P38 MAPK Links Oxidative Stress to Autophagy-Related Gene Expression in Cachectic Muscle Wasting
Open accessAbstract
Oxidative stress is a primary trigger of cachectic muscle wasting, but the signaling pathway(s) that links it to the muscle wasting processes remains to be defined. Here, we report that activation of p38 mitogen-activated protein kinase (MAPK) (phosphorylation) and increased oxidative stress (trans-4-hydroxy-2-nonenal protein modification) in skeletal muscle occur as early as 8 h after lipopolysaccharide (1 mg/kg) and 24 h after dexamethasone (25 mg/kg) injection (intraperitoneal) in mice, concurrent with upregulation of autophagy-related genes, Atg6, Atg7, and Atg12. Treating cultured C2C12 myotubes with oxidant hydrogen peroxide (4 h) resulted in increased p38 phosphorylation and reduced FoxO3 phosphorylation along with induced Atg7 mRNA expression without activation of NF-kappaB or FoxO3a transcriptional activities. Furthermore, inhibition of p38alpha/beta by SB202190 blocked hydrogen peroxide-induced atrophy with diminished upregulation of Atg7 and atrogenes [muscle atrophy F-box protein (MAFbx/Atrogin-1), muscle ring finger protein 1 (MuRF-1), and Nedd4]. These findings provide direct evidence for p38alpha/beta MAPK in mediating oxidative stress-induced autophagy-related genes, suggesting that p38alpha/beta MAPK regulates both the ubiquitin-proteasome and the autophagy-lysosome systems in muscle wasting.
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MAPK pathways are classically considered catabolic second messengers in myocytes upon activation by triggers such as inflammatory cytokines or ROS.
“MAPK pathways are classically considered as catabolic second messengers in myocytes, upon activation by different triggers such as inflammatory cytokines or ROS [170].”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [170]
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- Authors
- McClung, J. M., Judge, A. R., Powers, S. K., & Yan, Z.
- Affiliations
- Duke Medical Center (US)
- University of Florida (US)
- Exercise Biochemistry Laboratory and
- Corresponding author
- McClung, J. M.
- Yan, Z.
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2010-03
- Volume
- 298
- Issue
- 3
- Pages
- C542-C549
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- PMC
- PMC2838571
- OpenAlex
- W2080692874
- Cited by
- 277
- References
- 4
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 8 · 2023: 19 · 2022: 14 · 2021: 22 · 2020: 18 · 2019: 22 · 2018: 18 · 2017: 12 · 2016: 16 · 2015: 18 · 2014: 17 · 2013: 18 · 2012: 17
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG028740)
- National Heart, Lung, and Blood Institute (R01HL072789)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050429)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Keywords
- p38 MAPK, oxidative stress, skeletal muscle atrophy, autophagy-related genes, ATG7, ATG6, ATG12, FOXO3, hydrogen peroxide, lipopolysaccharide, dexamethasone, ubiquitin-proteasome system, autophagy-lysosome system, atrogin-1/MAFbx, MuRF1, NEDD4, skeletal muscle
- MeSH terms
- Forkhead Box Protein O3, Aldehydes, Animals, Autophagy, Cachexia, Cell Line, Dexamethasone, Enzyme Activation, Gene Expression Regulation, Glycolysis, Hydrogen Peroxide, Imidazoles, Lipopolysaccharides, Male, Mice, Inbred C57BL, Muscular Atrophy, Phosphorylation, Protein Processing, Post-Translational, Pyridines, Transfection, Signal Transduction, NF-kappa B, Oxidants, Oxidative Stress, Muscle Fibers, Skeletal, Proteasome Endopeptidase Complex, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 11, Mitogen-Activated Protein Kinase 14, Mice, Forkhead Transcription Factors, Ubiquitination
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