Research on muscular dystrophy using mouse developmental biotechnology

肌聚糖病（SGP）在临床特征和肌肉病理学方面与杜氏肌营养不良症（DMD）相似，但其遗传方式不同，大多数病例发病稍晚，心脏受累较少，无精神损害，进展稍慢。肌聚糖复合物（sarcoglycan complex，SGC）的4个亚基（α-、β-、γ-和δ-SG）分别以4种形式存在，为了分析SGC各亚基的生理功能，阐明肌肥大和退变的发病机制，我们采用基因打靶技术制备了γ-SG-缺陷（GSG-/-）小鼠。GSG-/-小鼠的四肢、肩部和骨盆肌肉随着年龄的增长表现出进行性的肌肉肥大和无力，这些发现与其他肢带和DMD小鼠模型中所观察到的结果相似。我们发现胫骨前肌的肌纤维数量随年龄增长而增加，肥大肌中的肌纤维多为中央有核再生纤维。肥大肌内可见纤维分支。因此，肌肉肥大可能是广泛的纤维分支和肌纤维增加的结果。肌肉肥大不是由于纤维和脂肪组织替代，如已被证明是在人类肌肉疾病中所谓的假性肥大的情况。肌肉病理学变得更加“营养不良”的小鼠超过一岁时，有一个显着的变化，纤维大小与间质纤维化。

Sarcoglycanopathy (SGP) is similar to Duchenne muscular dystrophy (DMD) with respect to clinical features and muscle pathology, except for its mode of inheritance, slightly later onset in most cases, less frequent cardiac involvement, absence of mental impairment, and slightly slower progression. The four sarcoglycan subunits (α-, β-, γ-, and δ-SG) of the sarcoglycan complex (SGC) have been shown in four respective forms of SGP.To analyze the physiological roles of the individual subunits of SGC and elucidate the pathogenetic mechanisms of muscle hypertrophy and degeneration, we generated γ-SG-deficient (GSG-/-) mice by gene targeting. The limb, shoulder, and pelvic muscles of the GSG-/- mice exhibited progressive muscle hypertrophy and weakness with age, and findings were similar to those seen in other mouse models for limb girdle and DMD.While calf muscle hypertrophy is a striking diagnostic finding in DMD and SGP, its pathogenetic mechanism remains unknown. We found that the number of muscle fibers in tibialis anterior muscle increased with age, and most of the fibers in the hypertrophic muscle were centrally nucleated regenerating fibers. Fiber branching was seen in hypertrophied muscle. Therefore, muscle hypertrophy may represent a consequence of extensive fiber branching and an increase of muscle fibers. Muscle hypertrophy is not due to fibrous and fat tissue replacement, as has been shown to be the case in the so-called pseudohypertrophy in muscle diseases in humans. The muscle pathology became more "dystrophic" in mice over one year of age when there was a marked variation in fiber size with interstitial fibrosis.