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Muscle satellite cells are functionally impaired in myasthenia gravis: consequences on muscle regeneration
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2017-07-29 , DOI: 10.1007/s00401-017-1754-2
Mohamed Attia , Marie Maurer , Marieke Robinet , Fabien Le Grand , Elie Fadel , Rozen Le Panse , Gillian Butler-Browne , Sonia Berrih-Aknin

Myasthenia gravis (MG) is a neuromuscular disease caused in most cases by anti-acetyl-choline receptor (AChR) autoantibodies that impair neuromuscular signal transmission and affect skeletal muscle homeostasis. Myogenesis is carried out by muscle stem cells called satellite cells (SCs). However, myogenesis in MG had never been explored. The aim of this study was to characterise the functional properties of myasthenic SCs as well as their abilities in muscle regeneration. SCs were isolated from muscle biopsies of MG patients and age-matched controls. We first showed that the number of Pax7+ SCs was increased in muscle sections from MG and its experimental autoimmune myasthenia gravis (EAMG) mouse model. Myoblasts isolated from MG muscles proliferate and differentiate more actively than myoblasts from control muscles. MyoD and MyoG were expressed at a higher level in MG myoblasts as well as in MG muscle biopsies compared to controls. We found that treatment of control myoblasts with MG sera or monoclonal anti-AChR antibodies increased the differentiation and MyoG mRNA expression compared to control sera. To investigate the functional ability of SCs from MG muscle to regenerate, we induced muscle regeneration using acute cardiotoxin injury in the EAMG mouse model. We observed a delay in maturation evidenced by a decrease in fibre size and MyoG mRNA expression as well as an increase in fibre number and embryonic myosin heavy-chain mRNA expression. These findings demonstrate for the first time the altered function of SCs from MG compared to control muscles. These alterations could be due to the anti-AChR antibodies via the modulation of myogenic markers resulting in muscle regeneration impairment. In conclusion, the autoimmune attack in MG appears to have unsuspected pathogenic effects on SCs and muscle regeneration, with potential consequences on myogenic signalling pathways, and subsequently on clinical outcome, especially in the case of muscle stress.



中文翻译:

重症肌无力中肌肉卫星细胞的功能受损:对肌肉再生的影响

重症肌无力(MG)是一种神经肌肉疾病,大多数情况下是由抗乙酰胆碱受体(AChR)自身抗体引起的,该抗体会削弱神经肌肉信号传递并影响骨骼肌稳态。肌发生是通过称为卫星细胞(SC)的肌肉干细胞进行的。然而,从未探讨过MG的肌发生。这项研究的目的是表征肌无力SC的功能特性及其在肌肉再生中的能力。从MG患者的肌肉活检组织和年龄匹配的对照组中分离出SC。我们首先表明,从MG及其实验性自身免疫性重症肌无力(EAMG)小鼠模型的肌肉切片中,Pax7 + SC的数量增加了。从MG肌肉中分离出来的成肌细胞比从对照肌肉中获得的成肌细胞更容易增殖和分化。与对照组相比,MyoD和MyoG在MG成肌细胞以及MG肌肉活检中的表达水平更高。我们发现,与对照血清相比,用MG血清或单克隆抗AChR抗体处理对照成肌细胞会增加分化和MyoG mRNA表达。为了研究MG肌肉的SC再生的功能能力,我们在EAMG小鼠模型中使用急性心毒素损伤诱导了肌肉再生。我们观察到成熟的延迟是由纤维大小和MyoG mRNA表达的减少以及纤维数量和胚胎肌球蛋白重链mRNA表达的增加所证明的。这些发现首次证明了与对照肌肉相比,MG的SCs的功能发生了改变。这些改变可能是由于抗AChR抗体通过调节肌原性标志物导致肌肉再生受损所致。总之,MG的自身免疫攻击似乎对SC和肌肉再生具有意想不到的致病作用,可能会对肌源性信号通路以及随后的临床结果产生潜在的影响,尤其是在肌肉紧张的情况下。

更新日期:2017-07-29
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