Knockdown of the E3 ubiquitin ligase UBR5 and its role in skeletal muscle anabolism

Author:

Hughes David C.1ORCID,Turner Daniel C.234,Baehr Leslie M.1ORCID,Seaborne Robert A.45,Viggars Mark4,Jarvis Jonathan C.4ORCID,Gorski Piotr P.23,Stewart Claire E.4,Owens Daniel J.4,Bodine Sue C.1ORCID,Sharples Adam P.234ORCID

Affiliation:

1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa

2. Norwegian School of Sport Sciences (NiH), Institute for Physical Performance, Oslo, Norway

3. School of Pharmacy and Bioengineering, Institute for Science & Technology in Medicine (ISTM), Keele University, Staffordshire, United Kingdom

4. Stem Cells, Ageing and Molecular Physiology Unit (SCAMP), Research Institute for Sport & Exercise Sciences (RISES), Liverpool John Moores University, Liverpool, United Kingdom

5. Centre for Genomics and Child Health, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

Abstract

UBR5 is an E3 ubiquitin ligase positively associated with anabolism, hypertrophy, and recovery from atrophy in skeletal muscle. The precise mechanisms underpinning UBR5’s role in the regulation of skeletal muscle mass remain unknown. The present study aimed to elucidate these mechanisms by silencing the UBR5 gene in vivo. To achieve this aim, we electroporated a UBR5-RNAi plasmid into mouse tibialis anterior muscle to investigate the impact of reduced UBR5 on anabolic signaling MEK/ERK/p90RSK and Akt/GSK3β/p70S6K/4E-BP1/rpS6 pathways. Seven days after UBR5 RNAi electroporation, although reductions in overall muscle mass were not detected, the mean cross-sectional area (CSA) of green fluorescent protein (GFP)-positive fibers were reduced (−9.5%) and the number of large fibers were lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis, ERK1/2, Akt, and GSK3β activity. Although p90RSK phosphorylation significantly increased, total p90RSK protein levels demonstrated a 45% reduction with UBR5-RNAi. Finally, these early events after 7 days of UBR5 knockdown culminated in significant reductions in muscle mass (−4.6%) and larger reductions in fiber CSA (−18.5%) after 30 days. This was associated with increased levels of phosphatase PP2Ac and inappropriate chronic elevation of p70S6K and rpS6 between 7 and 30 days, as well as corresponding reductions in eIF4e. This study demonstrates that UBR5 plays an important role in anabolism/hypertrophy, whereby knockdown of UBR5 culminates in skeletal muscle atrophy.

Funder

North Staffordshire Medical Institute

Doctoral Training Alliance

GlaxoSmithKline

Society for Endocrinology

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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