The E3 Ubiquitin Ligase TRAF6 Intercedes in Starvation-Induced Skeletal Muscle Atrophy through Multiple Mechanisms

AbstractWe 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.Key PointsWe have recently identified that a HECT domain E3 ubiquitin ligase, named UBR5, is altered epigenetically (via DNA methylation) after human skeletal muscle hypertrophy, where its gene expression is positively correlated with increasing lean leg mass after training and retraining.In the present study we extensively investigate this novel and uncharacterised E3 ubiquitin ligase (UBR5) in skeletal muscle atrophy, recovery from atrophy and injury, anabolism and hypertrophy.We demonstrated that UBR5 was epigenetically via altered DNA methylation during recovery from atrophy.We also determined that UBR5 was alternatively regulated versus well characterised E3 ligases, MuRF1/MAFbx, at the gene expression level during atrophy, recovery from atrophy and hypertrophy.UBR5 also increased at the protein level during recovery from atrophy and injury, hypertrophy and during human muscle cell differentiation.Finally, in humans, genetic variations of the UBR5 gene were strongly associated with larger fast-twitch muscle fibres and strength/power performance versus endurance/untrained phenotypes.

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The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy

Critical Care ◽

10.1186/s13054-014-0545-6 ◽

2014 ◽

Vol 18 (5) ◽

Cited By ~ 13

Author(s):

Franziska Schmidt ◽

Melanie Kny ◽

Xiaoxi Zhu ◽

Tobias Wollersheim ◽

Kathleen Persicke ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Skeletal Muscle Atrophy

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Faculty Opinions recommendation of Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1019081.218528 ◽

2004 ◽

Author(s):

Nadia Rosenthal

Keyword(s):

Skeletal Muscle ◽

Transcription Factors ◽

Muscle Atrophy ◽

Ubiquitin Ligase ◽

Skeletal Muscle Atrophy ◽

Foxo Transcription Factors

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

AJP Cell Physiology ◽

10.1152/ajpcell.00432.2020 ◽

2021 ◽

Vol 320 (1) ◽

pp. C45-C56

Author(s):

David C. Hughes ◽

Daniel C. Turner ◽

Leslie M. Baehr ◽

Robert A. Seaborne ◽

Mark Viggars ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Ubiquitin Ligase ◽

Fluorescent Protein ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Tibialis Anterior Muscle ◽

E3 Ubiquitin Ligase ◽

Skeletal Muscle Atrophy ◽

The Impact

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.

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Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy

Cell ◽

10.1016/s0092-8674(04)00400-3 ◽

2004 ◽

Vol 117 (3) ◽

pp. 399-412 ◽

Cited By ~ 1808

Author(s):

Marco Sandri ◽

Claudia Sandri ◽

Alex Gilbert ◽

Carsten Skurk ◽

Elisa Calabria ◽

...

Keyword(s):

Skeletal Muscle ◽

Transcription Factors ◽

Muscle Atrophy ◽

Ubiquitin Ligase ◽

Skeletal Muscle Atrophy ◽

Foxo Transcription Factors

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Faculty Opinions recommendation of Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1019081.214578 ◽

2004 ◽

Author(s):

Steven Burden

Keyword(s):

Skeletal Muscle ◽

Transcription Factors ◽

Muscle Atrophy ◽

Ubiquitin Ligase ◽

Skeletal Muscle Atrophy ◽

Foxo Transcription Factors

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Faculty Opinions recommendation of Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1019081.793492180 ◽

2014 ◽

Author(s):

Troy Hornberger

Keyword(s):

Skeletal Muscle ◽

Transcription Factors ◽

Muscle Atrophy ◽

Ubiquitin Ligase ◽

Skeletal Muscle Atrophy ◽

Foxo Transcription Factors

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Relation between skeletal muscle strength and ubiquitin ligase expression in muscle atrophy models in zebrafish larvae (Danio Rerio)

10.21203/rs.3.rs-70906/v1 ◽

2020 ◽

Author(s):

Jiao Liu ◽

Elisabeth Le ◽

Matthias Schwartzkopf ◽

Anders Arner

Keyword(s):

Skeletal Muscle ◽

Food Intake ◽

Muscle Weakness ◽

Muscle Atrophy ◽

Ubiquitin Ligase ◽

Muscle Function ◽

Skeletal Muscle Atrophy ◽

Active Force ◽

Zebrafish Larvae

Abstract Background Skeletal muscle atrophy is often seen in patients with chronic diseases or muscle disuse. Upregulated expression of ubiquitin ligases such as Muscle Ring Finger 1 (MuRF-1) and Muscle Atrophy F-box (MAFbx) has been shown in different immobilization-induced atrophy models, which is believed to be responsible for the enhanced muscle protein proteolysis and thereafter results in muscle weakness. However, currently used immobilization animal models can include artefacts due to difficulty of food intake and stress. Zebrafish larvae 5-6 days after hatching do not require active movement for food intake, and it is possible to assess the muscle function of their trunk muscle. Therefore, we established two muscle atrophy models using zebrafish larvae and aimed to investigate the role of the MuRFs and MAFbx in relation with muscle function.Methods An actin-myosin interaction blocker (BTS) was used to immobilize zebrafish larvae from 3-6 days after hatching; in another series, dexamethasone was fed to larvae from 3-5 days after hatching. Maximal active force of trunk muscles was examined and the distance between adjacent filaments in sarcomeric structure was measured using small angle x-ray diffraction. MuRF and MAFbx expression was determined using real time PCR. Two-way ANOVA was used to analyze the difference between groups.Results We found a significant up-regulation of MuRF-1 and a lower active force generation in dexamethasone treated larvae. However, although the BTS immobilization induced muscle weakness, it was associated with decreased of MuRF-1 to 3 and MAFbx. After 3 days of immobilization, sarcomere became more compressed compared to the controls.Conclusions Two kinds of muscle atrophy models were successfully established in zebrafish larvae. MuRFs and MAFbx was lowered in BTS treated model whereas MuRF-1 was up-regulated in dexamethasone treated model implicating the complex role of ubiquitin ligase in different muscle atrophy models.

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