Abstract：
Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.
摘要：
疾病发作和进展的变异性是肌萎缩侧索硬化症（ALS）的标志，无论是零星的和遗传的形式。最近,我们发现SOD1-G93A转基因小鼠表达相同数量的突变SOD1，但具有不同的遗传背景，C57BL/6JOlaHsd和129S2/SvHsd，显示缓慢和快速的肌肉萎缩和疾病进展，分别。这里,我们研究了肌肉萎缩的不同分子机制。尽管两种菌株都显示出相似的去神经诱导的肌肉蛋白降解，只有快速进展的小鼠在腓肠肌萎缩之前表现出早期和持续的STAT3激活。因此，我们研究了舒尼替尼的治疗潜力，一种已知能抑制STAT3并预防癌症引起的肌肉萎缩的酪氨酸激酶抑制剂。尽管舒尼替尼治疗减少了腓肠肌和腰脊髓中STAT3的激活，它没有保留脊髓运动神经元，改善神经肌肉损伤，快速进展的SOD1-G93A小鼠的肌肉萎缩和疾病进展。因此，舒尼替尼在与肌肉萎缩相关的不同疾病中的效果不相同。此外，鉴于STAT3在神经肌肉系统的外周和中枢区室中的复杂作用，本研究表明，其广泛的抑制作用可能会导致相反的效果，最终阻止ALS的潜在积极治疗作用。
