糖皮质激素受体在局部发挥作用,在疾病期间保护肌营养不良的肌肉和心脏。

IF 4 3区 医学 Q2 CELL BIOLOGY Disease Models & Mechanisms Pub Date : 2024-05-01 Epub Date: 2024-05-21 DOI:10.1242/dmm.050397
Trinitee Oliver, Nhu Y Nguyen, Christopher B Tully, Nikki M McCormack, Christina M Sun, Alyson A Fiorillo, Christopher R Heier
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引用次数: 0

摘要

缺乏肌营养不良蛋白会导致杜氏肌营养不良症(DMD)患者肌肉无力、慢性炎症和心肌病。药用皮质类固醇是 DMD 的标准治疗方法;然而,它们有严重的副作用,而且分子效益不明确。目前还不确定生理性皮质类固醇及其受体的信号传导是否在 DMD 的自然病因中起着调节作用。在这里,我们特异性敲除了野生型小鼠和 mdx52 小鼠肌纤维和心肌细胞中的糖皮质激素受体(GR,由 Nr3c1 编码),以研究其在肌肉萎缩症中的作用。双基因敲除小鼠在握力、悬垂时间、炎症病理和基因表达等方面的表型明显差于 mdx52 小鼠对照组。在心脏中,GR 基因缺失与肌营养不良蛋白缺失共同加剧了心肌病,导致心脏增大、病理基因表达和收缩功能障碍,这与矿质类固醇信号失衡是一致的。研究结果表明,GR 的生理功能在肌肉萎缩症中起到保护作用,这与它在其他疾病中的退化作用形成了直接对比。这些数据为了解皮质类固醇在疾病病理生理学中的作用提供了新的视角,并为研究核受体的细胞自主作用和药理皮质类固醇的作用机制建立了一个新的模型。
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The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease.

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.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
期刊最新文献
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