Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy.
Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy.
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DOI：
10.1186/1741-7015-10-24
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发表时间：
2012-03-07
期刊：
影响因子：
9.3
通讯作者：
Kothary R
中科院分区：
文献类型：
--
作者：
Bowerman M;Murray LM;Boyer JG;Anderson CL;Kothary R
脊髓性肌萎缩症（SMA）是婴儿死亡的主要遗传原因。它是由存活运动神经元1 （SMN1）基因突变/缺失引起的，典型表现为脊髓运动神经元丧失、肌肉萎缩，严重者死亡。SMN蛋白普遍表达，并研究了多种细胞和组织特异性功能来解释SMA中特定的运动神经元损失。我们之前的研究表明，在细胞和动物SMA模型中，RhoA/Rho激酶（ROCK）通路被错误调节，并且用化学物质Y-27632抑制ROCK可显着增加SMA小鼠模型的寿命。在本研究中，我们评估了临床批准的ROCK抑制剂法舒地尔的治疗潜力。法舒地尔于出生后第3天至第21天灌胃，浓度为30 mg/kg，每日2次。评估法舒地尔对SMA小鼠寿命和病理指标的影响，并与给药小鼠进行比较。Kaplan-Meier生存分析采用log-rank检验，P < 0.05认为生存曲线有显著差异。对于其余的分析，使用配对变量的学生双尾t检验和单因素方差分析（ANOVA）来检验样本之间的差异，在P < 0.05时认为数据有显著差异。法舒地尔可显著提高SMA小鼠的存活率。这种显著的表型改善不是由Smn蛋白的上调或运动神经元的保存介导的。然而，法舒地尔可导致肌纤维和突触后终板大小显著增加，并恢复骨骼肌发育标志物的正常表达，这表明法舒地尔的有益作用可能是肌肉特异性的。我们的工作强调了肌肉作为SMA治疗靶点的重要性，并强调了ROCK抑制剂作为SMA和其他以肌肉萎缩和突触后不成熟为特征的退行性疾病的治疗策略的有益潜力。
Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. It is caused by mutations/deletions of the survival motor neuron 1 (SMN1) gene and is typified by the loss of spinal cord motor neurons, muscular atrophy, and in severe cases, death. The SMN protein is ubiquitously expressed and various cellular- and tissue-specific functions have been investigated to explain the specific motor neuron loss in SMA. We have previously shown that the RhoA/Rho kinase (ROCK) pathway is misregulated in cellular and animal SMA models, and that inhibition of ROCK with the chemical Y-27632 significantly increased the lifespan of a mouse model of SMA. In the present study, we evaluated the therapeutic potential of the clinically approved ROCK inhibitor fasudil. Fasudil was administered by oral gavage from post-natal day 3 to 21 at a concentration of 30 mg/kg twice daily. The effects of fasudil on lifespan and SMA pathological hallmarks of the SMA mice were assessed and compared to vehicle-treated mice. For the Kaplan-Meier survival analysis, the log-rank test was used and survival curves were considered significantly different at P < 0.05. For the remaining analyses, the Student's two-tail t test for paired variables and one-way analysis of variance (ANOVA) were used to test for differences between samples and data were considered significantly different at P < 0.05. Fasudil significantly improves survival of SMA mice. This dramatic phenotypic improvement is not mediated by an up-regulation of Smn protein or via preservation of motor neurons. However, fasudil administration results in a significant increase in muscle fiber and postsynaptic endplate size, and restores normal expression of markers of skeletal muscle development, suggesting that the beneficial effects of fasudil could be muscle-specific. Our work underscores the importance of muscle as a therapeutic target in SMA and highlights the beneficial potential of ROCK inhibitors as a therapeutic strategy for SMA and for other degenerative diseases characterized by muscular atrophy and postsynaptic immaturity.
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影响因子：
3.7
作者：
Hammond SM;Gogliotti RG;Rao V;Beauvais A;Kothary R;DiDonato CJ
通讯作者：
DiDonato CJ
影响因子：
4
作者：
Dhawan, J;Helfman, DM
通讯作者：
Helfman, DM
影响因子：
4.8
作者：
Castellani, Loriana;Salvati, Erica;Falcone, Germana
通讯作者：
Falcone, Germana
影响因子：
4.8
作者：
Amano, M;Ito, M;Kaibuchi, K
通讯作者：
Kaibuchi, K
影响因子：
15.9
作者：
Chuang, De-Maw;Leng, Yan;Marinova, Zoya;Kim, Hyeon-Ju;Chiu, Chi-Tso
通讯作者：
Chiu, Chi-Tso