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BMC Med. 2012; 10: 24.
Published online Mar 7, 2012. doi:  10.1186/1741-7015-10-24
PMCID: PMC3310724
Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy
Melissa Bowerman,1,2 Lyndsay M Murray,1 Justin G Boyer,1,2 Carrie L Anderson,1 and Rashmi Kotharycorresponding author1,2,3
1Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6
2Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5
3Department of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5
corresponding authorCorresponding author.
Melissa Bowerman: melissabowerman/at/hotmail.com; Lyndsay M Murray: lmmurray82/at/googlemail.com; Justin G Boyer: jusboyer/at/hotmail.com; Carrie L Anderson: carrie.l.anderson/at/gmail.com; Rashmi Kothary: rkothary/at/ohri.ca
Received December 8, 2011; Accepted March 7, 2012.
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
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