Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model.
Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model.
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DOI：
10.1083/jcb.200407021
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发表时间：
2005-01-17
影响因子：
7.8
通讯作者：
Musaro, Antonio
中科院分区：
文献类型：
--
作者：
Dobrowolny, Gabriella;Giacinti, Cristina;Pelosi, Laura;Nicoletti, Carmine;Winn, Nadine;Barberi, Laura;Molinaro, Mario;Rosenthal, Nadia;Musaro, Antonio
肌萎缩性侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种进行性神经退行性疾病，其特征在于运动神经元的选择性变性、骨骼肌萎缩和瘫痪。尽管家族性ALS的很大一部分是由与显性SOD 1突变相关的毒性功能获得引起的，但该疾病的病因及其特定的细胞起源仍然难以确定。在这里，我们表明，肌肉限制性表达的局部胰岛素样生长因子（Igf）-1亚型保持肌肉的完整性和增强卫星细胞的活性在SOD 1G 93 A转基因小鼠，诱导钙调神经磷酸酶介导的再生途径。局部Igf-1（mIgf-1）同种型的肌肉特异性表达也稳定了神经肌肉接头，减少了脊髓炎症，并提高了SOD 1G 93 A小鼠运动神经元的存活率，延缓了疾病的发作和进展。这些研究确立了骨骼肌作为遗传性SOD 1突变显性作用的主要靶点，并表明肌纤维为神经元存活提供了适当的因子，如mIgf-1。
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective degeneration of motor neurons, atrophy, and paralysis of skeletal muscle. Although a significant proportion of familial ALS results from a toxic gain of function associated with dominant SOD1 mutations, the etiology of the disease and its specific cellular origins have remained difficult to define. Here, we show that muscle-restricted expression of a localized insulin-like growth factor (Igf) -1 isoform maintained muscle integrity and enhanced satellite cell activity in SOD1G93A transgenic mice, inducing calcineurin-mediated regenerative pathways. Muscle-specific expression of local Igf-1 (mIgf-1) isoform also stabilized neuromuscular junctions, reduced inflammation in the spinal cord, and enhanced motor neuronal survival in SOD1G93A mice, delaying the onset and progression of the disease. These studies establish skeletal muscle as a primary target for the dominant action of inherited SOD1 mutation and suggest that muscle fibers provide appropriate factors, such as mIgf-1, for neuron survival.