A decline in PABPN1 induces progressive muscle weakness in Oculopharyngeal muscle dystrophy and in muscle aging

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is caused by trinucleotide repeat expansion mutations in Poly(A) binding protein 1 (PABPN1). PABPN1 is a regulator of mRNA stability and is ubiquitously expressed. Here we investigated how symptoms in OPMD initiate only at midlife and why a subset of skeletal muscles is predominantly affected. Genome-wide RNA expression profiles from Vastus lateralis muscles human carriers of expanded-PABPN1 at pre-symptomatic and symptomatic stages were compared with healthy controls. Major expression changes were found to be associated with age rather than with expression of expanded-PABPN1, instead transcriptomes of OPMD and elderly muscles were significantly similar (P<0.05). Using k-means clustering we identified age-dependent trends in both OPMD and controls, but trends were often accelerated in OPMD. We report an age-regulated decline in PABPN1 levels in Vastus lateralis muscles from the fifth decade. In concurrence with severe muscle degeneration in OPMD, the decline in PABPN1 accelerated in OPMD and was specific to skeletal muscles. Reduced PABPN1 levels (30% to 60%) in muscle cells induced myogenic defects and morphological signatures of cellular aging in proportion to PABPN1 expression levels. We suggest that PABPN1 levels regulate muscle cell aging and OPMD represents an accelerated muscle aging disorder.

Proteasomal activity‐based probes mark protein homeostasis in muscles

“…We then assessed LWA300 fluorescence in adherent and fused C2C12 cell cultures using the Cellomics imaging system. In previous studies, we demonstrated that this imaging system is highly suitable for high‐throughput of fused muscle cell cultures 24, 30. In agreement with the flow cytometry experiments, also with the Cellomics, we measured the reduced LWA300 signal by Epox pre‐incubation (Figure 4D–4E).…”

Regulated Intron Retention and Nuclear Pre-mRNA Decay Contribute to PABPN1 Autoregulation

“…S1 in the supplemental material). However, it remains possible that the negative autoregulatory loop described in this study becomes sufficiently impaired during the 30-to 50-year period needed to develop the first OPMD symptoms to account for the altered levels of PABPN1 mRNA expressed from OPMD alleles (13,14), potentially resulting in the accumulation of aberrant PABPN1 protein.…”

“…Conversely, studies also have shown that overexpression of Pab2, the yeast homolog of PABPN1, results in growth inhibition in Schizosaccharomyces pombe (45), while the muscle-specific overexpression of wild-type mammalian PABPN1 in Drosophila results in muscle defects (46). In oculopharyngeal muscular dystrophy (OPMD), mutations in the PABPN1 coding sequence affect mRNA levels (13,14). Thus, the autoregulatory mechanism disclosed in this study supports the idea that PABPN1 expression needs to be strictly controlled for normal cell physiology.…”

“…OPMD mutations have been reported in more than 35 countries (11) and result in a PABPN1 protein with a slightly extended polyalanine tract, a consequence of short trinucleotide expansions in the PABPN1 coding sequence (12). Although the mechanism by which short GCG insertions in the PABPN1 gene cause OPMD remains unknown, altered PABPN1 mRNA levels were found in muscle biopsy specimens of OPMD patients relative to those of age-matched controls (13,14). In addition, reduced expression of PABPN1 mRNA correlates with a poor prognosis in non-smallcell lung cancer (15).…”

Current targeted therapeutic strategies for oculopharyngeal muscular dystrophy: from pharmacological to RNA replacement and gene editing therapies

“…Proposed mechanisms include sequestration of cellular factors by the mutant protein [14,15], defects in the potential clearance pathway (i.e. chaperones, and ubiquitin-proteasome pathway UPP) [14,15], alterations in transcription, histone acetylation alteration [16], aging-associated factors [17], Wnt pathway perturbation [18], and aberrant protein-protein interactions [19]. The toxic gain-of-function mechanism of OPMD supports the hypothesis that disease onset and progression is dependent upon the expansion of the polyalanine tract.…”