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Transcriptome of tibialis anterior muscle RNA samples from control and OPMD A17.1 mouse treated or not with a gene therapy approach

ABSTRACT: Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by short GCN repeat expansions within the gene encoding the nuclear poly(A)-binding protein 1 (PABPN1) that extend an N-terminal polyalanine tract in the protein. Mutant PABPN1 aggregates as nuclear inclusions in OMPD patient muscles. We have used the transgenic mouse A17.1 OPMD model that recapitulates the features of the human disorder: progressive muscle weakness, atrophy and formation of PABPN1 nuclear inclusions. Wild-type human PABPN1 contains a stretch of 10 alanines following the initial methionine, which is expanded to 11–18 alanines in OPMD patients. Transgenic A17.1 mouse overexpress an 17 alanine expanded PABPN1 under the control of the HSA promoter. To evaluate a gene therapy approach based on AAV delivery of a ‘suppress and replace’ strategy in OPMD we performed a transcriptomic analysis in treated muscles 18 weeks after injection. Using microarrays, tibialis anterior gene expression was compared between control muscles (FvB), OPMD muscles (A17), AAV-shRNA3x treated muscles (A17 shRNA3X), AAVoptPABPN1 treated muscles (A17 optPABPN1), and AAV-shRNA3x+AAV-optPABPN1 treated muscles (A17 dual).

ORGANISM(S): Mus musculus

PROVIDER: GSE89996 | GEO | 2017/06/12

SECONDARY ACCESSION(S): PRJNA354316

REPOSITORIES: GEO

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Project description: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. A17.1 transgenic mice have previously been described. Male A17.1 mice and WT controls were generated by crossing the heterozygous carrier strain A17.1 obtained from Rubinsztein's group with the FvB background mice. The mice were genotyped by PCR 3–4 weeks after birth. Wild type FvB and A17.1 mice were housed in minimal disease facilities (Royal Holloway, University of London) with food and water ad libitum. Total RNA was extracted from skeletal muscles using RNA Bee (Amsbio) according to the manufacturer's instructions. RNA integration number (RIN) was determined with RNA 6000 Nano (Agilent Technologies). RNA with RIN >7 were used for subsequent steps. RNA labelling was performed with the Illumina® TotalPrep RNA Amplification kit (Ambion) according to the manufacturer's protocol, and subsequently was hybridized to Illumina Mouse v1.1 Bead arrays.

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Transcriptome of tibialis anterior muscle RNA samples from control and OPMD A17.1 mouse treated or not with a gene therapy approach

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