Nonaka肌病的骨骼肌存在内质网应激改变

Affected muscle fibers in Nonaka myopathy with endoplasmic reticulum stress

目的探讨我国Nonaka肌病患者骨骼肌病理改变特点。方法收集2002年1月到2011年3月我院就诊的Nonaka肌病患者共13例，其中男性7例，女性6例，男女比例1．17：1，平均年龄39．5岁，平均病程4．15年，平均发病年龄35．4岁。主要表现为双足抬起无力，股四头肌早期不受累，1例患者以上肢无力起病。对13例患者进行骨骼肌活体组织检查，标本作组织病理学、超微病理学及免疫组织化学检查。免疫组织化学染色的第-抗体分别为tall蛋白、B-淀粉样蛋白、泛素抗体，抗内质网分子伴侣相对分子质量为78000的葡萄糖调节蛋白（GRP78）及calnexin抗体、抗凋亡蛋白细胞质天冬氨酸特异性半胱氨酸蛋白酶12（caspase-12）、Bax抗体，同时取3例慢性疲劳综合征患者的骨骼肌、2例肌原纤维肌病患者的骨骼肌分别作为健康对照和疾病对照。所有患者进行尿苷二磷酸-N-乙酰葡萄胺-2-表位酶基因序列检测。结果12例取材为胫前肌的患者经光镜检查显示肌营养不良样改变伴随肌纤维内镶边空泡形成。部分肌纤维空泡含有tau蛋白、B-淀粉样蛋白抗体及泛素阳性物质，内质网分子伴侣蛋白GRP78及calnexin在这些肌纤维内明显增加，凋亡相关蛋白caspase-12、Bax表达升高。结论Nonaka肌病患者的骨骼肌存在异常蛋白沉积，由此诱发的内质网应激和凋亡反应可能参与了肌纤维的损伤过程。

Objective To investigate the characteristic of pathology in Chinese patients with Nonaka myopathy. Methods Thirteen patients （7 males and 6 females） diagnosed with Nonaka myopathy in our laboratory from January 2002 to March 2011 were included in this study. Their mean age was 39.5 years old and the mean duration of illness was 4. 15 years. The most common symptoms were weakness of raising feet with sparing of quadriceps femoris muscles in the early stage of disease. One patient presented the initial symptoms of upper limb weakness. Muscles biopsies were obtained from all these 13 patients. Histology study including immunohistochemical （IHC） staining with antibody against amyloid β, phosphorylated tau protein, ubiquitin, glucose-regulated protein of molecular weight 78 000 （GRP78） , calnexin, caspase-12 and Bax were performed. Skeletal muscle samples from 3 chronic fatigue syndrome patients, 2 myofibrillar myopathy patients were used for control in the IHC staining. All coding exons of uridinediphospho-N- acetylglucosamine 2-epimerase gene were directly sequenced in genomic DNA from these patients. Results The main pathological changes of tibialis anterior muscle in 12 cases were muscle dystrophy with rimmed vacuoles. The rimmed vacuoles were positive for anti-β-amyloid, tau protein and ubiquitin in IHC studies. In the atrophy fibers, IHC showed the increased expression of endoplasmic reticulum stress related proteins GRP78 and calnexin, and apoptosis proteins of caspase-12 and Bax. Conclusions There is accumulation of abnormal proteins in muscle fibers in Chinese patients with Nonaka myopahty. These proteins may stimulate endoplasmic reticulum stress and apoptosis, which may be a mechanism responsible for muscle damage.