Expression of foetal type acetylcholine receptor is restricted to type 1 muscle fibres in human neuromuscular disorders
Expression of foetal type acetylcholine receptor is restricted to type 1 muscle fibres in human neuromuscular disorders
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DOI：
10.1093/brain/awf136
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发表时间：
2002-06-01
期刊：
影响因子：
14.5
通讯作者：
Marx, A
中科院分区：
文献类型：
--
作者：
Gattenlöhner, S;Schneider, C;Marx, A
在成人肌肉中，乙酰胆碱受体 (AChR) 主要局限于表达成人亚型（αβδε）的运动终板。当动物模型中骨骼肌去神经支配时，肌肉会萎缩，并且含有 γ 亚基的 AChR 胎儿亚型（alphabetagammadelta）的表达显着增加。 AChR 表达的类似变化被认为发生在人类肌肉中。虽然去神经支配在调节 AChR 基因表达中的作用已被广泛研究，但尚未确定负责定义不同纤维类型的转录程序是否对 AChR 基因的表达有影响。我们使用 RNase 保护测定、α/γ-双链逆转录酶聚合酶链反应、胎儿 AChR 免疫组织化学和 RNA 原位杂交，研究了患有广泛神经肌肉疾病的患者的活检，以了解 AChR α 和 γ 亚基的表达。所有患有神经源性疾病和较小程度的肌源性疾病患者的肌肉均表现出 AChR γ 亚基转录显着增加，但与之前的动物研究相反，并未显示 AChR α 亚基转录增加。此外，免疫组织化学和RNA原位杂交均表明，无论潜在的神经肌肉疾病如何，AChR γ亚基过度表达仅发生在1型萎缩肌纤维中，而不是在2型萎缩肌纤维中。我们得出的结论是，人类肌肉疾病中 AChR γ 亚基的上调仅限于 1 型肌纤维，因此，AChR γ 亚基的表达受肌纤维类型限制的转录程序控制。影响这种和其他功能蛋白表达的因素应该与一系列神经肌肉疾病的理解和治疗相关。
In adult muscle, acetylcholine receptors (AChR) are restricted mainly to the motor endplate where the adult isoform (alphabetadeltaepsilon) is expressed. When skeletal muscle is denervated in animal models, there is atrophy of the muscle and a marked increase in expression of the AChR foetal isoform (alphabetagammadelta) containing a gamma-subunit. Similar changes in AChR expression are thought to occur in human muscle. While the role of denervation in regulating AChR gene expression has been widely studied, it has not been determined whether the transcriptional programmes responsible for defining different fibre types have an impact on the expression of AChR genes. We investigated biopsies from patients with a wide spectrum of neuromuscular diseases for expression of the AChR alpha- and gamma-subunits using RNase protection assays, alpha/gamma-duplex reverse transcriptase polymerase chain reaction, immunohistochemistry for foetal AChR and RNA in situ hybridization. Muscle from all patients with neurogenic disorders and, to a lesser extent, myogenic disorders, exhibited markedly increased transcription of the AChR gamma-subunit but, in contrast to previous animal studies, did not show increased AChR alpha-subunit. Moreover, both immunohistochemistry and RNA in situ hybridization revealed that AChR gamma-subunit hyperexpression occurred exclusively in atrophic type 1 and not in atrophic type 2 muscle fibres, irrespective of the underlying neuromuscular disease. We conclude that up-regulation of the AChR gamma-subunit in human muscle disorders is restricted to type 1 muscle fibres and, therefore, that AChR gamma-subunit expression is controlled by a muscle fibre type-restricted transcriptional programme. The factors influencing expression of this and other functional proteins should be relevant to the understanding and treatment of a range of neuromuscular disorders.