A Key Role for the Ubiquitin Ligase UBR4 in Myofiber Hypertrophy in Drosophila and Mice

Hunt, Liam C.; Stover, Jared; Haugen, Benard; Shaw, Timothy I.; Li, Yuxin; Pagala, Vishwajeeth; Finkelstein, David; Barton, Elisabeth R.; Fan, Yiping; Labelle, Myriam; Peng, Junmin; Demontis, Fabio

doi:10.1016/j.celrep.2019.06.094

Cited by 69 publications

(100 citation statements)

References 61 publications

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“…Furthermore, increased gene expression of UBR5 in these models resulted in greater abundance of UBR5 protein content following FO-induced hypertrophy of the mouse plantaris muscle in-vivo, and over the timecourse of regeneration in primary human muscle cells in-vitro (Seaborne et al, 2019). A recent study also supported the role of UBR5 as being essential for muscle growth through RNAi screening in Drosophila larvae, where UBR5 inhibition led to smaller sized larvae (Hunt et al, 2019). Finally, unpublished data from our lab in bioengineered mouse SkM also demonstrated that UBR5 was the most significantly upregulated transcript after loading, amongst a selection of genes that are known to be regulated across the human transcriptome and methylome after acute RE (Seaborne et al, 2018b;Turner et al, 2019b).…”

Section: Introductionmentioning

confidence: 80%

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

Turner

Hughes

Baehr

et al. 2020

Preprint

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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 remain unknown. The present study aimed to investigate the mechanism of action of UBR5 by silencing the UBR5 gene in-vitro and in-vivo.The siRNA-induced reduction (-77%) in UBR5 gene expression in human myotubes was prevented by mechanical loading, suggesting that UBR5 gene expression was activated downstream of mechano-transduction signalling. MEK/ERK/p90S6K-signalling is an established mechano-sensitive-pathway involved in muscle anabolism/hypertrophy and importantly, has been shown to regulate UBR5 during growth of cancer cells. Therefore, we electroporated a UBR5 RNAi plasmid into mouse Tibialis Anterior muscle in-vivo to investigate the impact of reduced UBR5 on MEK/ERK/p90RSK-signalling. Electroporation resulted in a 55%/60% reduction in UBR5 mRNA/protein. Seven days post electroporation, while overall muscle mass was not significantly reduced, mean fibre CSA of GFP-positive fibres was reduced (-9.5%) and the number of large fibres were lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis (puromycin incorporation) and ERK1/2-phosphorylation. However, p90RSK-phosphorylation significantly increased, suggesting a potential compensatory mechanism following a reduction in UBR5. Finally, these acute changes evident after 7 days of UBR5 knockdown were exacerbated after 30 days, culminating in significant reductions in muscle mass (-4.6%) and fibre CSA (-18.5%). The present study supports the notion that UBR5 plays an important role in muscle anabolism/hypertrophy, and that a reduction in UBR5 is associated with alterations in ERK1/2 and p90RSK that culminates in atrophy.Running title: UBR5 knockdown reveals its important role in anabolism and hypertrophy

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Section: Introductionmentioning

confidence: 80%

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

Turner

Hughes

Baehr

et al. 2020

Preprint

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“…Ubiquitin ligases have been associated with atrophy. However, a recent RNAi screening for the ubiquitin ligases that control muscle mass identified UBR4 as a critical one for hypertrophy 37 . UBR4 induces hypertrophy via ubiquitination and degradation of a core set of target proteins, including the HAT1/RBBP4/RBBP7 histone-binding complex, that control histone acetylation and expression of growth-promoting genes.…”

Section: Metabolic Regulators That Sustain Muscle Growthmentioning

confidence: 99%

Mechanisms of muscle atrophy and hypertrophy: implications in health and disease

2021

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Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. Consequently, the growth or the loss of muscle mass can influence general metabolism, locomotion, eating and respiration. Therefore, it is not surprising that excessive muscle loss is a bad prognostic index of a variety of diseases ranging from cancer, organ failure, infections and unhealthy ageing. Muscle function is influenced by different quality systems that regulate the function of contractile proteins and organelles. These systems are controlled by transcriptional dependent programs that adapt muscle cells to environmental and nutritional clues. Mechanical, oxidative, nutritional and energy stresses, as well as growth factors or cytokines modulate signaling pathways that, ultimately, converge on protein and organelle turnover. Novel insights that control and orchestrate such complex network are continuously emerging and will be summarized in this review. Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non-hereditary diseases and for the improvement of the quality of life during ageing.

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“…Although the role of the ubiquitin proteasome system in muscle proteolysis is well established, the role, if any, this system plays in muscle growth has only recently been investigated. In both Drosophila and mouse myofibers, loss of UBR4, the N-end rule ubiquitin-protein ligase, induces hypertrophy by reducing the ubiquitination and degradation of a core set of target proteins, including the HAT1/RBBP4/RBBP7 histone-binding complex [ 95 ]. Interestingly, the importance of N-end rule ubiquitination in the regulation of muscle proteolysis was recognized over two decades ago.…”

Section: Regulators Of Proteolysismentioning

confidence: 99%

Signaling Pathways That Control Muscle Mass

Vainshtein¹,

Sandri

2020

IJMS

136

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The loss of skeletal muscle mass under a wide range of acute and chronic maladies is associated with poor prognosis, reduced quality of life, and increased mortality. Decades of research indicate the importance of skeletal muscle for whole body metabolism, glucose homeostasis, as well as overall health and wellbeing. This tissue’s remarkable ability to rapidly and effectively adapt to changing environmental cues is a double-edged sword. Physiological adaptations that are beneficial throughout life become maladaptive during atrophic conditions. The atrophic program can be activated by mechanical, oxidative, and energetic distress, and is influenced by the availability of nutrients, growth factors, and cytokines. Largely governed by a transcription-dependent mechanism, this program impinges on multiple protein networks including various organelles as well as biosynthetic and quality control systems. Although modulating muscle function to prevent and treat disease is an enticing concept that has intrigued research teams for decades, a lack of thorough understanding of the molecular mechanisms and signaling pathways that control muscle mass, in addition to poor transferability of findings from rodents to humans, has obstructed efforts to develop effective treatments. Here, we review the progress made in unraveling the molecular mechanisms responsible for the regulation of muscle mass, as this continues to be an intensive area of research.

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A Key Role for the Ubiquitin Ligase UBR4 in Myofiber Hypertrophy in Drosophila and Mice

Cited by 69 publications

References 61 publications

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

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

Mechanisms of muscle atrophy and hypertrophy: implications in health and disease

Signaling Pathways That Control Muscle Mass

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