PDF(Pubmed)
Abstract：
Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD. Here, we knocked out the glucocorticoid receptor (GR, encoded by Nr3c1) specifically in myofibers and cardiomyocytes within wild-type and mdx52 mice to dissect its role in muscular dystrophy. Double-knockout mice showed significantly worse phenotypes than mdx52 littermate controls in measures of grip strength, hang time, inflammatory pathology and gene expression. In the heart, GR deletion acted additively with dystrophin loss to exacerbate cardiomyopathy, resulting in enlarged hearts, pathological gene expression and systolic dysfunction, consistent with imbalanced mineralocorticoid signaling. The results show that physiological GR functions provide a protective role during muscular dystrophy, directly contrasting its degenerative role in other disease states. These data provide new insights into corticosteroids in disease pathophysiology and establish a new model to investigate cell-autonomous roles of nuclear receptors and mechanisms of pharmacological corticosteroids.
摘要：
缺乏肌营养不良蛋白会导致肌肉无力，Duchenne型肌营养不良症（DMD）的慢性炎症和心肌病。药物皮质类固醇是DMD护理标准；然而，它们有严重的副作用和不清楚的分子益处。尚不确定生理皮质类固醇及其受体的信号传导是否在DMD的自然病因中起修饰作用。这里,我们敲除了糖皮质激素受体(GR，由Nr3c1编码），特别是在野生型和mdx52小鼠的肌纤维和心肌细胞中，以剖析其在肌营养不良中的作用。双基因敲除小鼠在握力测量中表现出比mdx52同窝动物对照明显更差的表型，挂断时间,炎症病理和基因表达。在心中,GR缺失与肌营养不良蛋白丢失相加，加剧心肌病，导致心脏扩大，病理基因表达和收缩功能障碍，与盐皮质激素信号不平衡一致。结果表明，生理GR功能在肌营养不良期间提供保护作用，直接对比其在其他疾病状态中的退化作用。这些数据为皮质类固醇在疾病病理生理学中的作用提供了新的见解，并建立了一个新的模型来研究核受体的细胞自主作用和药理学皮质类固醇的机制。
