kappaB pathway activity and were used to evaluate pathway activity with p65 levels included as loading control. This indirect measure for IKK/NF-kappaB pathway activity was validated by a p65 binding assay. Results: Evaluating the effects of heritability, age, sex, obesity, aerobic capacity, and several hormonal factors (eg insulin and TNF-alpha), only sex and age were significant predictors of IkappaBbeta to p65 ratio (28% decreased ratio in the elderly, P < 0.01, and 49% increased in males P < 0.01). IkappaBbeta to p65 ratio was unrelated to peripheral insulin sensitivity (P = 0.51) and in accordance with this also unrelated to proximal insulin signaling (P = 0.81). Although no association was seen with plasma glucose after oral glucose challenge, there was a tendency for lower IkappaBbeta to p65 ratio (adjusted for age and sex) in subjects with impaired as opposed to normal glucose tolerance (P = 0.055). Conclusions: Altogether the subtle elevated IKK/NF-kappaB pathway activity seen in glucose-intolerant subjects suggests that IKK/NF-kappaB pathway activation may be secondary to impaired glucose tolerance and that skeletal muscle IKK/NF-kappaB pathway activity is unlikely to play any major role in the control of skeletal muscle insulin action in nondiabetic subjects.
  • Fritzen, Andreas Mæchel, et al. (författare)
  • ApoA-1 improves glucose tolerance by increasing glucose uptake into heart and skeletal muscle independently of AMPKα2
  • 2020
  • Ingår i: Molecular Metabolism. - : Elsevier GmbH. - 2212-8778. ; 35
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Acute administration of the main protein component of high-density lipoprotein, apolipoprotein A-I (ApoA-1), improves glucose uptake in skeletal muscle. The molecular mechanisms mediating this are not known, but in muscle cell cultures, ApoA-1 failed to increase glucose uptake when infected with a dominant-negative AMP-activated protein kinase (AMPK) virus. We therefore investigated whether AMPK is necessary for ApoA-1-stimulated glucose uptake in intact heart and skeletal muscle in vivo. Methods: The effect of injection with recombinant human ApoA-1 (rApoA-1) on glucose tolerance, glucose-stimulated insulin secretion, and glucose uptake into skeletal and heart muscle with and without block of insulin secretion by injection of epinephrine (0.1 mg/kg) and propranolol (5 mg/kg), were investigated in 8 weeks high-fat diet-fed (60E%) wild-type and AMPKα2 kinase-dead mice in the overnight-fasted state. In addition, the effect of rApoA-1 on glucose uptake in isolated skeletal muscle ex vivo was studied. Results: rApoA-1 lowered plasma glucose concentration by 1.7 mmol/l within 3 h (6.1 vs 4.4 mmol/l; p < 0.001). Three hours after rApoA-1 injection, glucose tolerance during a 40-min glucose tolerance test (GTT) was improved compared to control (area under the curve (AUC) reduced by 45%, p < 0.001). This was accompanied by an increased glucose clearance into skeletal (+110%; p < 0.001) and heart muscle (+100%; p < 0.001) and an increase in glucose-stimulated insulin secretion 20 min after glucose injection (+180%; p < 0.001). When insulin secretion was blocked during a GTT, rApoA-1 still enhanced glucose tolerance (AUC lowered by 20% compared to control; p < 0.001) and increased glucose clearance into skeletal (+50%; p < 0.05) and heart muscle (+270%; p < 0.001). These improvements occurred to a similar extent in both wild-type and AMPKα2 kinase-dead mice and thus independently of AMPKα2 activity in skeletal- and heart muscle. Interestingly, rApoA-1 failed to increase glucose uptake in isolated skeletal muscles ex vivo. Conclusions: In conclusion, ApoA-1 stimulates in vivo glucose disposal into skeletal and heart muscle independently of AMPKα2. The observation that ApoA-1 fails to increase glucose uptake in isolated muscle ex vivo suggests that additional systemic effects are required.
  • Ling, Charlotte, et al. (författare)
  • Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins.
  • 2004
  • Ingår i: Journal of Clinical Investigation. - : Am Soc Clin Investig. - 0021-9738. ; 114:10, s. 1518-1526
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha}) and PGC-1ß genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1{alpha} gene. Insulin increased and aging reduced skeletal muscle PGC-1{alpha} and PGC-1ß mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1{alpha} Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1{alpha} in a complex fashion. Whereas expression of PGC-1{alpha} in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1ß expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1{alpha} and PGC-1ß expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1{alpha} and PGC-1ß on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.
  • Thorell, Anders, et al. (författare)
  • Exerciseand insulin cause GLUT-4 translocation in human skeletal muscle
  • 1999
  • Ingår i: American Journal of Physiology. - : American Physiological Society. - 0002-9513 .- 2163-5773. ; 277:4, s. E733-E741
  • Tidskriftsartikel (refereegranskat)abstract
    • Studies in rodents have established that GLUT-4 translocation is the major mechanism by which insulin and exercise increase glucose uptake in skeletal muscle. In contrast, much less is known about the translocationphenomenon in human skeletal muscle. In the current study, nine healthy volunteers were studied on two different days. On one day, biopsies of vastus lateralis muscle were taken before and after a 2-h euglycemic- hyperinsulinemic clamp (0.8 mU · kg-1 · min-1). On another day, subjects exercised for 60 min at 70% of maximal oxygen consumption (VO(2max)), a biopsy was obtained, and the same clamp and biopsy procedure was performed as that during the previous experiment. Compared with insulin treatment alone, glucose infusion rates were significantly increased during the postexercise clamp for the periods 0-30 min, 30-60 min, and 60-90 min, but not during the last 30 min of the clamp. Plasma membrane GLUT-4 content was significantly increased in response to physiological hyperinsulinemia (32% above rest), exercise (35%), and the combination of exercise plus insulin(44%). Phosphorylation of Akt, a putative signaling intermediary for GLUT-4 translocation, was increased inresponse to insulin (640% above rest), exercise (280%), and exercise plus insulin (1,000%). These data demonstrate that two normal physiological conditions, moderate intensity exercise and physiological hyperinsulinemia ~56 μU/ml, cause GLUT-4 translocation and Akt phosphorylation in human skeletal muscle.
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  • Resultat 1-8 av 8

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