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.
Highlights
The landscape of mRNA in eukaryotic cells is partly maintained by mRNA processing at the 3’-UTR of transcripts [1]. mRNA processing is regulated by multiple RNA binding proteins, including poly(A) binding protein nuclear 1 (PABPN1), a regulator of poly-A tail length [2], mRNA decay [3] and proximal polyadenylation site (PAS) utilization at the 3’-UTR [4, 5]
PABPN1 is a multifunctional regulator of mRNA processing and its levels are reduced in skeletal muscles from midlife onwards
We show that PABPN1-regulated muscle atrophy is regulated, in part, by up regulation of Atrogin1 and reduced expression of proteasome genes via an alternative polyadenylation site utilization
Summary
The landscape of mRNA in eukaryotic cells is partly maintained by mRNA processing at the 3’-UTR of transcripts [1]. mRNA processing is regulated by multiple RNA binding proteins, including poly(A) binding protein nuclear 1 (PABPN1), a regulator of poly-A tail length [2], mRNA decay [3] and proximal polyadenylation site (PAS) utilization at the 3’-UTR [4, 5]. Expanded PABPN1 forms intranuclear aggregates [7] entrapping additional nuclear proteins [8]. Whether these aggregates are toxic in physiological conditions is unsettled. Despite the ubiquitous expression of PABPN1, in OPMD symptoms manifest predominantly in skeletal muscles from mid-life onwards [10]. PABPN1 expression levels in skeletal muscles are lower compared to other tissues [11]. As symptoms in OPMD predominantly affect skeletal muscles, others and we suggested that in muscles of OPMD patients PABPN1 levels decline below a critical threshold leading to molecular aberrations and cellular defects [12, 13]. Whether reduced PABPN1 levels leads to muscle pathology is not resolved yet
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
