The TWEAK–Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice
Open accessAbstract
Skeletal muscle atrophy occurs in a variety of clinical settings, including cachexia, disuse, and denervation. Inflammatory cytokines have been shown to be mediators of cancer cachexia; however, the role of cytokines in denervation- and immobilization-induced skeletal muscle loss remains unknown. In this study, we demonstrate that a single cytokine, TNF-like weak inducer of apoptosis (TWEAK), mediates skeletal muscle atrophy that occurs under denervation conditions. Transgenic expression of TWEAK induces atrophy, fibrosis, fiber-type switching, and the degradation of muscle proteins. Importantly, genetic ablation of TWEAK decreases the loss of muscle proteins and spared fiber cross-sectional area, muscle mass, and strength after denervation. Expression of the TWEAK receptor Fn14 (fibroblast growth factor–inducible receptor 14) and not the cytokine is significantly increased in muscle upon denervation, demonstrating an unexpected inside-out signaling pathway; the receptor up-regulation allows for TWEAK activation of nuclear factor κB, causing an increase in the expression of the E3 ubiquitin ligase MuRF1. This study reveals a novel mediator of skeletal muscle atrophy and indicates that the TWEAK–Fn14 system is an important target for preventing skeletal muscle wasting.
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Fn14 is not induced by dexamethasone treatment.
“However, Fn14 does not increase in all the conditions of muscle atrophy, for instance, it is not induced by dexamethasone treatment72.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [72]
TWEAK knockout mice display less atrophy during denervation.
“TWEAK knockout mice display less atrophy during denervation as well as reduced NF-κB activation and MuRF1 expression.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [72]
TWEAK knockout mice display reduced NF-κB activation and MuRF1 expression.
“TWEAK knockout mice display less atrophy during denervation as well as reduced NF-κB activation and MuRF1 expression.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [72]
Fn14 is upregulated in denervated muscle, allowing NF-κB activation and consequently MuRF1 but not atrogin-1/MAFbx expression.
“Fn14 is upregulated in denervated muscle allowing NF-κB activation and consequently MuRF1 but not atrogin-1/MAFbx expression72.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [72]
NF-κB and the atrophy program are positively modulated by TWEAK.
“NF-kB and the atrophy program are also positively modulated by tumor necrosis factor-like weak inducer of apoptosis (TWEAK), which is a member of the TNF superfamily72.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [72]
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TWEAK and TRAF6 regulate skeletal muscle atrophy
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The TWEAK ‐ Fn14 system as a potential drug target
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Molecular and neuroendocrine mechanisms of cancer cachexia
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Bhatnagar, S., Mittal, A., Gupta, S. K., & Kumar, A. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22821 · Cited by 87 · see citing works
Self-citationHarper, S. A., Roberts, L. M., Layne, A. S., Jaeger, B. C., Gardner, A. K., Sibille, K. T., Wu, S. S., Vincent, K. R., Fillingim, R. B., Manini, T. M., et al. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8020265 · Cited by 86 · see citing works
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Self-citationTWEAK and cIAP1 Regulate Myoblast Fusion Through the Noncanonical NF-κB Signaling Pathway
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Delayed Recovery of Skeletal Muscle Mass following Hindlimb Immobilization in mTOR Heterozygous Mice
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TWEAK/Fn14 Axis: A Promising Target for the Treatment of Cardiovascular Diseases
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Mechanisms of exercise as a preventative measure to muscle wasting
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TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis
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Self-citationTWEAK/Fn14 Signaling Axis Mediates Skeletal Muscle Atrophy and Metabolic Dysfunction
Sato, S., Ogura, Y., & Kumar, A. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00018 · Cited by 72 · see citing works
Self-citationRegulatory circuitry of TWEAK‐Fn14 system and PGC‐1α in skeletal muscle atrophy program
Hindi, S. M., Mishra, V. K., Bhatnagar, S., Tajrishi, M. M., Ogura, Y., Yan, Z., Burkly, L. C., Zheng, T. S., & Kumar, A. (2013) · The FASEB Journal · doi:10.1096/fj.13-242123 · Cited by 68 · see citing works
