title: Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy.
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.
authors.affiliation: Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bowerman
authors.forename: Lyndsay M
authors.initials: LM
authors.lastname: Murray
authors.forename: Justin G
authors.initials: JG
authors.lastname: Boyer
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Anderson
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005684:Gait / Q000187:drug effects; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009045:Motor Endplate / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D024510:Muscle Development / Q000187:drug effects*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018008:Myogenin / Q000378:metabolism; D010641:Phenotype; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016019:Survival Analysis; D055540:Survival of Motor Neuron 2 Protein / Q000172:deficiency / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D018008:Myogenin; D055540:Survival of Motor Neuron 2 Protein; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil