Skeletal Muscle 11beta-HSD1 Controls Glucocorticoid-Induced Proteolysis and Expression of E3 Ubiquitin Ligases Atrogin-1 and MuRF-1

被引:36
|
作者
Biedasek, Katrin [1 ]
Andres, Janin [1 ]
Mai, Knut [1 ]
Adams, Stephanie [2 ]
Spuler, Simone [2 ]
Fielitz, Jens [3 ]
Spranger, Joachim [1 ]
机构
[1] Charite, Dept Endocrinol Diabet & Nutr, D-13353 Berlin, Germany
[2] Charite, Muscle Res Unit, Expt & Clin Res Ctr, D-13353 Berlin, Germany
[3] Charite, Dept Cardiol, D-13353 Berlin, Germany
来源
PLOS ONE | 2011年 / 6卷 / 01期
关键词
11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; FOXO TRANSCRIPTION FACTORS; C2C12; MYOTUBES; ADIPOSE-TISSUE; PROTEIN BREAKDOWN; ATROPHY; OBESITY; RESPONSES; PATHWAY; L6;
D O I
10.1371/journal.pone.0016674
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Recent studies demonstrated expression and activity of the intracellular cortisone-cortisol shuttle 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in skeletal muscle and inhibition of 11beta-HSD1 in muscle cells improved insulin sensitivity. Glucocorticoids induce muscle atrophy via increased expression of the E3 ubiquitin ligases Atrogin-1 (Muscle Atrophy F-box (MAFbx)) and MuRF-1 (Muscle RING-Finger-1). We hypothesized that 11beta-HSD1 controls glucocorticoid-induced expression of atrophy E3 ubiquitin ligases in skeletal muscle. Primary human myoblasts were generated from healthy volunteers. 11beta-HSD1-dependent protein degradation was analyzed by [H-3]-tyrosine release assay. RT-PCR was used to determine mRNA expression of E3 ubiquitin ligases and 11beta-HSD1 activity was measured by conversion of radioactively labeled [H-3]-cortisone to [H-3]-cortisol separated by thin-layer chromatography. We here demonstrate that 11beta-HSD1 is expressed and biologically active in interconverting cortisone to active cortisol in murine skeletal muscle cells (C2C12) as well as in primary human myotubes. 11beta-HSD1 expression increased during differentiation from myoblasts to mature myotubes (p<0.01), suggesting a role of 11beta-HSD1 in skeletal muscle growth and differentiation. Treatment with cortisone increased protein degradation by about 20% (p<0.001), which was paralleled by an elevation of Atrogin-1 and MuRF-1 mRNA expression (p<0.01, respectively). Notably, pre-treatment with the 11beta-HSD1 inhibitor carbenoxolone (Cbx) completely abolished the effect of cortisone on protein degradation as well as on Atrogin-1 and MuRF-1 expression. In summary, our data suggest that 11beta-HSD1 controls glucocorticoid-induced protein degradation in human and murine skeletal muscle via regulation of the E3 ubiquitin ligases Atrogin-1 and MuRF-1.
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页数:6
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