PABPN1-Dependent mRNA Processing Induces Muscle Wasting

Muhammad Riaz; Yotam Raz; Maaike van Putten; Guillem Paniagua-Soriano; Yvonne D Krom; Bogdan I Florea; Vered Raz

doi:10.1371/journal.pgen.1006031

PABPN1-Dependent mRNA Processing Induces Muscle Wasting

PLoS Genet. 2016 May 6;12(5):e1006031. doi: 10.1371/journal.pgen.1006031. eCollection 2016 May.

Authors

Muhammad Riaz¹, Yotam Raz^{1

2}, Maaike van Putten¹, Guillem Paniagua-Soriano³, Yvonne D Krom⁴, Bogdan I Florea³, Vered Raz¹

Affiliations

¹ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
² Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
³ Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden, The Netherlands.
⁴ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics*
Aging / pathology
Animals
Dependovirus / genetics
Gene Expression Regulation
Humans
Mice
Muscle Proteins / biosynthesis*
Muscle Proteins / genetics
Muscle, Skeletal / metabolism
Muscle, Skeletal / pathology
Muscular Dystrophy, Oculopharyngeal / genetics*
Muscular Dystrophy, Oculopharyngeal / metabolism
Muscular Dystrophy, Oculopharyngeal / pathology
Poly(A)-Binding Protein I / biosynthesis
Poly(A)-Binding Protein I / genetics*
RNA, Messenger / biosynthesis
SKP Cullin F-Box Protein Ligases / biosynthesis*
SKP Cullin F-Box Protein Ligases / genetics

Substances

Muscle Proteins
PABPN1 protein, mouse
Poly(A)-Binding Protein I
RNA, Messenger
Fbxo32 protein, mouse
SKP Cullin F-Box Protein Ligases

Grants and funding

The study is supported by The Prinses Beatrix Spierfonds and by the Association Française Centre les Myopathies (PBF 31122). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.