ERK2 is required for efficient terminal differentiation of skeletal myoblasts
Abstract
Terminal differentiation of skeletal myoblasts involves alignment of the mononucleated cells, fusion into multinucleated syncitia, and transcription of muscle-specific genes. Myogenesis in vivo is regulated partially by IGF-I initiated signaling that results in activation of an intracellular phosphatidylinositol 3 kinase (PI3K) signaling cascade. Downstream signaling through the Raf/MEK/ERK axis, a pathway initiated by IGF-I, also is implicated in the regulation of muscle formation. The involvement of ERK1 and ERK2 during myogenesis was examined in C2C12 myoblasts. C2C12 myoblasts stably expressing a small interfering RNA (siRNA) directed against ERK1 or ERK2 were created. Both of the kinases were reduced to trace levels as measured by Western for total ERK and retained the capacity to become phosphorylated. C2C12siERK2 knockdown myoblasts failed to fuse into multinucleated myofibers. By contrast, cells expressing a scrambled siRNA or ERK1 siRNA fused into large multinucleated structures. The block to muscle formation did not involve continued cell cycle progression or apoptosis. C2C12siERK1 myoblasts expressed an increased amount of ERK2 protein and formed larger myofibers in response to IGF-I treatment. Interestingly, IGF-I treatment of C2C12 ERK2 knockdown myoblasts did not reinstate the myogenic program arguing that ERK2 is required for differentiation. These results provide evidence for ERK2 as a positive regulator of myogenesis and suggest that ERK1 is dispensable for myoblast proliferation and differentiation.
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During late stages of differentiation, ERK1/2 becomes phosphorylated, promoting fusion and formation of myotubes.
“In contrast to this inhibitory effect during the early stages of differentiation ERK1/2 becomes phosphorylated during the late stages of differentiation promoting the fusion and formation of myotubes [129,130].”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [130]
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Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity
FUJII, N. L., Boppart, M. D., Dufresne, S. D., Crowley, P. F., Jozsi, A. C., Sakamoto, K., Yu, H., Aschenbach, W. G., Kim, S., Miyazaki, H., et al. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00415.2003 · Cited by 53 · see citing works
Activated Raf inhibits avian myogenesis through a MAPK-dependent mechanism
Dorman, C. M., & Johnson, S. (1999) · Oncogene · doi:10.1038/sj.onc.1202907 · Cited by 49 · see citing works
Self-citationWeyman, C. M., Ramocki, M. B., Taparowsky, E. J., et al. (1997) · Oncogene · doi:10.1038/sj.onc.1200874 · Cited by 49 · see citing works
Activated Raf kinase inhibits muscle cell differentiation through a MEF2-dependent mechanism
Winter, B., & Arnold, H.-H. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.23.4211 · Cited by 47 · see citing works
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Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration
Tachtsis, B., Camera, D., & Lacham-Kaplan, O. (2018) · Nutrients · doi:10.3390/nu10030309 · Cited by 104 · see citing works
- Authors
- Li, J., & Johnson, S. E.
- Affiliations
- University of Florida (US)
- Corresponding author
- Johnson, Sally E.
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 345
- Issue
- 4
- Pages
- 1425-1433
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2011006146
- Cited by
- 137
- References
- 227
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 7 · 2022: 9 · 2021: 6 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 8 · 2015: 10 · 2014: 7 · 2013: 15 · 2012: 6
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (R01-AR048830)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- ERK2, ERK1, myogenesis, skeletal myoblasts, terminal differentiation, IGF-1 signaling, Raf/MEK/ERK pathway, PI3K signaling, C2C12 myoblasts, siRNA knockdown
- MeSH terms
- Cell Differentiation, Cell Line, Insulin-Like Growth Factor I, Myofibrils, Transfection, Blotting, Western, Signal Transduction, Fibroblast Growth Factor 2, Myogenin, Mitogen-Activated Protein Kinase 1, Myoblasts, Skeletal, RNA, Small Interfering, Mitogen-Activated Protein Kinase 3, Cell Proliferation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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