Muscle-specific expression of insulin-like growth factor 1 improves outcome in Lama2Dy-w mice, a model for congenital muscular dystrophy type 1A
Muscle-specific expression of insulin-like growth factor 1 improves outcome in Lama2Dy-w mice, a model for congenital muscular dystrophy type 1A
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DOI：
10.1093/hmg/ddr126
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发表时间：
2011-06-15
影响因子：
3.5
通讯作者：
Girgenrath, Mahasweta
中科院分区：
文献类型：
--
作者：
Kumar, Ajay;Yamauchi, Jenny;Girgenrath, Mahasweta
MDC1a是第二种最常见的先天性肌营养不良症，由层粘连蛋白-α2链缺陷引起。这种疾病的特点是广泛的肌肉萎缩，导致骨骼肌极度虚弱。患有MDC1a的儿童中有很大比例面临呼吸困难和行动不便。我们在Lama2(Dy-w)小鼠身上研究了过表达胰岛素样生长因子-1(IGF-1)作为治疗这种疾病的潜在靶点的效果，这是一种与人类MDC1A非常相似的模型。转IGF-1基因的Lama2(Dy-w)小鼠的存活率、体重和肌肉重量均增加。此外，这些小鼠表现出更好的后肢站立能力：这是健康小鼠的典型探索行为。组织学和免疫组织化学分析显示，转IGF-1基因Lama2(Dy-w)肌肉的再生能力和增殖能力增强。Western印迹分析显示Akt和ERK1/2的磷酸化增加，这两种蛋白都能促进肌肉发生。此外，我们还看到再生标记MyoD、Mygenin和胚胎肌球蛋白(Myosin Heavy Chain 3，MYH3)的表达增加。我们的结论是，在Lama2(Dy-w)小鼠中过表达IGF-1主要通过恢复受损的肌肉再生来延长寿命并改善它们的整体健康状况，因为在这种疾病模型中，IGF-1不影响纤维化或炎症。我们的结果表明，IGF-1在MDC1A的治疗中具有很好的治疗潜力。
MDC1A, the second most prevalent form of congenital muscular dystrophy, results from laminin-alpha 2 chain deficiency. This disease is characterized by extensive muscle wasting that results in extremely weak skeletal muscles. A large percentage of children with MDC1A are faced with respiratory as well as ambulatory difficulties. We investigated the effects of overexpressing insulin-like growth factor-1 (IGF-1) as a potential therapeutic target for the disease in the Lama2(Dy-w) mouse, a model that closely resembles human MDC1A. IGF-1 transgenic Lama2(Dy-w) mice showed increased survivability, body weight and muscle weight. In addition, these mice showed better ability to stand up on their hind limbs: a typical exploratory behavior seen in healthy mice. Histology and immunohistochemistry analyses revealed increased regenerative capacity and proliferation in IGF-1 transgenic Lama2(Dy-w) muscles. Western blot analysis showed increased phosphorylation of Akt and ERK1/2, both known to enhance myogenesis. Additionally, we saw increases in the expression of the regeneration markers MyoD, myogenin and embryonic myosin (myosin heavy chain 3, MYH3). We conclude that overexpression of IGF-1 in Lama2(Dy-w) mice increases lifespan and improves their overall wellbeing mainly through the restoration of impaired muscle regeneration, as fibrosis or inflammation was not impacted by IGF-1 in this disease model. Our results demonstrate that IGF-1 has a promising therapeutic potential in the treatment of MDC1A.