Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy

• Published in: BMC medicine 2012-03, Vol.10 (1), p.24-24, Article 24
• Main Authors: Bowerman, Melissa, Murray, Lyndsay M, Boyer, Justin G, Anderson, Carrie L, Kothary, Rashmi
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - administration & dosage; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - therapeutic use; Animals; Anterior Horn Cells - drug effects; Anterior Horn Cells - pathology; Atrophy, Muscular; Colleges & universities; Complications and side effects; Disease Models, Animal; Dosage and administration; Dose-Response Relationship, Drug; Drug dosages; Drug therapy; fasudil; FDA approval; Gait - drug effects; Infants; Kinases; Laboratories; Longevity - drug effects; Medical research; Mice; Mice, Inbred C57BL; Motor Endplate - drug effects; Motor Endplate - pathology; Motor Endplate - physiopathology; Motor Neurons - drug effects; Motor Neurons - pathology; muscle; Muscle Development - drug effects; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - drug effects; Muscle, Skeletal - growth & development; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscular Atrophy, Spinal - drug therapy; Muscular Atrophy, Spinal - pathology; Muscular Atrophy, Spinal - physiopathology; Muscular system; Musculoskeletal system; Mutation; Myogenin - metabolism; NMJ; Pathogenesis; Patient outcomes; Phenotype; Prognosis; Spinal Cord - drug effects; Spinal Cord - pathology; Spinal Cord - physiopathology; spinal muscular atrophy; Survival Analysis; survival motor neuron protein; Survival of Motor Neuron 2 Protein - deficiency; Survival of Motor Neuron 2 Protein - metabolism; Vasodilators; Weight Gain - drug effects
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/1741-7015-10-24

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.