DNA double-strand breaks in inclusion body myositis

目的：研究s-IBM细胞的DNA损伤反应。背景资料：在散发性包涵体肌炎中，一些研究表明，肌纤维异常可能与其发病密切相关。材料和方法：来自s-IBM（n=17）、多发性肌炎（15）、皮肌炎（10）和其他对照（10）患者的活检材料中的免疫组织化学。针对1）磷酸化组蛋白H2 AX（γ H2 AX）的抗体，其积累到具有DNA双链断裂（DSB）的受损位点;和2）DNA-PK，其是参与DSB修复的酶。DNA-PK由催化亚基（DNA-PKcs）和调节亚基（Ku 70和Ku 80）组成。结果如下：在s-IBM和其他肌炎对照中，一部分肌核显示出强的γ H2 AX和DNA-PK免疫反应性，而正常对照显示出弱的肌细胞反应性。在s-IBM的空泡肌纤维中，空泡边缘常为γ H2 AX和DNA-PK阳性。而DNA-PKcs和Ku 80与空泡化纤维中的DNA相关，Ku 70在细胞质中作为包涵体观察到。结论：炎性肌病中部分肌核存在DSB。在s-IBM中，DNA-PK的Ku 70调节组分的胞质积累可能阻止它们易位到细胞核和DSB位点。DSB的积累可能导致s-IBM的肌变性。

Objectives: To examine DNA damage response in s-IBM. Background: In sporadic inclusion body myositis, several studies have indicated that myonuclear abnormality may be closely associated with its pathogenesis. Materials & Methods: Immunhistochemistry in biopsy materials from patients with s-IBM (n=17), polymyositis (15), dermatomyositis (10) and other controls (10). Antibodies against 1) phosphorylated histone H2AX (γH2AX) that accumulates to the damaged sites with DNA double-strand breaks (DSB); and 2) DNA-PK that is an enzyme involved in DSB repair. DNA-PK consists of a catalytic subunit (DNA-PKcs) and regulatory subunits (Ku70 and Ku80). Results: In s-IBM and other myositis controls, a proportion of myonuclei showed strong immunoreactivity of γH2AX and DNA-PK while normal controls showed weak myonuclear reactivity. In muscle fibers with vacuoles in s-IBM, vacuolar rims were frequently positive for γH2AX and DNA-PK. Whereas DNA-PKcs and Ku80 were associated with DNA in vacuolated fibers, Ku70 was observed in the cytoplasm as inclusions. Conclusions: DSB occurs in some myonuclei in inflammatory myopathies. In s-IBM, the cytoplasmic accumulation of Ku70 regulatory component of DNA-PK may prevent their translocation to the nucleus and DSB sites. Accumulation of DSB may lead to the myonuclear degeneration in s-IBM.