Kumamoto Toshihide, Ueyama Hidetsugu, Tsumura Hiroshi, Toyoshima Itaru, Tsuda Tomiyasu
Division of Neurology and Neuromuscular Disorders, Department of Immunology and Allergy, Oita Medical University, Idaigaoka 1-1, Hasama, 879-5593, Oita, Japan.
Acta Neuropathol. 2004 Jan;107(1):59-65. doi: 10.1007/s00401-003-0774-2. Epub 2003 Sep 26.
Despite the unknown etiology and pathogenesis of sporadic inclusion body myositis (s-IBM), investigators have speculated that the lysosome system in muscle fiber plays a central role in rimmed vacuole formation, a hallmark of s-IBM. We explored the role of receptor-mediated intracellular transport and autophagy in the lysosomal system in the abnormal accumulation of rimmed vacuoles in s-IBM. Expressions of mannose 6-phosphate receptor (M6PR), clathrin and hApg5 and hApg12 were analyzed in muscle biopsy specimens from patients with s-IBM, amyotrophic lateral sclerosis (ALS) or peripheral neuropathy and in normal human muscle specimens by means of immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Most muscle fibers in control specimens showed little or no immunoreactivity for clathrin and M6PR, which are involved in the receptor-mediated intracellular transport. Abnormal increases in both proteins were observed mainly in the sarcoplasm of atrophic fibers in all diseased specimens. In s-IBM muscles in particular, clathrin and M6PR were often observed inside rimmed vacuoles and in the sarcoplasm of vacuolated or non-vacuolated fibers. mRNA levels of hApg5 and hApg12, which are involved in autophagic vacuole formation, as well as of M6PR and clathrin were significantly increased in s-IBM muscles in comparison to levels in normal and ALS/peripheral neuropathy muscles. Our results suggest that the transport of newly synthesized lysosomal enzymes from the secretory pathway via the trans-Golgi network of the Golgi apparatus and autophagic vacuole formation (i.e., autophagy) in the lysosome system are activated in s-IBM muscles. Remarkable accumulation of rimmed vacuoles is thought to occur because of abnormal lysosome function, especially the formation or turnover of autolysosomes after the fusion of autophagic vacuoles with the early endosomes or because of the increase in the rate of muscle fiber breakdown.
尽管散发性包涵体肌炎（s-IBM）的病因和发病机制尚不清楚，但研究人员推测，肌纤维中的溶酶体系统在镶边空泡形成中起核心作用，而镶边空泡是s-IBM的一个标志。我们探讨了受体介导的细胞内运输和自噬在溶酶体系统中对s-IBM中镶边空泡异常积累的作用。通过免疫组织化学和逆转录聚合酶链反应（RT-PCR）分析了s-IBM、肌萎缩侧索硬化症（ALS）或周围神经病患者的肌肉活检标本以及正常人肌肉标本中甘露糖6-磷酸受体（M6PR）、网格蛋白以及hApg5和hApg12的表达。对照标本中的大多数肌纤维对参与受体介导的细胞内运输的网格蛋白和M6PR几乎没有或没有免疫反应性。在所有患病标本中，主要在萎缩纤维的肌浆中观察到这两种蛋白质的异常增加。特别是在s-IBM肌肉中，经常在镶边空泡内以及空泡化或未空泡化纤维的肌浆中观察到网格蛋白和M6PR。与正常和ALS/周围神经病肌肉相比，参与自噬泡形成的hApg5和hApg12以及M6PR和网格蛋白的mRNA水平在s-IBM肌肉中显著增加。我们的结果表明，在s-IBM肌肉中，溶酶体系统中来自分泌途径经高尔基体反式高尔基体网络的新合成溶酶体酶的运输以及自噬泡形成（即自噬）被激活。镶边空泡的显著积累被认为是由于溶酶体功能异常，特别是自噬泡与早期内体融合后自溶酶体的形成或周转异常，或者是由于肌纤维分解速率增加所致。
