Seaborne, RA, Hughes, DC, Turner, DC, Owens, DJ, Baehr, LM, Gorski, P, Semenova, EA, Borisov, OV, Larin, AK, Popov, DV, Generozov, EV, Sutherland, H, Ahmetov, II, Jarvis, JC, Bodine, SC and Sharples, AP (2019) UBR5 is a novel E3 ubiquitin ligase involved in skeletal muscle hypertrophy and recovery from atrophy. The Journal of Physiology, 597 (14). pp. 3727-3749. ISSN 1469-7793

[thumbnail of Accepted ONLINE VERSION- JP278073.pdf]
Accepted ONLINE VERSION- JP278073.pdf - Accepted Version
Available under License Creative Commons Attribution Non-commercial.

Download (2MB) | Preview


We aimed to investigate a novel and uncharacterised E3 ubiquitin ligase in skeletal muscle atrophy, recovery from atrophy/injury, anabolism and hypertrophy. We demonstrated an alternate gene expression profile for UBR5 versus well characterised E3-ligases, MuRF1/MAFbx, where after atrophy evoked by continuous-low-frequency electrical-stimulation in rats, MuRF1/MAFbx were both elevated yet UBR5 was unchanged. Furthermore, after recovery of muscle mass post tetrodotoxin (TTX) induced-atrophy in rats, UBR5 was hypomethylated and increased at the gene expression level, while a suppression of MuRF1/MAFbx was observed. At the protein level, we also demonstrated a significant increase in UBR5 after recovery of muscle mass from hindlimb unloading in both adult and aged rats, and after recovery from atrophy evoked by nerve crush injury in mice. During anabolism and hypertrophy, UBR5 gene expression increased following acute loading in three-dimensional bioengineered mouse muscle in-vitro, and after chronic electrical-stimulation-induced hypertrophy in rats in-vivo, without increases in MuRF1/MAFbx. Additionally, UBR5 protein abundance increased following functional overload-induced hypertrophy of the plantaris muscle in mice and during differentiation of primary human muscle cells. Finally, in humans, genetic association studies (>700,000 SNPs) demonstrated that the A alleles of rs10505025 and rs4734621 SNPs in the UBR5 gene were strongly associated with larger cross-sectional area of fast-twitch muscle fibres and favoured strength/power versus endurance/untrained phenotypes. Overall, we suggest that UBR5 is a novel E3 ubiquitin ligase that is inversely regulated to MuRF1/MAFbx, is epigenetically regulated, and is elevated at both the gene expression and protein level during recovery from skeletal muscle atrophy and hypertrophy. This article is protected by copyright. All rights reserved.

Item Type: Article
Additional Information: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Wiley at - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: skeletal muscle, atrophy, recovery
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Related URLs:
Depositing User: Symplectic
Date Deposited: 06 Jun 2019 09:37
Last Modified: 15 May 2020 01:30

Actions (login required)

View Item
View Item