Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients
Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients
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DOI：
10.1038/labinvest.3700163
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发表时间：
2004-10-01
影响因子：
5
通讯作者：
Gies, JP
中科院分区：
文献类型：
--
作者：
Arnold, AS;Gueye, M;Gies, JP
脊髓性肌萎缩症(SMA)是一种以运动神经元变性和骨骼肌萎缩为特征的常染色体隐性遗传病。在最严重的情况下，它会导致2岁以下的死亡。虽然运动神经元的原发变性在这种疾病中得到了很好的证实，这导致了骨骼肌的神经源性萎缩，但我们之前已经报告了原发肌肉缺陷的证据。在这项研究中，我们使用来自SMA患者和对照组的胚胎人类骨骼肌细胞的原代培养来检测在没有神经成分的情况下肌肉纤维分化的影响。培养的SMA骨骼肌细胞不能正确融合形成多核肌管，多核肌管是肌纤维的前体。我们还发现，集聚蛋白诱导的烟碱型乙酰胆碱受体聚集，这是神经肌肉连接形成的最早步骤之一，不能在SMA患者的细胞上用共聚焦显微镜观察到。在结合实验中，我们证明这种聚集的缺乏是由于SMA患者肌管中烟碱型乙酰胆碱受体的缺陷表达，而无论肌细胞类型(SMA或对照)，α-银环蛇毒素对其受体的亲和力保持不变。这些观察表明，SMA患者的肌肉细胞存在固有的异常，可能会影响神经肌肉接头的正常形成。
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of motoneurons and skeletal muscle atrophy. In its most severe form, it leads to death before the age of 2 years. While primary degeneration of motor neurons is well established in this disease, and this results in neurogenic atrophy of skeletal muscle, we have previously reported evidence for a primary muscle defect. In this study, we used primary cultures of embryonic human skeletal muscle cells from patients with SMA and from controls to examine the effects of muscle fiber differentiation in the absence of a nerve component. Cultured SMA skeletal muscle cells are unable to fuse correctly to form multinuclear myotubes, the precursors of the myofibers. We also show that agrin-induced aggregates of nicotinic acetylcholine receptors, one of the earliest steps of neuromuscular junction formation, cannot be visualized by confocal microscopy on cells from SMA patients. In binding experiments, we demonstrate that this lack of clustering is due to defective expression of the nicotinic acetylcholine receptors in the myotubes of SMA patients whereas the affinity of alpha-bungarotoxin for its receptor remains unchanged regardless of muscle cell type (SMA or control). These observations suggest that muscle cells from SMA patients have intrinsic abnormalities that may affect proper formation of the neuromuscular junction.