Gorospe J R, Tharp M, Demitsu T, Hoffman E P
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA 15261.
Neuromuscul Disord. 1994 Jul;4(4):325-33. doi: 10.1016/0960-8966(94)90068-x.
Duchenne muscular dystrophy is the most common inherited lethal X-linked disorder of mankind and is caused by dystrophin deficiency. The steps involved in the dystrophin-deficiency-induced cascade which lead to myofiber necrosis, progressive muscle wasting in humans and dogs and prominent muscle hypertrophy in mice and cats are obscure. Dystrophin is an intracellular component of the membrane cytoskeleton and its absence would be expected to cause necrosis of isolated myofibers (cell autonomous defect). However, all dystrophin-deficient muscles characteristically show simultaneous degeneration of large groups of muscle fibers (grouped necrosis). This implies that cell death may be mediated by extracellular, non-cell autonomous factors which occur as a secondary consequence of dystrophin deficiency. We have proposed a model where tissue pathology may be mediated by infiltrating mast cells (Gorospe et al., J Neurol Sci 1994). Here we show that intramuscular injections of purified mast cell granules induce widespread myofiber necrosis in dystrophin-deficient mdx mice, but not in normal mice. These data support the hypothesis that dystrophin acts as a plasma membrane stabilizer and that its deficiency renders myofibers more susceptible to damage from mast cell proteases. Moreover, our results support the hypothesis that mast cell degranulation may be a trigger for myofiber death in dystrophin-deficient muscle.
杜兴氏肌营养不良症是人类最常见的遗传性致死性X连锁疾病，由肌营养不良蛋白缺乏引起。肌营养不良蛋白缺乏引发的一系列导致肌纤维坏死、人类和犬类肌肉进行性萎缩以及小鼠和猫显著肌肉肥大的过程尚不清楚。肌营养不良蛋白是膜细胞骨架的细胞内成分，其缺失预计会导致分离的肌纤维坏死（细胞自主缺陷）。然而，所有肌营养不良蛋白缺乏的肌肉都有特征性地表现出大量肌纤维同时变性（成群坏死）。这意味着细胞死亡可能由细胞外非细胞自主因素介导，这些因素是肌营养不良蛋白缺乏的继发后果。我们提出了一个模型，其中组织病理学可能由浸润的肥大细胞介导（戈罗斯佩等人，《神经科学杂志》，1994年）。在这里，我们表明，向肌营养不良蛋白缺乏的mdx小鼠肌肉内注射纯化的肥大细胞颗粒会诱导广泛的肌纤维坏死，但正常小鼠不会。这些数据支持以下假设：肌营养不良蛋白作为质膜稳定剂，其缺乏使肌纤维更容易受到肥大细胞蛋白酶的损伤。此外，我们的结果支持以下假设：肥大细胞脱颗粒可能是肌营养不良蛋白缺乏的肌肉中肌纤维死亡的触发因素。
