Integrated genomic and proteomic analyses identify stimulus-dependent molecular changes associated with distinct modes of skeletal muscle atrophy

Hunt, Liam C.; Graça, Flávia A.; Pagala, Vishwajeeth; Wang, Yongdong; Li, Yuxin; Yuan, Zuo‐Fei; Fan, Yiping; Labelle, Myriam; Peng, Junmin; Demontis, Fabio

doi:10.1016/j.celrep.2021.109971

Cited by 50 publications

(39 citation statements)

References 99 publications

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“…The UBE2D and E families have been previously shown to increase expression in atrophy; in C2C12 cells, mRNA expression of UBE2D1, 2 and E1 increases following 48 hours of dexamethasone treatment [22,48]. Furthermore, transcriptomics of mice treated with dexamethasone for 14 days have shown increased expression of UBE2D2, D3, N, V1, and V2 [49]. This evidence reveals the treatment and time dependent nature of atrophy-models used.…”

Section: Discussionmentioning

confidence: 83%

“…This evidence reveals the treatment and time dependent nature of atrophy-models used. The transient expression of UBE2s shown in our work (Fig 5) highlights the limitation of a using a single time point in previous work [22,49,50]. Having identified MuRF1 partnering UBE2s, future work would benefit from screening multiple time points of atrophy for UBE2s.…”

Section: Discussionmentioning

confidence: 84%

“…The possibility of MuRF1-instigated mono-ubiquitylation being used by other E2-E3s pairings, implies a sophisticated complex of ubiquitylation activity. It is therefore crucial to understand the diversity of ubiquitin chain types generated by this mechanism, since chain types determine the fate of substrates [48,49]. Beyond interaction, these MuRF1-interacting UBE2s we observed being upregulated during atrophy.…”

Section: Discussionmentioning

confidence: 99%

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The Role of UBE2-Conjugating Enzymes in the Mechanism of MuRF1 Ubiquitylation

Dawson

Baehr

Hughes

et al. 2022

Preprint

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MuRF1 (Muscle-specific RING finger protein 1; gene name TRIM63) is a ubiquitin E3 ligase, associated with the progression of muscle atrophy. As a RING (Really Interesting New Gene)-type E3 ligase, its unique activity of ubiquitylation is driven by a specific interaction with UBE2 (ubiquitin conjugating enzyme) to ubiquitylate its substrate protein. The understanding of MuRF1 function remains unclear as candidate UBE2 has not been elucidated and thus the mechanism of ubiquitylation is inconclusive. In the present study, we screened human ubiquitin dependent E2s using in-vitro ubiquitylation assays. We found that MuRF1 engages in ubiquitylation/auto-ubiquitylation with UBE2D, UBE2E, UBE2N/V families and UBE2W. Our result indicated that MuRF1 can cause mono-ubiquitylation, K48, and K63 specific poly-ubiquitin chains in a UBE2-dependent manner. Interestingly, we identified a two-step UBE2-dependent mechanism by which UBE2W allows MuRF1 to mono-ubiquitylate which then acts as an anchor for UBE2N/V and UBE2D generated poly-ubiquitin chain formation. Furthermore, MuRF1 was shown to cooperate with the identified interacting UBE2s to directly ubiquitylate substrates Titin (A168-A170), Desmin, and MYLPF (Myosin Light Chain, Phosphorylatable, Fast Skeletal Muscle; also called Myosin Light Regulatory Chain 2). Our work presents a novel insight into the mechanisms that underpin MuRF1 activity by highlighting the diversity of MuRF1 ubiquitylation enabled by different UBE2s.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Role of UBE2-Conjugating Enzymes in the Mechanism of MuRF1 Ubiquitylation

Dawson

Baehr

Hughes

et al. 2022

Preprint

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“…The proteins such as NDUFS3 identified by the GCN link prediction methods are important for reversion of myopathies in mice [ 40 ]. These are atrophy associated proteins ( NDUFS3 , NDUBF2 part of the ubiquitin-proteasome system [ 41 ]. The loss of other target genes such as MEF2A results in progressive atrophy [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Detection of Target Genes for Drug Repurposing to Treat Skeletal Muscle Atrophy in Mice Flown in Spaceflight

