title: Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres.
abstract: Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)(8-13) expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets.
authors.affiliation: Royal Holloway, University of London, Egham, UK.
authors.forename: Capucine
authors.initials: C
authors.lastname: Trollet
authors.forename: Seyed Yahya
authors.initials: SY
authors.lastname: Anvar
authors.forename: Andrea
authors.initials: A
authors.lastname: Venema
authors.forename: Iain P
authors.initials: IP
authors.lastname: Hargreaves
authors.forename: Keith
authors.initials: K
authors.lastname: Foster
authors.forename: Alban
authors.initials: A
authors.lastname: Vignaud
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.forename: Elisa
authors.initials: E
authors.lastname: Negroni
authors.forename: Christophe
authors.initials: C
authors.lastname: Hourde
authors.forename: Martin A
authors.initials: MA
authors.lastname: Baraibar
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.forename: Janet E
authors.initials: JE
authors.lastname: Davies
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Heales
authors.forename: Vincent
authors.initials: V
authors.lastname: Mouly
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
authors.forename: Vered
authors.initials: V
authors.lastname: Raz
authors.forename: George
authors.initials: G
authors.lastname: Dickson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D020869:Gene Expression Profiling; D006019:Glycolysis / Q000502:physiology; D007150:Immunohistochemistry; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009119:Muscle Contraction / Q000502:physiology; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism*; D039141:Muscular Dystrophy, Oculopharyngeal / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D039122:Poly(A)-Binding Protein I / Q000235:genetics; D025341:Principal Component Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D039122:Poly(A)-Binding Protein I