Role of TNF-α signaling in regeneration of cardiotoxin-injured muscle
Open accessAbstract
Recent data suggest a physiological role for the proinflammatory cytokine TNF-alpha in skeletal muscle regeneration. However, the underlying mechanism is not understood. In the present study, we analyzed TNF-alpha-activated signaling pathways involved in myogenesis in soleus muscle injured by cardiotoxin (CTX) in TNF-alpha receptor double-knockout mice (p55(-/-)p75(-/-)). We found that activation of p38MAPK, which is critical for myogenesis, was blocked in CTX-injured p55(-/-)p75(-/-) soleus on day 3 postinjury when myogenic differentiation was being initiated, while activation of ERK1/2 and JNK MAPK, as well as transcription factor NF-kappaB, was not reduced. Consequently, the phosphorylation of transcription factor myocyte enhancer factor-2C, which is catalyzed by p38 and crucial for the expression of muscle-specific genes, was blunted. Meanwhile, expression of p38-dependent differentiation marker myogenin and p21 were suppressed. In addition, expression of cyclin D1 was fivefold that in wild-type (WT) soleus. These results suggest that myogenic differentiation is blocked or delayed in the absence of TNF-alpha signaling. Histological studies revealed abnormalities in regenerating p55(-/-)p75(-/-) soleus. On day 5 postinjury, new myofiber formation was clearly observed in WT soleus but not in p55(-/-)p75(-/-) soleus. To the contrary, p55(-/-)p75(-/-) soleus displayed renewed inflammation and dystrophic calcification. On day 12 postinjury, the muscle architecture of WT soleus was largely restored. Yet, in p55(-/-)p75(-/-) soleus, multifocal areas of inflammation, myofiber death, and myofibers with smaller cross-sectional area were observed. Functional studies demonstrated an attenuated recovery of contractile force in injured p55(-/-)p75(-/-) soleus. These data suggest that TNF-alpha signaling plays a critical regulatory role in muscle regeneration.
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TNF-α and IL-6 play an important role in early stages of muscle regeneration following injury by enhancing myoblast proliferation and inhibiting differentiation.
“Although being considered pro-inflammatory, TNF-α and IL-6 also appear to play important role in the early stages of muscle regeneration following injury by enhancing myoblast proliferation and inhibiting differentiation [73,74,75].”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [74]
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- Authors
- Chen, S.-E., Gerken, E., Zhang, Y., Zhan, M., Mohan, R. K., Li, A. S., Reid, M. B., & Li, Y.-P.
- Affiliations
- Baylor College of Medicine (US)
- University of Kentucky (US)
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2005-11
- Volume
- 289
- Issue
- 5
- Pages
- C1179-C1187
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- PMC
- PMC3099530
- OpenAlex
- W2114596120
- Cited by
- 162
- References
- 50
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 9 · 2023: 9 · 2022: 6 · 2021: 4 · 2020: 9 · 2019: 7 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 10 · 2014: 15 · 2013: 5 · 2012: 11
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL59878, R01HL059878)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR049022, AR049022)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- TNF signaling, skeletal muscle regeneration, cardiotoxin injury, p38 MAPK, myogenesis, myogenin, p21, cyclin D1, TNF receptor p55, TNF receptor 2, muscle inflammation, dystrophic calcification, soleus muscle
- MeSH terms
- Animals, Cobra Cardiotoxin Proteins, Enzyme Activation, Muscle Contraction, Muscular Diseases, Regeneration, Tumor Necrosis Factor-alpha, Signal Transduction, Receptors, Tumor Necrosis Factor, Mice, Knockout, Muscle, Skeletal, Muscle Development, p38 Mitogen-Activated Protein Kinases, Mice
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