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Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 to Treat Neuromuscular Diseases in Rodents

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PABPN1-Dependent mRNA Processing Induces Muscle Wasting.

Muhammad Riaz¹, Yotam Raz^1,2, Maaike van Putten¹

¹Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

|May 7, 2016

Summary

Reduced levels of Poly(A) Binding Protein Nuclear 1 (PABPN1) cause muscle wasting by altering gene expression and proteasome function. This finding links PABPN1 to age-related muscle decline and OPMD.

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Area of Science:

Molecular Biology
Muscle Physiology
Genetics

Background:

Poly(A) Binding Protein Nuclear 1 (PABPN1) is crucial for mRNA processing and its levels decrease in aging muscles.
PABPN1 mutations cause oculopharyngeal muscle dystrophy (OPMD), a rare myopathy, and reduced PABPN1 expression correlates with OPMD symptoms.
PABPN1 influences alternative polyadenylation site (PAS) utilization, but its role in cell and tissue function remains unclear.

Purpose of the Study:

To investigate if altered PABPN1 expression levels contribute to muscle wasting.
To understand the impact of PABPN1-mediated alternative PAS utilization on muscle pathology.

Main Methods:

Stable down-regulation of PABPN1 in mouse tibialis anterior (TA) muscles using adeno-associated viruses (AAVs) expressing shRNA against PABPN1 (shPab).
Analysis of muscle pathology, including myofiber atrophy, extracellular matrix changes, and myofiber-type transitions.
Assessment of alternative PAS utilization in the 3'-UTRs of OPMD-dysregulated genes.
Measurement of Atrogin-1 and proteasomal gene expression, proteasomal activity, and MyHC isoform expression.

Main Results:

Mild reduction in PABPN1 levels induced muscle pathology, characterized by myofiber atrophy and extracellular matrix thickening.
Decreased PABPN1 led to reduced distal PAS utilization in specific OPMD-dysregulated genes.
Alternative PAS utilization resulted in increased Atrogin-1 expression and decreased proteasomal gene expression.
Reduced PABPN1 levels impaired proteasomal activity and altered MyHC isoform expression patterns.

Conclusions:

PABPN1-mediated alternative PAS utilization is a key mechanism contributing to aging-associated muscle wasting.
Altered PABPN1 levels and subsequent changes in PAS utilization play a significant role in muscle pathology observed in OPMD and aging.