PABPN1-Dependent mRNA Processing Induces Muscle Wasting

• Published in: PLoS genetics Vol. 12; no. 5; p. e1006031
• Main Authors: Riaz, Muhammad, Raz, Yotam, van Putten, Maaike, Paniagua-Soriano, Guillem, Krom, Yvonne D, Florea, Bogdan I, Raz, Vered
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.05.2016; Public Library of Science (PLoS)
• Subjects: Aging; Aging - genetics; Aging - pathology; Animals; Biology and Life Sciences; Cell culture; Dependovirus - genetics; Experiments; Gene expression; Gene Expression Regulation; Genetic aspects; Humans; Medicine and Health Sciences; Messenger RNA; Methods; Mice; Muscle cells; Muscle Proteins - biosynthesis; Muscle Proteins - genetics; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Dystrophy, Oculopharyngeal - genetics; Muscular Dystrophy, Oculopharyngeal - metabolism; Muscular Dystrophy, Oculopharyngeal - pathology; Mutation; Pathology; Physiological aspects; Poly(A)-Binding Protein I - biosynthesis; Poly(A)-Binding Protein I - genetics; Proteins; Research and Analysis Methods; RNA sequencing; RNA, Messenger - biosynthesis; SKP Cullin F-Box Protein Ligases - biosynthesis; SKP Cullin F-Box Protein Ligases - genetics
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006031

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.