The Ubiquitin Ligase Nedd4-1 Participates in Denervation-Induced Skeletal Muscle Atrophy in Mice
Open accessAbstract
Skeletal muscle atrophy is a consequence of muscle inactivity resulting from denervation, unloading and immobility. It accompanies many chronic disease states and also occurs as a pathophysiologic consequence of normal aging. In all these conditions, ubiquitin-dependent proteolysis is a key regulator of the loss of muscle mass, and ubiquitin ligases confer specificity to this process by interacting with, and linking ubiquitin moieties to target substrates through protein:protein interaction domains. Our previous work suggested that the ubiquitin-protein ligase Nedd4-1 is a potential mediator of skeletal muscle atrophy associated with inactivity (denervation, unloading and immobility). Here we generated a novel tool, the Nedd4-1 skeletal muscle-specific knockout mouse (myo(Cre);Nedd4-1(flox/flox)) and subjected it to a well validated model of denervation induced skeletal muscle atrophy. The absence of Nedd4-1 resulted in increased weights and cross-sectional area of type II fast twitch fibres of denervated gastrocnemius muscle compared with wild type littermates controls, at seven and fourteen days following tibial nerve transection. These effects are not mediated by the Nedd4-1 substrates MTMR4, FGFR1 and Notch-1. These results demonstrate that Nedd4-1 plays an important role in mediating denervation-induced skeletal muscle atrophy in vivo.
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Nedd4, another muscle-specific E3-ubiquitin ligase acting through Notch1 signaling, has recently drawn attention because of its implication in denervation-induced muscle atrophy, here unrelated to Notch1 activation.
“Nedd4, another muscle-specific E3-ubiquitin ligase acting through Notch1 signaling [167], has recently drawn attention because of its implication in denervation-induced muscle atrophy [168], here unrelated to Notch1 activation.”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [168]
The Discussion reports that deleting Nedd4-1 from skeletal muscle protected mice from early denervation-induced atrophy. It also says the authors found no evidence that Nedd4-1 engages Notch-1 to mediate that atrophy. Calling the mechanism definitively unrelated to Notch-1 activation is stronger than the paper’s qualified conclusion. (LLM, conf=0.86)
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- Authors
- Nagpal, P., Plant, P. J., Correa, J., Bain, A., Takeda, M., Kawabe, H., Rotin, D., Bain, J. R., & Batt, J. A. E.
- Affiliations
- St. Michael's Hospital (CA)
- University of Toronto (CA)
- Max Planck Society (DE)
- Hospital for Sick Children (CA)
- McMaster University (CA)
- Corresponding author
- Batt, Jane A. E.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-10-26
- Volume
- 7
- Issue
- 10
- Pages
- e46427
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3482220
- OpenAlex
- W2044120589
- Cited by
- 85
- References
- 52
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 8 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 12 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 14 · 2015: 7 · 2014: 9 · 2013: 6
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- ALS Society of Canada
- Muscular Dystrophy Canada
- Deutsche Forschungsgemeinschaft (SPP1365/KA3423/1-1, SPP 1365)
- Fritz Thyssen Stiftung
- Canadian Institutes of Health Research (90959_1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Keywords
- NEDD4-1, skeletal muscle atrophy, denervation, ubiquitin ligase, ubiquitin-proteasome system, muscle unloading, tibial nerve transection, gastrocnemius, FGFR1, Notch1
- MeSH terms
- Nedd4 Ubiquitin Protein Ligases, Animals, Cells, Cultured, Female, Immunohistochemistry, Male, Muscle Denervation, Muscular Atrophy, Blotting, Western, Mice, Knockout, Myoblasts, Satellite Cells, Skeletal Muscle, Ubiquitin-Protein Ligases, Mice, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Notch1, Protein Tyrosine Phosphatases, Non-Receptor, Endosomal Sorting Complexes Required for Transport
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