p38γ Mitogen-Activated Protein Kinase Is a Key Regulator in Skeletal Muscle Metabolic Adaptation in Mice
Open accessAbstract
Regular endurance exercise induces skeletal muscle contractile and metabolic adaptations, conferring salutary health benefits, such as protection against the metabolic syndrome. The plasticity of skeletal muscle has been extensively investigated, but how the adaptive processes are precisely controlled is largely unknown. Using muscle-specific gene deletion in mice, we now show that p38gamma mitogen-activated protein kinase (MAPK), but not p38alpha and p38beta, is required for endurance exercise-induced mitochondrial biogenesis and angiogenesis, whereas none of the p38 isoforms are required for IIb-to-IIa fiber-type transformation. These phenotypic findings were further supported by microarray and real-time PCR analyses revealing contractile activity-dependent p38gamma target genes, including peroxisome proliferator-activated receptor gamma co-activator-1alpha (Pgc-1alpha) and vascular endothelial growth factor (Vegf), in skeletal muscle following motor nerve stimulation. Gene transfer-mediated overexpression of a dominant negative form of p38gamma, but not that of p38alpha or p38beta, blocked motor nerve stimulation-induced Pgc-1alpha transcription. These findings provide direct evidence for an obligated role of p38gamma MAPK-PGC-1alpha regulatory axis in endurance exercise-induced metabolic adaptation, but not contractile adaptation, in skeletal muscle.
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The decrease in glycogen activates p38, which, like AMPK, can increase the transcription and activity of PGC-1α.
“The decrease in glycogen also activates the 38 kDa mitogen-activated protein kinase (p38), which, like AMPK, can increase the transcription and activity of PGC-1α [35–37].”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [36]
The Discussion (page not available in our copy) links exercise-induced p38 MAPK activation to PGC-1α regulation, and reports that loss of p38γ diminishes induced Pgc-1α mRNA expression. It does not establish that a decrease in glycogen activates p38 or make the comparison with AMPK. (LLM, conf=0.86)
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- Authors
- Pogozelski, A. R., Geng, T., Li, P., Yin, X., Lira, V. A., Zhang, M., Chi, J.-T., & Yan, Z.
- Affiliations
- Duke Medical Center (US)
- University of Virginia (US)
- Corresponding author
- Yan, Zhen
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-11-20
- Volume
- 4
- Issue
- 11
- Pages
- e7934
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2775956
- OpenAlex
- W2060618287
- Cited by
- 164
- References
- 49
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 4 · 2020: 12 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 10 · 2015: 16 · 2014: 17 · 2013: 18 · 2012: 15
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- Boehringer Ingelheim
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050429, AR 050429)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- p38γ MAPK, endurance exercise, mitochondrial biogenesis, angiogenesis, PGC-1α, vascular endothelial growth factor, muscle fiber type shift, motor nerve stimulation
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Genes, Dominant, Male, Mice, Inbred C57BL, Muscle Contraction, Neovascularization, Pathologic, Physical Conditioning, Animal, Transcription Factors, Trans-Activators, Gene Expression Regulation, Enzymologic, Muscle, Skeletal, Protein Isoforms, Oligonucleotide Array Sequence Analysis, MAP Kinase Signaling System, Vascular Endothelial Growth Factor A, p38 Mitogen-Activated Protein Kinases, Mice
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