title: Increasing SMN levels using the histone deacetylase inhibitor SAHA ameliorates defects in skeletal muscle microvasculature in a mouse model of severe spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA), a primarily childhood form of motor neuron disease, is caused by reduced levels of a single, ubiquitously expressed protein: the survival motor neuron (SMN) protein. Low levels of SMN cause motor neuron degeneration but recent reports describe effects of low SMN levels in multiple tissues and organs, including the vasculature. Previously we have reported a significant defect in the vascular beds of SMA affected skeletal muscle. Here we examine the effects of ubiquitously increasing SMN levels, via treatment with the histone deacetylase inhibitor SAHA, on this vascular defect in the Taiwanese mouse: FVB.Cg-Tg(SMN2)2Hung Smn1(tm1Hung)/J mouse model of severe SMA. SAHA treatment resulted in an increase in the weight of SMA mice compared to untreated SMA mice and almost completely restored motor function at P10, the late symptomatic time point analysed. Vascular density in skeletal muscle was then assessed by morphological quantitation of immunofluorescence staining of vessels and quantitative fluorescent western blotting for a key endothelial protein PECAM-1. At P10 a severe vascular defect was present with a significant (P<0.01) ~82% reduction in vascular density in SMA mice when compared to control littermates. SAHA significantly increases SMN levels and also increased vascular density in SMA mice (P<0.05), suggesting that the vascular defect in SMA mice is amenable to SAHA treatment.
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Eilidh
authors.initials: E
authors.lastname: Somers
authors.forename: Markus
authors.initials: M
authors.lastname: Riessland
authors.forename: Julia
authors.initials: J
authors.lastname: Schreml
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
authors.forename: Simon H
authors.initials: SH
authors.lastname: Parson
mesh_terms: D000818:Animals; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D051379:Mice; D008833:Microcirculation / Q000187:drug effects*; D055806:Microvessels / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology*; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000503:physiopathology*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors