Histopathology of the tongue in a mouse model of oculopharyngeal muscular dystrophy reveals progressive PABPN1 deposition associated with muscle wasting.
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PROVIDER: PRJNA1097542 | ENA |
REPOSITORIES: ENA
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Project description: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.
2024-12-04 | GSE263433 | GEO
Project description:Reduced PABPN1 levels cause aging-associated muscle wasting. PABPN1 is a multi-functional regulator of mRNA processing. To elucidate the molecular mechanisms causing PABPN1-mediated muscle wasting, we compared the transcriptome to the proteome in mouse muscles expressing shRNA to PABPN1 (shPab). We found greater variations in the proteome as compared to mRNA expression profiles. Protein accumulation in the shPab proteome was concomitant with reduced proteasomal activity. Notably, protein acetylation appeared to be enriched in shPab versus control proteomes (63%). An acetylome study in shPab muscles revealed prominent peptide deacetylation associated with elevated sirtuin-1 (SIRT1) deacetylase. We show that SIRT1 mRNA levels are controlled by PABPN1 via an alternative polyadenylation site utilization. SIRT1 inhibition reversed PABPN1 activity and muscle cell function. Moreover, deacetylation inhibition increased PABPN1 levels and reversed muscle wasting. We suggest that perturbation of a multifactorial regulatory loop involving PABPN1 and SIRT1 plays an imperative role in aging-associated muscle wasting.
2022-02-28 | PXD011534 | Pride
Project description:Poly(A) binding protein nuclear 1 (PABPN1) is a multifunctional regulator of mRNA processing. PABPN1 inhibits alternative polyadenylation (APA), and in conditions with reduced PABPN1 levels APA utilization causes genome-wide mRNA dysregulation. PABPN1 levels decline from midlife onwards in Oculopharyngeal Muscular Dystrophy (OPMD) and in aged muscles. Reduced PABPN1 levels cause muscle atrophy by altering mRNA levels of the ubiquitin proteasome system. The effect of PABPN1-mediated APA utilization on the proteome has not been investigated yet. We report the PABPN1-mediated proteome in Tibialis anterior (TA) mouse muscles, signifying functional impact for the mitochondria, cytoskeleton and translation cellular machineries. Central nucleation and split myofibers marked PABPN1-derived muscle histology. We show that up-regulation of the cytoskeletal proteins: Murc, Pfn1 and Csrp3, is highly associated with PABPN1-mediated muscle pathology and with reduced PABPN1 levels. Elevation of PABPN1 levels by sirtinol treatment reversed muscle pathology and restored levels of those cytoskeletal proteins. We suggest that restoration of PABPN1 levels in aged muscles could be a novel therapeutic strategy to mitigate muscle waste.
2020-07-06 | PXD004865 | Pride
Project description:Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment.
| S-EPMC5380963 | biostudies-literature
Project description:Purpose: Muscle wasting (or atrophy) occurs in primary neuromuscular diseases and during aging, with sarcopenia affecting 35.4% and 75.5% of women and man over 60 years of age. Mitochondrial dysfunction is proposed to contribute to muscle wasting. Here, we show that chronic adaptation to mitochondrial Precursor Over-accumulation Stress (mPOS) causes muscle wasting. mPOS is a newly discovered cell stress mechanism caused by the saturation or damage of the mitochondrial protein import machinery, which consequently leads to the toxic accumulation of precursor proteins in the cytosol. Methods: We generated transgenic mice with a two-fold increase of Ant1, an adenine nucleotide translocase involved in ATP/ADP exchange on the inner mitochondrial membrane (IMM). We found that these animals progressively lose muscle mass. At two years of age, the skeletal muscle becomes barely quantifiable, without affecting the overall lifespan. We then performed whole-transcriptome RNA-sequencing on skeletal muscle samples of male and female mice at 6 months of age. Results: After alignment and quantification, we show that the ANT1-transgenic muscles have a drastically remodeled transcriptome that represses protein synthesis, and stimulates proteasomal function, autophagy, lysosomal amplification and Gadd45a-signaling. These four processes are all known to promote muscle wasting. Conclusions: These results suggest that chronic proteostatic adaptation to mPOS is a robust mechanism of muscle wasting, and it leads to or depends in part on a robust set of transcriptional adaptations. This finding may help the understanding of how mitochondria contribute to muscle wasting during aging. It may also have implications for diseases that are associated with ANT1 overexpression.
2019-08-09 | GSE135584 | GEO
Project description:ObjectiveOculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant adult-onset disease characterized by progressive ptosis, dysphagia, and proximal limb weakness. The genetic cause is an expanded (GCN)n mutation in the PABPN1 gene encoding for the polyadenylate-binding protein nuclear 1. We hypothesized a potential correlation between the size of the (GCN)n expansion and the severity of the phenotype. To do this, we characterized the distribution of the genotypes as well as their correlation with age at diagnosis and phenotypical features in a large cohort of heterozygous and homozygous patients with OPMD in France with a confirmed molecular diagnosis of PABPN1.MethodsWe explored 354 unrelated index cases recruited between 1999 and 2014 in several neuromuscular centers in France.ResultsThis cohort allowed us to characterize the frequency of mutated alleles in the French population and to demonstrate a statistical correlation between the size of the expansion and the mean age at diagnosis. We also confirmed that homozygous patients present with a more severe disease.ConclusionsIt has been difficult to establish phenotype-genotype correlations because of the rare nature of this disease. Our work demonstrates that patients with OPMD with longer PABPN1 expansion are on average diagnosed at an earlier age than patients with a shorter expansion, confirming that polyalanine expansion size plays a role in OPMD, with an effect on disease severity and progression.
| S-EPMC5272966 | biostudies-literature
Project description:Alternative polyadenylation (APA) at the 3' UTR of transcripts contributes to the cell transcriptome. APA is suppressed by the nuclear RNA-binding protein PABPN1. Aging-associated reduced PABPN1 levels in skeletal muscles lead to muscle wasting. Muscle weakness in oculopharyngeal muscular dystrophy (OPMD) is caused by short alanine expansion in PABPN1 exon1. The expanded PABPN1 forms nuclear aggregates, an OPMD hallmark. Whether the expanded PABPN1 affects APA and how it contributes to muscle pathology is unresolved. To investigate these questions, we developed a procedure including RNA library preparation and a simple pipeline calculating the APA-shift ratio as a readout for PABPN1 activity. Comparing APA-shift results to previously published PAS utilization and APA-shift results, we validated this procedure. The procedure was then applied on the OPMD cell model and on RNA from OPMD muscles. APA-shift was genome-wide in the mouse OPMD model, primarily affecting muscle transcripts. In OPMD individuals, APA-shift was enriched with muscle transcripts. In an OPMD cell model APA-shift was not significant. APA-shift correlated with reduced expression levels of a subset of PABPN1 isoforms, whereas the expression of the expanded PABPN1 did not correlate with APA-shift. PABPN1 activity is not affected by the expression of expanded PABPN1, but rather by reduced PABPN1 expression levels. In muscles, PABPN1 activity initially affects muscle transcripts. We suggest that muscle weakness in OPMD is caused by PABPN1 loss-of-function leading to APA-shift that primarily affects in muscle transcripts.
| S-EPMC10840355 | biostudies-literature
Project description:The effect of PABPN1 on translation efficiency was assessed using RNA sequencing of polysomal fractions from muscle cells: parental vs. cells with stable PABPN1 down-regulation (shPAB). The library was constructed after rRNA depletion, allowing to investigate the abundance of different RNA biotypes.
2022-05-17 | GSE165609 | GEO
Project description:Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of particular muscles. OPMD is caused by short GCG 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 created a Drosophila model of OPMD that recapitulates the features of the human disorder: progressive muscle degeneration, with muscle defects proportional to the number of alanines in the tract, and formation of PABPN1 nuclear inclusions. Wild-type human PABPN1 contains a stretch of 10 alanines following the initial methionine, which is expanded to 12–17 alanines in OPMD patients. In Drosophila, the PABPN1 homolog is the poly(A)-binding protein 2 (PABP2), which has the same function as PABPN1 in nuclear polyadenylation but lacks a polyalanine tract at the N-terminus. We used the UAS/Gal4 system to express mammalian PABPN1 in Drosophila. An alanine-expanded PABPN1 cDNA (encoding the 17 alanine tract) was cloned downstream of UAS sequences (UAS-PABPN1). Transgenic lines containing this construct were crossed to a Mhc-Gal4 driver, leading to muscle-specific expression. To gain insight into the molecular and physiological defects in OPMD we performed a transcriptomic analysis in OPMD fly muscles. Using microarrays, thorax gene expression was compared between control flies (Mhc-Gal4/+) and flies expressing PABPN1-17ala in thoracic muscles (UAS-PABPN1-17ala/+; Mhc-Gal4/+), at three time points (days 2, 6 and 11). Transcriptome of thorax RNA samples from control (Mhc-Gal4/+) flies and flies expressing PABPN1-17ala (UAS-PABPN1-17ala/+; Mhc-Gal4/+)
2014-12-12 | GSE64094 | GEO
Project description:Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of particular muscles. OPMD is caused by short GCG 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 created a Drosophila model of OPMD that recapitulates the features of the human disorder: progressive muscle degeneration, with muscle defects proportional to the number of alanines in the tract, and formation of PABPN1 nuclear inclusions. Strikingly, the polyalanine tract is not absolutely required for muscle degeneration, whereas another domain of PABPN1, the RNA-binding domain and its function in RNA binding are required. This demonstrates that OPMD does not result from polyalanine toxicity, but from an intrinsic property of PABPN1. We also identify several suppressors of the OPMD phenotype. This establishes our OPMD Drosophila model as a powerful in vivo test to understand the disease process and develop novel therapeutic strategies.
| S-EPMC1462976 | biostudies-literature