title: PABPN1-Dependent mRNA Processing Induces Muscle Wasting.
abstract: Poly(A) Binding Protein Nuclear 1 (PABPN1) is a multifunctional regulator of mRNA processing, and its expression levels specifically decline in aging muscles. An expansion mutation in PABPN1 is the genetic cause of oculopharyngeal muscle dystrophy (OPMD), a late onset and rare myopathy. Moreover, reduced PABPN1 expression correlates with symptom manifestation in OPMD. PABPN1 regulates alternative polyadenylation site (PAS) utilization. However, the impact of PAS utilization on cell and tissue function is poorly understood. We hypothesized that altered PABPN1 expression levels is an underlying cause of muscle wasting. To test this, we stably down-regulated PABPN1 in mouse tibialis anterior (TA) muscles by localized injection of adeno-associated viruses expressing shRNA to PABPN1 (shPab). We found that a mild reduction in PABPN1 levels causes muscle pathology including myofiber atrophy, thickening of extracellular matrix and myofiber-type transition. Moreover, reduced PABPN1 levels caused a consistent decline in distal PAS utilization in the 3'-UTR of a subset of OPMD-dysregulated genes. This alternative PAS utilization led to up-regulation of Atrogin-1, a key muscle atrophy regulator, but down regulation of proteasomal genes. Additionally reduced PABPN1 levels caused a reduction in proteasomal activity, and transition in MyHC isotope expression pattern in myofibers. We suggest that PABPN1-mediated alternative PAS utilization plays a central role in aging-associated muscle wasting.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Muhammad
authors.identifier: 0000-0003-0702-5158
authors.initials: M
authors.lastname: Riaz
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Raz
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: van Putten
authors.affiliation: Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden, The Netherlands.
authors.forename: Guillem
authors.initials: G
authors.lastname: Paniagua-Soriano
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yvonne D
authors.initials: YD
authors.lastname: Krom
authors.affiliation: Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden, The Netherlands.
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Florea
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vered
authors.initials: V
authors.lastname: Raz
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D039122:Poly(A)-Binding Protein I / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D009124:Muscle Proteins; C000608101:PABPN1 protein, mouse; D039122:Poly(A)-Binding Protein I; D012333:RNA, Messenger; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases