UBR5 is a Novel E3 Ubiquitin Ligase involved in Skeletal Muscle Hypertrophy and Recovery from Atrophy

Seaborne, Robert A.; Dc, Hughes; Turner, DC; Owens, DJ; Baehr, LM; Gorski, Piotr P.; Семенова, Е. Г.; Borisov, OV; Larin, AK; Popov, D. V.; Генерозов, Э. В.; Sutherland, Hazel; Ahmetov, II; Jarvis, JC; Bodine, SC; Sharples, AP

doi:10.1101/592980

Cited by 4 publications

(7 citation statements)

References 75 publications

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“…Thus, as noted for all models described in this Section, some caution is warranted when interpreting aspects of mechanistic regulation from these models and extrapolating to human exercise contexts. One notable development has been the development of models of electrical stimulation that are more episodic in nature, and can be applied to deliver low frequency continuous or higher frequency intermittent stimulation to mimic various types of exercise (76,344,345,603).…”

Section: Models Of Increased Contractile Activity That Do Not Mimic H...mentioning

confidence: 99%

Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training

Egan

Sharples

2023

Physiological Reviews

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Repeated, episodic bouts of skeletal muscle contraction undertaken frequently as structured exercise training is a potent stimulus for physiological adaptation in many organs. Specifically in skeletal muscle, remarkable plasticity is demonstrated by the remodeling of muscle structure and function in terms of muscular size, force, endurance, and contractile velocity as a result of the functional demands induced by various types of exercise training. This plasticity, and the mechanistic basis for adaptations to skeletal muscle in response to exercise training, is underpinned by activation and/or repression of molecular pathways and processes induced in response to each individual acute exercise session. These pathways include the transduction of signals arising from neuronal, mechanical, metabolic, and hormonal stimuli through complex signal transduction networks, which are linked to a myriad of effector proteins involved in the regulation of pre- and post-transcriptional processes, and protein translation and degradation processes. This review therefore describes acute exercise-induced signal transduction and the molecular responses to acute exercise in skeletal muscle including emerging concepts such as epigenetic pre- and post-transcriptional regulation, and the regulation of protein translation and degradation. A critical appraisal of methodological approaches and the current state of knowledge informs a series of recommendations offered as future directions in the field.

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Section: Models Of Increased Contractile Activity That Do Not Mimic H...mentioning

confidence: 99%

Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training

Egan

Sharples

2023

Physiological Reviews

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“…Despite marginal non-MyoF proteome alterations in MA participants with training, there were interesting targets that were altered. For instance, the UBR7 E3 ligase was upregulated, and recent evidence suggests that an E3 ligase in this same protein family (UBR5) is required for load-induced skeletal muscle hypertrophy (53). Additionally, the knockdown of another member of this family (UBR4) promotes hypertrophy in Drosophila and mice (54).…”

Section: Proteolysis Targets Manually Interrogated In Both Fractionsmentioning

confidence: 99%

A novel deep proteomic approach in human skeletal muscle unveils distinct molecular signatures affected by aging and resistance training

Roberts,

Ruple,

Godwin

et al. 2023

Preprint

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We examined the myofibrillar (MyoF) and non-myofibrillar (non-MyoF) proteomic profiles of the vastus lateralis (VL) muscle of younger (Y, 22+/-2 years old; n=5) and middle-aged participants (MA, 56+/-8 years old; n=6), and MA following eight weeks of knee extensor resistance training (RT, 2d/week). Shotgun/bottom-up proteomics in skeletal muscle typically yields wide protein abundance ranges that mask lowly expressed proteins. Thus, we adopted a novel approach whereby the MyoF and non-MyoF fractions were separately subjected to protein corona nanoparticle complex formation prior to digestion and Liquid Chromatography Mass Spectrometry (LC-MS) analysis. A total of 10,866 proteins (4,421 MyoF and 6,445 non-MyoF) were identified. Across all participants, the number of non-MyoF proteins detected averaged to be 5,645+/-266 (range: 4,888 to 5,987) and the number of MyoF proteins detected averaged to be 2,611+/-326 (range: 1,944 to 3,101). Differences in the non-MyoF (8.4%) and MyoF (2.5%) proteome were evident between age cohorts. Further, most of these age-related non-MyoF proteins (447/543) were more enriched in MA versus Y. Several biological processes in the non-MyoF fraction were predicted to be operative in MA versus Y including (but not limited to) increased cellular stress, mRNA splicing, translation elongation, and ubiquitin-mediated proteolysis. Non-MyoF proteins associated with splicing and proteostasis were further interrogated, and in agreement with bioinformatics, alternative protein variants, spliceosome-associated proteins (snRNPs), and proteolysis-related targets were more abundant in MA versus Y. RT in MA non-significantly increased VL muscle cross-sectional area (+6.5%, p=0.066) and significantly increased knee extensor strength (+8.7%, p=0.048). However, RT modestly altered the MyoF (~0.3%, 11 upregulated and two downregulated proteins) and non-MyoF proteomes (~1.0%, 56 upregulated and eight downregulated proteins, p<0.01). Further, RT did not affect predicted biological processes in either fraction. Although participant numbers were limited, these preliminary results using a novel deep proteomic approach in skeletal muscle suggest that aging and RT predominantly affects protein abundances in the non-contractile protein pool. However, the marginal proteome adaptations occurring with RT suggest either: a) this may be an aging-associated phenomenon, b) more rigorous RT may stimulate more robust effects, or c) RT, regardless of age, subtly affects skeletal muscle protein abundances in the basal state.

