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- Barres, R., et al.
(författare)
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Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density
- 2009
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 10:3, s. 189-98
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic modification through DNA methylation is implicated in metabolic disease. Using whole-genome promoter methylation analysis of skeletal muscle from normal glucose-tolerant and type 2 diabetic subjects, we identified cytosine hypermethylation of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha) in diabetic subjects. Methylation levels were negatively correlated with PGC-1alpha mRNA and mitochondrial DNA (mtDNA). Bisulfite sequencing revealed that the highest proportion of cytosine methylation within PGC-1alpha was found within non-CpG nucleotides. Non-CpG methylation was acutely increased in human myotubes by exposure to tumor necrosis factor-alpha (TNF-alpha) or free fatty acids, but not insulin or glucose. Selective silencing of the DNA methyltransferase 3B (DNMT3B), but not DNMT1 or DNMT3A, prevented palmitate-induced non-CpG methylation of PGC-1alpha and decreased mtDNA and PGC-1alpha mRNA. We provide evidence for PGC-1alpha hypermethylation, concomitant with reduced mitochondrial content in type 2 diabetic patients, and link DNMT3B to the acute fatty-acid-induced non-CpG methylation of PGC-1alpha promoter.
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| 2. |
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| 3. |
- Rune, A., et al.
(författare)
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Evidence against a sexual dimorphism in glucose and fatty acid metabolism in skeletal muscle cultures from age-matched men and post-menopausal women
- 2009
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 197:3, s. 207-215
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Tidskriftsartikel (refereegranskat)abstract
- Aim: In vivo whole body differences in glucose/lipid metabolism exist between men and women. Thus, we tested the hypothesis that intrinsic sex differences exist in skeletal muscle gene expression and glucose/lipid metabolism using cultured myotubes. Methods: Myotube cultures were prepared for gene expression and metabolic studies from vastus lateralis skeletal muscle biopsies obtained from age-matched men (n = 11; 59 +/- 2 years) and post-menopausal women (n = 10; 60 +/- 1 years). Results: mRNA expression of several genes involved in glucose and lipid metabolism was higher in skeletal muscle biopsies from female vs. male donors, but unaltered between the sexes in cultured myotubes. Basal and insulin-stimulated glucose uptake, as well as glucose incorporation into glycogen, was similar in myotube cultures derived from male vs. female donors. In males vs. females, insulin increased glucose uptake (1.3 +/- 0.1 vs. 1.5 +/- 0.1-fold respectively) and incorporation into glycogen (2.3 +/- 0.3 vs. 2.0 +/- 0.3-fold respectively) to the same extent. Basal fatty acid oxidation and rate of uptake/accumulation was similar between sexes. In response to the 5'AMP-activated protein kinase activator AICAR, lipid oxidation was increased to the same extent in myotubes established from male vs. female donors (1.6 +/- 0.6 vs. 2.0 +/- 0.3-fold respectively). Moreover, the AICAR-induced rate of uptake/accumulation was similar between sexes. Conclusion: Differences in metabolic parameters and gene expression profiles between age-matched men and post-menopausal women noted in vivo are not observed in cultured human skeletal muscle cells. Thus, the sexual dimorphism in glucose and lipid metabolism is likely a consequence of systemic whole body factors, rather than intrinsic differences in the skeletal muscle proper.
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