title: 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.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, the Netherlands.
authors.forename: Seyed Yahya
authors.initials: SY
authors.lastname: Anvar
authors.forename: Yotam
authors.initials: Y
authors.lastname: Raz
authors.forename: Nisha
authors.initials: N
authors.lastname: Verway
authors.forename: Barbara
authors.initials: B
authors.lastname: van der Sluijs
authors.forename: Andrea
authors.initials: A
authors.lastname: Venema
authors.forename: Jelle J
authors.initials: JJ
authors.lastname: Goeman
authors.forename: John
authors.initials: J
authors.lastname: Vissing
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.forename: Vered
authors.initials: V
authors.lastname: Raz
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D000818:Animals; D016022:Case-Control Studies; D016922:Cellular Senescence; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D008875:Middle Aged; D018908:Muscle Weakness / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics / Q000378:metabolism*; D039122:Poly(A)-Binding Protein I / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D055815:Young Adult
chemical_list: C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; D012333:RNA, Messenger