1 Institute for Clinical Neurobiology, University of Würzburg, Germany.
Brain. 2014 May;137(Pt 5):1374-93. doi: 10.1093/brain/awu059. Epub 2014 Mar 27.
Spinal muscular atrophy with respiratory distress type 1 is a neuromuscular disorder characterized by progressive weakness and atrophy of the diaphragm and skeletal muscles, leading to death in childhood. No effective treatment is available. The neuromuscular degeneration (Nmd(2J)) mouse shares a crucial mutation in the immunoglobulin mu-binding protein 2 gene (Ighmbp2) with spinal muscular atrophy with respiratory distress type 1 patients and also displays some basic features of the human disease. This model serves as a promising tool in understanding the complex mechanisms of the disease and in exploring novel treatment modalities such as insulin-like growth factor 1 (IGF1) which supports myogenic and neurogenic survival and stimulates differentiation during development. Here we investigated the treatment effects with polyethylene glycol-coupled IGF1 and its mechanisms of action in neurons and muscles. Polyethylene glycol-coupled IGF1 was applied subcutaneously every second day from post-natal Day 14 to post-natal Day 42 and the outcome was assessed by morphology, electromyography, and molecular studies. We found reduced IGF1 serum levels in Nmd(2J) mice 2 weeks after birth, which was normalized by polyethylene glycol-coupled IGF1 treatment. Nmd(2J) mice showed marked neurogenic muscle fibre atrophy in the gastrocnemius muscle and polyethylene glycol-coupled IGF1 treatment resulted in muscle fibre hypertrophy and slowed fibre degeneration along with significantly higher numbers of functionally active axonal sprouts. In the diaphragm with predominant myogenic changes a profound protection from muscle fibre degeneration was observed under treatment. No effects of polyethylene glycol-coupled IGF1 were monitored at the level of motor neuron survival. The beneficial effects of polyethylene glycol-coupled IGF1 corresponded to a marked activation of the IGF1 receptor, resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase in striated muscles and spinal cord from Nmd(2J) mice. Based on these findings, polyethylene glycol-coupled IGF1 may hold promise as a candidate for future treatment trials in human patients with spinal muscular atrophy with respiratory distress type 1.
1 型脊髓性肌萎缩伴呼吸窘迫症是一种神经肌肉疾病，其特征是膈肌和骨骼肌进行性无力和萎缩，导致儿童死亡。目前尚无有效的治疗方法。神经肌肉退化（Nmd(2J)）小鼠与 1 型脊髓性肌萎缩伴呼吸窘迫症患者共享免疫球蛋白 mu 结合蛋白 2 基因（Ighmbp2）的关键突变，并且还表现出人类疾病的一些基本特征。该模型是理解疾病复杂机制以及探索新型治疗方法（如胰岛素样生长因子 1（IGF1））的有前途的工具，IGF1 支持肌源性和神经源性存活，并在发育过程中刺激分化。在这里，我们研究了聚乙二醇结合 IGF1 的治疗效果及其在神经元和肌肉中的作用机制。从出生后第 14 天到第 42 天，每隔一天皮下给予聚乙二醇结合 IGF1，并通过形态学、肌电图和分子研究评估结果。我们发现 Nmd(2J) 小鼠出生后 2 周 IGF1 血清水平降低，聚乙二醇结合 IGF1 治疗可使其正常化。Nmd(2J) 小鼠的腓肠肌表现出明显的神经源性肌纤维萎缩，聚乙二醇结合 IGF1 治疗导致肌纤维肥大和纤维变性减慢，同时功能性轴突芽的数量显著增加。在以肌源性改变为主的膈中，观察到肌肉纤维退化得到了显著的保护。在运动神经元存活水平上未监测到聚乙二醇结合 IGF1 的作用。聚乙二醇结合 IGF1 的有益作用与 IGF1 受体的显著激活相对应，导致 Nmd(2J) 小鼠的横纹肌和脊髓中的 Akt（蛋白激酶 B）和核糖体蛋白 S6 激酶磷酸化增强。基于这些发现，聚乙二醇结合 IGF1 可能有望成为未来治疗 1 型脊髓性肌萎缩伴呼吸窘迫症人类患者的候选药物。