Manian

Orozco-Sandoval

Díaz-Martínez

et al. 2022

Genes

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Skeletal muscle atrophy is a common condition in aging, diabetes, and in long duration spaceflights due to microgravity. This article investigates multi-modal gene disease and disease drug networks via link prediction algorithms to select drugs for repurposing to treat skeletal muscle atrophy. Key target genes that cause muscle atrophy in the left and right extensor digitorum longus muscle tissue, gastrocnemius, quadriceps, and the left and right soleus muscles are detected using graph theoretic network analysis, by mining the transcriptomic datasets collected from mice flown in spaceflight made available by GeneLab. We identified the top muscle atrophy gene regulators by the Pearson correlation and Bayesian Markov blanket method. The gene disease knowledge graph was constructed using the scalable precision medicine knowledge engine. We computed node embeddings, random walk measures from the networks. Graph convolutional networks, graph neural networks, random forest, and gradient boosting methods were trained using the embeddings, network features for predicting links and ranking top gene-disease associations for skeletal muscle atrophy. Drugs were selected and a disease drug knowledge graph was constructed. Link prediction methods were applied to the disease drug networks to identify top ranked drugs for therapeutic treatment of skeletal muscle atrophy. The graph convolution network performs best in link prediction based on receiver operating characteristic curves and prediction accuracies. The key genes involved in skeletal muscle atrophy are associated with metabolic and neurodegenerative diseases. The drugs selected for repurposing using the graph convolution network method were nutrients, corticosteroids, anti-inflammatory medications, and others related to insulin.

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“…Genomic, transcriptomic, and proteomic approaches have been employed to study muscle aging in laboratory animals and in humans, including deep quantitative proteomic and transcriptomic profiling of several age groups in humans 7,8 and in mice. [9][10][11] However, protein function in biological systems is under complex regulation and includes factors in addition to abundance levels, such as modifications, localization, conformations, and protein-protein interactions. While large-scale studies have also been applied to investigate differential mitochondrial protein modifications with age, including phosphorylation, acetylation, succinylation and others, [12][13][14] quantitation of large-scale changes in protein conformations and protein-protein interactions, collectively referred to here as the interactome, has previously not been possible.…”

Section: Mainmentioning

confidence: 99%

Mitochondrial interactome remodeling in aging mouse skeletal muscle associated with functional decline

Bakhtina

Pharaoh

Keller

et al. 2022

Preprint

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Genomic, transcriptomic, and proteomic approaches have been employed to gain insight into molecular underpinnings of aging in laboratory animals and in humans. However, protein function in biological systems is under complex regulation and includes factors in addition to abundance levels, such as modifications, localization, conformation, and protein-protein interactions. We have applied new robust quantitative chemical cross-linking technologies to uncover changes muscle mitochondrial interactome contributing to functional decline in aging. Statistically significant age-related changes in protein cross-link levels relating to assembly of electron transport system complexes I and IV, activity of glutamate dehydrogenase, and coenzyme-A binding in fatty acid beta-oxidation and TCA enzymes were observed. These changes showed remarkable correlation with measured CI based respiration differences within the same young-old animal pairs, indicating these cross-link levels offer new molecular insight on commonly observed age-related phenotypic differences. Overall, these system-wide quantitative mitochondrial interactome data provide the first molecular-level insight on ETS complex and substrate utilization enzyme remodeling that occur during age-related mitochondrial dysfunction. Each observed cross-link can serve as a protein conformational or protein-protein interaction probe in future studies making this dataset a unique resource for many additional in-depth molecular studies that are needed to better understand complex molecular changes that occur with aging.

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Integrated genomic and proteomic analyses identify stimulus-dependent molecular changes associated with distinct modes of skeletal muscle atrophy

Cited by 50 publications

References 99 publications

The Role of UBE2-Conjugating Enzymes in the Mechanism of MuRF1 Ubiquitylation

The Role of UBE2-Conjugating Enzymes in the Mechanism of MuRF1 Ubiquitylation

Detection of Target Genes for Drug Repurposing to Treat Skeletal Muscle Atrophy in Mice Flown in Spaceflight

Mitochondrial interactome remodeling in aging mouse skeletal muscle associated with functional decline

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