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

Hughes, D, Turner, DC, Baehr, LM, Seaborne, RA, Viggars, M, Jarvis, JC, Gorski, P, Stewart, CE, Owens, DJ, Bodine, S and Sharples, AP (2021) Knockdown of the E3 Ubiquitin ligase UBR5 and its role in skeletal muscle anabolism. American Journal of Physiology: Cell Physiology, 320 (1). C45-C56. ISSN 0363-6143

UBR5 silencing paper-AJP Cell_R1_Final CLEAN.pdf - Accepted Version

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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 remains 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 mechanotransduction signalling MEK/ERK/p90RSK and Akt/GSK3β/p70S6K/4E-BP1/rpS6 pathways. Seven days post UBR5 RNAi electroporation, while reductions in overall muscle mass were not detected, mean CSA of GFP-positive fibers was reduced (-9.5%) and the number of large fibers was lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis, ERK1/2, Akt and GSK3β activity. Whilst 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 the phosphatase PP2Ac, and inappropriate chronic elevation of p70S6K and rpS6 between 7 and 30 days, and corresponding reductions in eIF4e. This study demonstrates UBR5 plays an important role in anabolism/hypertrophy, whereby knockdown of UBR5 culminatesin skeletal muscle atrophy.

Item Type: Article
Uncontrolled Keywords: 0601 Biochemistry and Cell Biology, 0606 Physiology, 1116 Medical Physiology
Subjects: Q Science > QM Human anatomy
Q Science > QP Physiology
R Medicine > RC Internal medicine > RC1200 Sports Medicine
R Medicine > RM Therapeutics. Pharmacology
Divisions: Sport & Exercise Sciences
Publisher: American Physiological Society
Date Deposited: 09 Oct 2020 10:01
Last Modified: 01 Jan 2022 00:50
DOI or ID number: 10.1152/ajpcell.00432.2020
URI: https://researchonline.ljmu.ac.uk/id/eprint/13814
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