散发性包涵体肌炎来源的肌管培养显示出肌肉细胞自主表达谱。 - Suppr | 超能文献

Abstract

Sporadic inclusion body myositis (sIBM) is a muscle disease in older people and is characterized by inflammatory cell invasion into intact muscle fibers and rimmed vacuoles. The pathomechanism of sIBM is not fully elucidated yet, and controversy exists as to whether sIBM is a primary autoimmune disease or a degenerative muscle disease with secondary inflammation. Previously, we established a method of collecting CD56-positive myoblasts from human skeletal muscle biopsy samples. We hypothesized that the myoblasts derived from these patients are useful to see the cell-autonomous pathomechanism of sIBM. With these resources, myoblasts were differentiated into myotubes, and the expression profiles of cell-autonomous pathology of sIBM were analyzed. Myoblasts from three sIBM cases and six controls were differentiated into myotubes. In the RNA-sequencing analysis of these "myotube" samples, 104 differentially expressed genes (DEGs) were found to be significantly upregulated by more than twofold in sIBM, and 13 DEGs were downregulated by less than twofold. For muscle biopsy samples, a comparative analysis was conducted to determine the extent to which "biopsy" and "myotube" samples differed. Fifty-three DEGs were extracted of which 32 (60%) had opposite directions of expression change (e.g., increased in biopsy vs decreased in myotube). Apolipoprotein E (apoE) and transmembrane protein 8C (TMEM8C or MYMK) were commonly upregulated in muscle biopsies and myotubes from sIBM. ApoE and myogenin protein levels were upregulated in sIBM. Given that enrichment analysis also captured changes in muscle contraction and development, the triggering of muscle atrophy signaling and abnormal muscle differentiation via MYMK or myogenin may be involved in the pathogenesis of sIBM. The presence of DEGs in sIBM suggests that the myotubes formed from sIBM-derived myoblasts revealed the existence of muscle cell-autonomous degeneration in sIBM. The catalog of DEGs will be an important resource for future studies on the pathogenesis of sIBM focusing on primary muscle degeneration.

摘要

散发性包涵体肌炎（sIBM）是一种好发于老年人的肌肉疾病，其特征为炎性细胞侵入完整的肌纤维以及出现镶边空泡。sIBM的发病机制尚未完全阐明，关于sIBM是原发性自身免疫性疾病还是继发炎症的退行性肌肉疾病存在争议。此前，我们建立了一种从人骨骼肌活检样本中收集CD56阳性成肌细胞的方法。我们推测，源自这些患者的成肌细胞有助于了解sIBM的细胞自主发病机制。利用这些资源，将成肌细胞分化为肌管，并分析sIBM细胞自主病理的表达谱。来自3例sIBM病例和6例对照的成肌细胞被分化为肌管。在对这些“肌管”样本的RNA测序分析中，发现104个差异表达基因（DEG）在sIBM中显著上调两倍以上，13个DEG下调不到两倍。对于肌肉活检样本，进行了比较分析以确定“活检”和“肌管”样本的差异程度。提取了53个DEG，其中32个（60%）的表达变化方向相反（例如，活检中增加而肌管中减少）。载脂蛋白E（apoE）和跨膜蛋白8C（TMEM8C或MYMK）在sIBM的肌肉活检和肌管中均上调。sIBM中apoE和肌细胞生成素蛋白水平上调。鉴于富集分析还捕捉到了肌肉收缩和发育的变化，通过MYMK或肌细胞生成素触发肌肉萎缩信号和异常肌肉分化可能参与了sIBM的发病机制。sIBM中DEG的存在表明，由sIBM来源的成肌细胞形成的肌管揭示了sIBM中肌肉细胞自主变性的存在。DEG目录将成为未来聚焦于原发性肌肉变性的sIBM发病机制研究的重要资源。