Department of Pediatrics, Taubman Medical Research Institute, University of Michigan Medical Center, Ann Arbor, MI 48109-2200, USA.
Dis Model Mech. 2012 Nov;5(6):852-9. doi: 10.1242/dmm.009746. Epub 2012 May 24.
Myotubular myopathy (MTM) is a severe congenital muscle disease characterized by profound weakness, early respiratory failure and premature lethality. MTM is defined by muscle biopsy findings that include centralized nuclei and disorganization of perinuclear organelles. No treatments currently exist for MTM. We hypothesized that aberrant neuromuscular junction (NMJ) transmission is an important and potentially treatable aspect of the disease pathogenesis. We tested this hypothesis in two murine models of MTM. In both models we uncovered evidence of a disorder of NMJ transmission: fatigable weakness, improved strength with neostigmine, and electrodecrement with repetitive nerve stimulation. Histopathological analysis revealed abnormalities in the organization, appearance and size of individual NMJs, abnormalities that correlated with changes in acetylcholine receptor gene expression and subcellular localization. We additionally determined the ability of pyridostigmine, an acetylcholinesterase inhibitor, to ameliorate aspects of the behavioral phenotype related to NMJ dysfunction. Pyridostigmine treatment resulted in significant improvement in fatigable weakness and treadmill endurance. In all, these results describe a newly identified pathological abnormality in MTM, and uncover a potential disease-modifying therapy for this devastating disorder.
肌管性肌病（MTM）是一种严重的先天性肌肉疾病，其特征是严重的肌无力、早期呼吸衰竭和过早死亡。MTM 的定义是肌肉活检发现包括中央核和核周细胞器的紊乱。目前尚无针对 MTM 的治疗方法。我们假设异常的神经肌肉接头（NMJ）传递是疾病发病机制的一个重要且潜在可治疗的方面。我们在两种 MTM 小鼠模型中验证了这一假设。在这两种模型中，我们都发现了 NMJ 传递障碍的证据：易疲劳性无力、新斯的明改善肌力和重复神经刺激的电极衰减。组织病理学分析显示单个 NMJ 的组织、外观和大小存在异常，这些异常与乙酰胆碱受体基因表达和亚细胞定位的变化相关。我们还确定了吡啶斯的明（一种乙酰胆碱酯酶抑制剂）改善与 NMJ 功能障碍相关的行为表型的能力。吡啶斯的明治疗可显著改善易疲劳性无力和跑步机耐力。总之，这些结果描述了 MTM 中一种新发现的病理异常，并揭示了针对这种毁灭性疾病的潜在疾病修饰治疗方法。
