A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure.
A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure.
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DOI：
10.1152/ajpendo.00512.2011
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发表时间：
2012-05
期刊：
影响因子：
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通讯作者：
Monica L. Watson;Leslie M. Baehr;Holger M. Reichardt;Jan P. Tuckermann;Sue C. Bodine;J. Furlow
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文献类型：
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作者：
Monica L. Watson;Leslie M. Baehr;Holger M. Reichardt;Jan P. Tuckermann;Sue C. Bodine;J. Furlow
糖皮质激素（GC）是骨骼肌质量的重要调节剂，长时间暴露会导致显著的肌肉萎缩。为了更好地理解GC水平升高诱导的骨骼肌萎缩的机制，我们研究了三种不同的模型：外源性合成GC治疗[地塞米松（DEX）]、营养剥夺和去神经支配。具体而言，我们通过使用Cre-lox技术创建肌肉特异性GR敲除小鼠系（MGR（e3）KO）来测试糖皮质激素受体（GR）在骨骼肌萎缩中的直接贡献。在MGR（e3）KO小鼠中，我们发现GR对于高剂量DEX治疗引起的肌肉萎缩至关重要。此外，MGR（e3）KO小鼠中完全消除了DEX对多个基因（包括两个重要的萎缩标志物MuRF 1和MAFbx）的调控。在内源性GC升高的条件下，如营养缺乏，MGR（e3）KO小鼠中MuRF 1和MAFbx的诱导受到抑制，但未完全阻断。响应坐骨神经损伤和后肢肌肉去神经支配，肌肉萎缩和MuRF 1和MAFbx的上调在野生型和MGR（e3）KO小鼠中发生相同程度，表明在这些条件下不需要功能性GR来诱导萎缩。因此，我们最终证明，GR是一个重要的调解人的骨骼肌萎缩和相关的基因表达在体内响应外源性合成GC和MGR（e3）KO小鼠是一个有用的模型，用于研究的GR及其靶基因在多种骨骼肌萎缩模型的作用。
Glucocorticoids (GCs) are important regulators of skeletal muscle mass, and prolonged exposure will induce significant muscle atrophy. To better understand the mechanism of skeletal muscle atrophy induced by elevated GC levels, we examined three different models: exogenous synthetic GC treatment [dexamethasone (DEX)], nutritional deprivation, and denervation. Specifically, we tested the direct contribution of the glucocorticoid receptor (GR) in skeletal muscle atrophy by creating a muscle-specific GR-knockout mouse line (MGR(e3)KO) using Cre-lox technology. In MGR(e3)KO mice, we found that the GR is essential for muscle atrophy in response to high-dose DEX treatment. In addition, DEX regulation of multiple genes, including two important atrophy markers, MuRF1 and MAFbx, is eliminated completely in the MGR(e3)KO mice. In a condition where endogenous GCs are elevated, such as nutritional deprivation, induction of MuRF1 and MAFbx was inhibited, but not completely blocked, in MGR(e3)KO mice. In response to sciatic nerve lesion and hindlimb muscle denervation, muscle atrophy and upregulation of MuRF1 and MAFbx occurred to the same extent in both wild-type and MGR(e3)KO mice, indicating that a functional GR is not required to induce atrophy under these conditions. Therefore, we demonstrate conclusively that the GR is an important mediator of skeletal muscle atrophy and associated gene expression in response to exogenous synthetic GCs in vivo and that the MGR(e3)KO mouse is a useful model for studying the role of the GR and its target genes in multiple skeletal muscle atrophy models.