title: Myogenic program dysregulation is contributory to disease pathogenesis in spinal muscular atrophy.
abstract: Mutations in the survival motor neuron (SMN1) gene lead to the neuromuscular disease spinal muscular atrophy (SMA). Although SMA is primarily considered as a motor neuron disease, the importance of muscle defects in its pathogenesis has not been fully examined. We use both primary cell culture and two different SMA model mice to demonstrate that reduced levels of Smn lead to a profound disruption in the expression of myogenic genes. This disruption was associated with a decrease in myofiber size and an increase in immature myofibers, suggesting that Smn is crucial for myogenic gene regulation and early muscle development. Histone deacetylase inhibitor trichostatin A treatment of SMA model mice increased myofiber size, myofiber maturity and attenuated the disruption of the myogenic program in these mice. Taken together, our work highlights the important contribution of myogenic program dysregulation to the muscle weakness observed in SMA.
authors.affiliation: Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada K1H 8L6 Department of Cellular and Molecular Medicine.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Boyer
authors.affiliation: Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada K1H 8L6 Department of Cellular and Molecular Medicine.
authors.forename: Marc-Olivier
authors.initials: MO
authors.lastname: Deguise
authors.affiliation: Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada K1H 8L6.
authors.forename: Lyndsay M
authors.initials: LM
authors.lastname: Murray
authors.affiliation: Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada K1H 8L6 Department of Cellular and Molecular Medicine.
authors.forename: Armin
authors.initials: A
authors.lastname: Yazdani
authors.affiliation: Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada K1H 8L6.
authors.forename: Yves
authors.initials: Y
authors.lastname: De Repentigny
authors.affiliation: School of Human Kinetics, Laurentian University, Sudbury, ON, Canada P3E 2C6.
authors.forename: Céline
authors.initials: C
authors.lastname: Boudreau-Larivière
authors.affiliation: Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada K1H 8L6 Department of Cellular and Molecular Medicine Department of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5 rkothary@ohri.ca.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009121:Muscle Denervation; D024510:Muscle Development / Q000187:drug effects / Q000235:genetics*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000473:pathology*; D032446:Myoblasts / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; C012589:trichostatin A