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Histopathology of the tongue in a mouse model of oculopharyngeal muscular dystrophy reveals progressive PABPN1 deposition associated with muscle wasting.

ABSTRACT: The tongue facilitates vital activities such as swallowing. Swallowing difficulties (dysphagia) are common in the elderly and in many adult-onset neuromuscular diseases. In oculopharyngeal muscular dystrophy (OPMD), dysphagia is often the first symptom. OPMD is an autosomal dominant myopathy caused by a trinucleotide expansion mutation in the gene encoding PABPN1. The expanded PABPN1 forms insoluble nuclear aggregates that reduce the levels of the soluble form. Clinical tongue involvement in OPMD has been documented but is poorly understood. Tongue histopathology was investigated in OPMD mouse models using light and electron microscopy. Muscle histopathology was predominantly affected by age. PABPN1 nuclear aggregates were found at moderate levels, whereas deposition of insoluble PABPN1 in blood vessels was already prominent in 4-month-old mice. RNA signatures of the OPMD tongue were enriched for mitochondrial and cytoskeletal genes, suggesting an energy and contractile deficit.

ORGANISM(S): Mus musculus

PROVIDER: GSE263433 | GEO | 2024/12/04

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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Histopathology of the tongue in a mouse model of oculopharyngeal muscular dystrophy reveals progressive PABPN1 deposition associated with muscle wasting.

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