Self-citationThe TWEAK-Fn14 pathway: A potent regulator of skeletal muscle biology in health and disease
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Self-citationMechanism of skeletal muscle atrophy after spinal cord injury: A narrative review
Xu, X. P., Talifu, Z., Zhang, C.-J., Gao, F., Ke, H., Pan, Y., Gong, H., Du, H., Yu, Y. H., Jing, Y.-L., et al. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1099143 · Cited by 65 · see citing works
Cellular and molecular features of neurogenic skeletal muscle atrophy
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Genetic Ablation of TWEAK Augments Regeneration and Post-Injury Growth of Skeletal Muscle in Mice
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Self-citationSingle Muscle Fiber Gene Expression with Run Taper
Murach, K. A., Raue, U., Wilkerson, B. S., Minchev, K., Jemioło, B., Bagley, J. R., Luden, N. D., & Trappe, S. W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108547 · Cited by 61 · see citing works
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TAK1 regulates skeletal muscle mass and mitochondrial function
Hindi, S. M., Sato, S., Xiong, G., Bohnert, K. R., Gibb, A., Gallot, Y. S., McMillan, J. D., Hill, B. G., Uchida, S., & Kumar, A. (2018) · JCI Insight · doi:10.1172/jci.insight.98441 · Cited by 59 · see citing works
Self-citationBilski, J., Mazur-Biały, A. I., Wierdak, M., & Brzozowski, T. (2013) · PubMed · Cited by 55 · see citing works
TWEAK/Fn14 axis is an important player in fibrosis
Zhang, Y., Zeng, W., & Xia, Y. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.30089 · Cited by 56 · see citing works
The dependency of autophagy and ubiquitin proteasome system during skeletal muscle atrophy
Singh, A. P., Phogat, J., Yadav, A., & Dabur, R. (2021) · Biophysical Reviews · doi:10.1007/s12551-021-00789-7 · Cited by 55 · see citing works
The Composition, Development, and Regeneration of Neuromuscular Junctions
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Immune and myodegenerative pathomechanisms in inclusion body myositis
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TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy
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The TWEAK-Fn14 System: Breaking the Silence of Cytokine-Induced Skeletal Muscle Wasting
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Self-citationTWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice
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TWEAK promotes exercise intolerance by decreasing skeletal muscle oxidative phosphorylation capacity
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Self-citationImmunoregulation in cancer-associated cachexia
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Mechanisms for maintaining muscle
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Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration
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Self-citationMuscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials
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Sato, S., Ogura, Y., Tajrishi, M. M., & Kumar, A. (2014) · The FASEB Journal · doi:10.1096/fj.14-260703 · Cited by 34 · see citing works
Self-citationRabinovich, R. A., Drost, E., Manning, J. R., Dunbar, D. R., Díaz-Ramos, M., Lakhdar, R., Bastos, R., & MacNee, W. (2015) · Respiratory Research · doi:10.1186/s12931-014-0139-5 · Cited by 88 · see citing works
- Authors
- Mittal, A., Bhatnagar, S., Kumar, A., Lach-Trifilieff, E., Wauters, S., Li, H., Makonchuk, D. Y., Glass, D. J., & Kumar, A.
- Affiliations
- University of Louisville (US)
- Novartis Institutes for BioMedical Research, Inc., Cambridge, MA 02139 2
- Corresponding author
- Kumar, Ashok
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2010-03-22
- Volume
- 188
- Issue
- 6
- Pages
- 833-849
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2845082
- OpenAlex
- W2167935306
- Cited by
- 250
- References
- 54
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 13 · 2023: 11 · 2022: 10 · 2021: 20 · 2020: 15 · 2019: 9 · 2018: 14 · 2017: 17 · 2016: 19 · 2015: 18 · 2014: 24 · 2013: 21 · 2012: 19
- FWCI
- 7.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute on Aging (R01AG029623, R01 AG129623)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- TWEAK, Fn14, skeletal muscle atrophy, denervation, inside-out signaling, NF-κB, MuRF1, E3 ubiquitin ligase, muscle protein degradation, muscle atrophy, muscle fibrosis, cachexia
- MeSH terms
- Cytokine TWEAK, TWEAK Receptor, Animals, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Muscle Denervation, Muscular Atrophy, Receptors, Tumor Necrosis Factor, Mice, Knockout, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factors, Mice
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