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.
Highlights
Protein aggregation is a pathological hallmark in a large spectrum of late-onset neurodegenerative disorders
This suggests that the levels of soluble Poly(A) binding protein 1 (PABPN1) rather than a gain-of function of mutant PABPN1 affects muscle cell function
We found a natural decrease in PABPN1 mRNA levels in Vastus lateralis (VL) muscles starting from the fifth decade onwards and progresses more rapid in Oculopharyngeal muscular dystrophy (OPMD) patients compared with controls
Summary
Protein aggregation is a pathological hallmark in a large spectrum of late-onset neurodegenerative disorders. Single amino acid repeat expansions are among the common genetic cause of those disorders [1]. These disorders are recognized by the presence of saltresistant insoluble bodies, resulting from accumulation of the expanded mutant proteins. The presence of disease-associated protein aggregation is often an indication of failure of cellular processes maintaining protein homeostasis [3]. Despite their evident occurrence in late-onset neurodegenerative disorders, a pathogenic role of these aggregates remains controversial [4]
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