Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy
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RESEARCH ARTICLE
Open Access
Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy Melissa Bowerman1,2, Lyndsay M Murray1, Justin G Boyer1,2, Carrie L Anderson1 and Rashmi Kothary1,2,3*
Abstract Background: 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. Methods: 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. Results: 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. Conclusions: 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. Keywords: spinal muscular atrophy, fasudil, survival motor neuron protein, NMJ, muscle
Background As the leading genetic cause of infant deaths, spinal muscular atrophy (SMA) is a devastating and incurable neuromuscular disorder [1,2]. SMA affects 1 in 6,000 to 10,000 births and results from deletions or mutations in the survival motor neuron 1 (SMN1) gene [1-3]. The * Correspondence: [email protected] 1 Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 Full list of author information is available at the end of the article
primary pathological hallmark of SMA is the loss of lower motor neurons from the spinal cord and corresponding mu
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