RT Journal Article SR Electronic T1 UBR5 is a Novel E3 Ubiquitin Ligase involved in Skeletal Muscle Hypertrophy and Recovery from Atrophy JF bioRxiv FD Cold Spring Harbor Laboratory SP 592980 DO 10.1101/592980 A1 RA Seaborne A1 DC Hughes A1 DC Turner A1 DJ Owens A1 LM Baehr A1 P Gorski A1 EA Semenova A1 OV Borisov A1 AK Larin A1 DV Popov A1 EV Generozov A1 H Sutherland A1 II Ahmetov A1 JC Jarvis A1 SC Bodine A1 AP Sharples YR 2019 UL http://biorxiv.org/content/early/2019/03/30/592980.abstract AB 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.