Journal article
Knockdown of the E3 ubiquitin ligase UBR5 and its role in skeletal muscle anabolism
American Journal of Physiology: Cell Physiology, Vol.320(1), pp.C45-C56
01/01/2021
DOI: 10.1152/ajpcell.00432.2020
PMID: 33052072
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.
Details
- Title: Subtitle
- Knockdown of the E3 ubiquitin ligase UBR5 and its role in skeletal muscle anabolism
- Creators
- David C. Hughes - Roy J. and Lucille A. Carver College of MedicineDaniel C. Turner - Norwegian School of Sport SciencesLeslie M. Baehr - Roy J. and Lucille A. Carver College of MedicineRobert A. Seaborne - Queen Mary University of LondonMark Viggars - Liverpool John Moores UniversityJonathan C. Jarvis - Liverpool John Moores UniversityPiotr P. Gorski - Norwegian School of Sport SciencesClaire E. Stewart - Liverpool John Moores UniversityDaniel J. Owens - Liverpool John Moores UniversitySue C Bodine - Roy J. and Lucille A. Carver College of MedicineAdam P. Sharples - Norwegian School of Sport Sciences
- Resource Type
- Journal article
- Publication Details
- American Journal of Physiology: Cell Physiology, Vol.320(1), pp.C45-C56
- DOI
- 10.1152/ajpcell.00432.2020
- PMID
- 33052072
- ISSN
- 0363-6143
- eISSN
- 1522-1563
- Grant note
- name: North Staffordshire Medical Institute; name: Doctoral Training Alliance; DOI: 10.13039/100004330, name: GlaxoSmithKline, award: na; DOI: 10.13039/501100000382, name: Society for Endocrinology
- Language
- English
- Date published
- 01/01/2021
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359579802771
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