Urasawa Nobuyuki, Wada Michiko R, Machida Noboru, Yuasa Katsutoshi, Shimatsu Yoshiki, Wakao Yoshito, Yuasa Shigeki, Sano Toshiaki, Nonaka Ikuya, Nakamura Akinori, Takeda Shin'ichi
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan.
Circulation. 2008 May 13;117(19):2437-48. doi: 10.1161/CIRCULATIONAHA.107.739326. Epub 2008 May 5.
Respiratory support therapy significantly improves life span in patients with Duchenne muscular dystrophy; cardiac-related fatalities, including lethal arrhythmias, then become a crucial issue. It is therefore important to more thoroughly understand cardiac involvement, especially pathology of the conduction system, in the larger Duchenne muscular dystrophy animal models such as dystrophic dogs.
When 10 dogs with canine X-linked muscular dystrophy in Japan (CXMD(J)) were examined at the age of 1 to 13 months, dystrophic changes of the ventricular myocardium were not evident; however, Purkinje fibers showed remarkable vacuolar degeneration as early as 4 months of age. The degeneration of CXMD(J) Purkinje fibers was coincident with overexpression of Dp71 at the sarcolemma and translocation of mu-calpain to the cell periphery near the sarcolemma or in the vacuoles. Immunoblotting of the microdissected fraction showed that mu-calpain-sensitive proteins such as desmin and cardiac troponin-I or -T were selectively degraded in the CXMD(J) Purkinje fibers. Utrophin was highly upregulated in the earlier stage of CXMD(J) Purkinje fibers, but the expression was dislocated when vacuolar degeneration was recognized at 4 months of age. Nevertheless, the expression of dystrophin-associated proteins alpha-, beta-, gamma-, and delta-sarcoglycans and beta-dystroglycan was well maintained at the sarcolemma of Purkinje fibers.
Selective vacuolar degeneration of Purkinje fibers was found in the early stages of dystrophin deficiency. Dislocation of utrophin besides upregulation of Dp71 can be involved with this pathology. The degeneration of Purkinje fibers can be associated with the distinct deep Q waves in ECG and fatal arrhythmia seen in dystrophin deficiency.
呼吸支持疗法显著延长了杜氏肌营养不良症患者的寿命；包括致命性心律失常在内的心脏相关死亡便成为一个关键问题。因此，在更大的杜氏肌营养不良症动物模型（如营养不良犬）中更全面地了解心脏受累情况，尤其是传导系统的病理变化，非常重要。
对日本10只患有犬X连锁肌营养不良症（CXMD(J)）的犬在1至13月龄时进行检查，心室心肌的营养不良性改变并不明显；然而，早在4月龄时，浦肯野纤维就出现了明显的空泡变性。CXMD(J)浦肯野纤维的变性与肌膜上Dp71的过度表达以及μ-钙蛋白酶向肌膜附近的细胞周边或空泡内的转位同时发生。对显微解剖部分进行免疫印迹分析表明，在CXMD(J)浦肯野纤维中，结蛋白、心肌肌钙蛋白-I或-T等对μ-钙蛋白酶敏感的蛋白质被选择性降解。在CXMD(J)浦肯野纤维的早期阶段，抗肌萎缩蛋白上调，但在4月龄出现空泡变性时，其表达发生错位。尽管如此，浦肯野纤维肌膜上抗肌萎缩蛋白相关蛋白α-、β-、γ-和δ-肌聚糖以及β-抗肌萎缩蛋白聚糖的表达仍保持良好。
在抗肌萎缩蛋白缺乏的早期阶段发现了浦肯野纤维的选择性空泡变性。除了Dp71上调外，抗肌萎缩蛋白的错位也可能与这种病理变化有关。浦肯野纤维的变性可能与抗肌萎缩蛋白缺乏时心电图中明显的深Q波和致命性心律失常有关。
