Quattrocelli Mattia, Salamone Isabella M, Page Patrick G, Warner James L, Demonbreun Alexis R, McNally Elizabeth M
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Am J Pathol. 2017 Nov;187(11):2520-2535. doi: 10.1016/j.ajpath.2017.07.017. Epub 2017 Aug 18.
The muscular dystrophies are genetically diverse. Shared pathological features among muscular dystrophies include breakdown, or loss of muscle, and accompanying fibrotic replacement. Novel strategies are needed to enhance muscle repair and function and to slow this pathological remodeling. Glucocorticoid steroids, like prednisone, are known to delay loss of ambulation in patients with Duchenne muscular dystrophy but are accompanied by prominent adverse effects. However, less is known about the effects of steroid administration in other types of muscular dystrophies, including limb-girdle muscular dystrophies (LGMDs). LGMD 2B is caused by loss of dysferlin, a membrane repair protein, and LGMD 2C is caused by loss of the dystrophin-associated protein, γ-sarcoglycan. Herein, we assessed the efficacy of steroid dosing on sarcolemmal repair, muscle function, histopathology, and the regenerative capacity of primary muscle cells. We found that in murine models of LGMD 2B and 2C, daily prednisone dosing reduced muscle damage and fibroinflammatory infiltration. However, daily prednisone dosing also correlated with increased muscle adipogenesis and atrophic remodeling. Conversely, intermittent dosing of prednisone, provided once weekly, enhanced muscle repair and did not induce atrophy or adipogenesis, and was associated with improved muscle function. These data indicate that dosing frequency of glucocorticoid steroids affects muscle remodeling in non-Duchenne muscular dystrophies, suggesting a positive outcome associated with intermittent steroid dosing in LGMD 2B and 2C muscle.
肌营养不良症在遗传上具有多样性。肌营养不良症的共同病理特征包括肌肉分解或丧失，以及随之而来的纤维化替代。需要新的策略来促进肌肉修复和功能，并减缓这种病理重塑。已知糖皮质激素，如泼尼松，可延缓杜氏肌营养不良症患者行走能力的丧失，但会伴有明显的不良反应。然而，对于类固醇给药在其他类型的肌营养不良症中的作用，包括肢带型肌营养不良症（LGMDs），人们了解较少。LGMD 2B是由膜修复蛋白dysferlin缺失引起的，LGMD 2C是由肌营养不良蛋白相关蛋白γ-肌聚糖缺失引起的。在此，我们评估了类固醇给药对肌膜修复、肌肉功能、组织病理学以及原代肌肉细胞再生能力的疗效。我们发现，在LGMD 2B和2C的小鼠模型中，每日给予泼尼松可减少肌肉损伤和纤维炎性浸润。然而，每日给予泼尼松也与肌肉脂肪生成增加和萎缩性重塑相关。相反，每周一次间歇性给予泼尼松可增强肌肉修复，且不会诱导萎缩或脂肪生成，并与肌肉功能改善相关。这些数据表明，糖皮质激素的给药频率会影响非杜氏肌营养不良症中的肌肉重塑，提示间歇性给予类固醇在LGMD 2B和2C肌肉中会产生积极结果。
