Dept. of Neurobiology, Physiology, and Behavior, Univ. of California, One Shields Ave., Davis, CA 95616-8519, USA.
Am J Physiol Endocrinol Metab. 2012 May 1;302(10):E1210-20. doi: 10.1152/ajpendo.00512.2011. Epub 2012 Feb 21.
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.
糖皮质激素（GCs）是骨骼肌质量的重要调节剂，长期暴露会导致明显的肌肉萎缩。为了更好地理解升高的 GC 水平引起的骨骼肌萎缩的机制，我们检查了三种不同的模型：外源性合成 GC 处理[地塞米松（DEX）]、营养剥夺和去神经支配。具体来说，我们使用 Cre-lox 技术创建了一种肌肉特异性 GR 敲除小鼠系（MGR(e3)KO），以测试糖皮质激素受体（GR）在骨骼肌萎缩中的直接作用。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是必需的。此外，DEX 对包括两个重要萎缩标志物 MuRF1 和 MAFbx 在内的多个基因的调节在 MGR(e3)KO 小鼠中完全消除。在内源性 GCs 升高的情况下，例如营养剥夺，MuRF1 和 MAFbx 的诱导被抑制，但并未完全阻断，在 MGR(e3)KO 小鼠中。在坐骨神经损伤和后肢肌肉去神经支配的情况下，野生型和 MGR(e3)KO 小鼠的肌肉萎缩和 MuRF1 和 MAFbx 的上调程度相同，表明在这些情况下，功能性 GR 不是诱导萎缩所必需的。因此，我们明确证明，GR 是体内外源性合成 GCs 引起的骨骼肌萎缩和相关基因表达的重要介质，并且 MGR(e3)KO 小鼠是研究 GR 及其靶基因在多种骨骼肌萎缩模型中的作用的有用模型。
