Sorbonne Universités, UPMC Université Paris 6, Paris, France.
INSERM U974, Centre de Recherche en Myologie (CRM), GH Pitié-Salpêtrière, Paris 13, France.
Acta Neuropathol. 2017 Dec;134(6):869-888. doi: 10.1007/s00401-017-1754-2. Epub 2017 Jul 29.
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.
重症肌无力（MG）是一种神经肌肉疾病，在大多数情况下是由抗乙酰胆碱受体（AChR）自身抗体引起的，这些自身抗体损害神经肌肉信号传递并影响骨骼肌内稳态。成肌发生是由称为卫星细胞（SCs）的肌肉干细胞进行的。然而，MG 中的成肌发生从未被探索过。本研究的目的是表征肌无力SCs 的功能特性及其在肌肉再生中的能力。SCs 从 MG 患者和年龄匹配的对照者的肌肉活检中分离出来。我们首先表明，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+SCs 的数量增加。与对照肌肉的成肌细胞相比，从 MG 肌肉中分离的成肌细胞增殖和分化更为活跃。与对照相比，MG 成肌细胞以及 MG 肌肉活检中表达更高水平的 MyoD 和 MyoG。我们发现，与对照血清相比，MG 血清或单克隆抗 AChR 抗体处理对照成肌细胞可增加分化和 MyoG mRNA 表达。为了研究 MG 肌肉SCs 再生的功能能力，我们在 EAMG 小鼠模型中使用急性心脏毒素损伤诱导肌肉再生。我们观察到成熟延迟的证据，表现为纤维大小和 MyoG mRNA 表达减少，以及纤维数量和胚胎肌球蛋白重链 mRNA 表达增加。这些发现首次证明了与对照肌肉相比，MG 肌肉的SCs 功能发生改变。这些改变可能是由于抗 AChR 抗体通过调节成肌标志物导致肌肉再生受损。总之，MG 中的自身免疫攻击似乎对SCs 和肌肉再生具有意想不到的致病作用，对成肌信号通路有潜在影响，进而对临床结果有潜在影响，特别是在肌肉受到压力的情况下。
