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PABPN1-Dependent mRNA Processing Induces Muscle Wasting

Muhammad Riaz1, Yotam Raz1,2, Maaike van Putten1

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

Plos Genetics
|May 7, 2016
PubMed

Insights

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.

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.

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