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“…Indeed, there seems to be a trend that a larger proportion of the genes that demonstrate hypomethylation are associated with a 'gene turn on' profile in SkM in response to resistance/strength (16,19), high-intensity (15) and aerobic exercise (18,23,24). Importantly, DNA methylome studies have identified novel exercise-responsive genes in human SkM that have not been previously highlighted in mRNA/transcriptome studies (14,25,26). Finally, DNA methylation in SkM also seems to be sensitive to high fat dietary interventions after resistance exercise (27).…”

Section: Introductionmentioning

confidence: 99%

“…19.524676 doi: bioRxiv preprint (16,19), high-intensity (15) and aerobic exercise (18,23,24). Importantly, DNA methylome studies have identified novel exercise-responsive genes in human SkM that have not been previously highlighted in mRNA/transcriptome studies (14,25,26). Finally, DNA methylation in SkM also seems to be sensitive to high fat dietary interventions after resistance exercise (27).…”

Section: Introductionmentioning

confidence: 99%

Human skeletal muscle methylome after low carbohydrate energy balanced exercise

Gorski

Turner

Iraki³

et al. 2023

Preprint

Self Cite

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We aimed to investigate the human skeletal muscle (SkM) DNA methylome after exercise in low carbohydrate (CHO) energy balance (with high fat) compared with exercise in low-CHO energy deficit (with low fat) conditions. The objective to identify novel epigenetically regulated genes and pathways associated with train-low sleep-low paradigms. The sleep-low conditions included 9 males that cycled to deplete muscle glycogen while reaching a set energy expenditure. Post-exercise, low-CHO meals (protein-matched) completely replaced (using high-fat) or only partially replaced (low-fat) the energy expended. The following morning resting baseline biopsies were taken and the participants then undertook 75 minutes of cycling exercise, with skeletal muscle biopsies collected 30 minutes and 3.5 hours post exercise. Discovery of genome-wide DNA methylation was undertaken using Illumina EPIC arrays and targeted gene expression analysis was conducted by RT-qPCR. At baseline participants under energy balance (high fat) demonstrated a predominantly hypermethylated (60%) profile across the genome compared to energy deficit-low fat conditions. However, post exercise performed in energy balance (with high fat) elicited a more prominent hypomethylation signature 30 minutes post-exercise in gene regulatory regions important for transcription (CpG islands within promoter regions) compared with exercise in energy deficit (with low fat) conditions. Such hypomethylation was enriched within pathways related to: IL6-JAK-STAT signalling, metabolic processes, p53 / cell cycle and oxidative / fatty acid metabolism. Hypomethylation within the promoter regions of genes: HDAC2, MECR, IGF2 and c13orf16 were associated with significant increases in gene expression in the post-exercise period in energy balance compared with energy deficit. Furthermore, histone deacetylase, HDAC11 was oppositely regulated at the gene expression level compared with HDAC2, where HDAC11 was hypomethylated yet increased in energy deficit compared with energy balance conditions. Overall, we identify some novel epigenetically regulated genes associated with train-low sleep-low paradigms.

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UBR5 is a Novel E3 Ubiquitin Ligase involved in Skeletal Muscle Hypertrophy and Recovery from Atrophy

Cited by 4 publications

References 75 publications

Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training

Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training

A novel deep proteomic approach in human skeletal muscle unveils distinct molecular signatures affected by aging and resistance training

Human skeletal muscle methylome after low carbohydrate energy balanced exercise

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