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Research Paper|Volume 5, Issue 6|pp 412—426

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

Seyed Yahya Anvar1, Yotam Raz2, Nisha Verwey1, Barbara van der Sluijs4, Andrea Venema1, Jelle J Goeman3, John Vissing6, Silvère M van der Maarel1, Peter A.C. ‘t Hoen1, Baziel G.M. van Engelen4, Vered Raz1
  • 1Center for Human and Clinical Genetics, Leiden University Medical Center, the Netherlands
  • 2Department of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands
  • 3Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, the Netherlands
  • 4Department of Neurology, Radboud University Nijmegen Medical Center, the Netherlands
  • 5Department of Anaesthesia, Canisius-Wilhelmina Hospital, Nijmegen, the Netherlands
  • 6Neuromuscular Research Unit and Department of Neurology, Rigshospitalet Copenhagen, Denmark

* * Equal contribution

Received: May 21, 2013Accepted: June 14, 2013Published: June 16, 2013
https://doi.org/10.18632/aging.100567

Copyright: © 2013 Anvar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.