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Deacetylation Inhibition Reverses PABPN1-Dependent Muscle Wasting

48 Pages Posted: 29 Jan 2019 Sneak Peek Status: Published

See all articles by Cyriel S. Olie

Cyriel S. Olie

Leiden University - Department of Human Genetics

Muhammad Riaz

Leiden University - Department of Human Genetics

Rebecca Konietzny

University of Oxford - Target Discovery Institute

Philip D. Charles

University of Oxford - Target Discovery Institute

Adan Pinto-Fernandez

University of Oxford - Target Discovery Institute

Szymon M. Kiełbasa

Leiden University - Department of Medical Statistics and Bioinformatics

A. Aartsma-Rus

Leiden University - Department of Human Genetics

Benedikt M. Kessler

University of Oxford - Target Discovery Institute

Vered Raz

Leiden University - Department of Human Genetics

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Abstract

Reduced PABPN1 levels cause aging-associated muscle wasting. PABPN1 is a multi-functional regulator of mRNA processing. To elucidate the molecular mechanisms causing PABPN1-mediated muscle wasting, we compared the transcriptome to the proteome in mouse muscles expressing shRNA to PABPN1 (shPab). We found greater variations in the proteome as compared to mRNA expression profiles. Protein accumulation in the shPab proteome was concomitant with reduced proteasomal activity. Notably, protein acetylation appeared to be enriched in shPab versus control proteomes (63%). An acetylome study in shPab muscles revealed prominent peptide deacetylation associated with elevated sirtuin-1 (SIRT1) deacetylase. We show that SIRT1 mRNA levels are controlled by PABPN1 via an alternative polyadenylation site utilization. SIRT1 inhibition reversed PABPN1 activity and muscle cell function. Moreover, deacetylation inhibition increased PABPN1 levels and reversed muscle wasting. We suggest that perturbation of a multifactorial regulatory loop involving PABPN1 and SIRT1 plays an imperative role in aging-associated muscle wasting.

Suggested Citation

Olie, Cyriel S. and Riaz, Muhammad and Konietzny, Rebecca and Charles, Philip D. and Pinto-Fernandez, Adan and Kiełbasa, Szymon M. and Aartsma-Rus, A. and Kessler, Benedikt M. and Raz, Vered, Deacetylation Inhibition Reverses PABPN1-Dependent Muscle Wasting (September 6, 2018). Available at SSRN: https://ssrn.com/abstract=3245221 or http://dx.doi.org/10.2139/ssrn.3245221
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Cyriel S. Olie

Leiden University - Department of Human Genetics

Postbus 9500
Leiden, 2300 RA
Netherlands

Muhammad Riaz

Leiden University - Department of Human Genetics

Postbus 9500
Leiden, 2300 RA
Netherlands

Rebecca Konietzny

University of Oxford - Target Discovery Institute

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Philip D. Charles

University of Oxford - Target Discovery Institute

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Adan Pinto-Fernandez

University of Oxford - Target Discovery Institute

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Szymon M. Kiełbasa

Leiden University - Department of Medical Statistics and Bioinformatics

Leiden
Netherlands

A. Aartsma-Rus

Leiden University - Department of Human Genetics

Postbus 9500
Leiden, 2300 RA
Netherlands

Benedikt M. Kessler

University of Oxford - Target Discovery Institute

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Vered Raz (Contact Author)

Leiden University - Department of Human Genetics ( email )

Postbus 9500
Leiden, 2300 RA
Netherlands

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