Abstract
Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays important roles during inflammation. However, its roles in myoblast differentiation and muscle regeneration remain unexplored. We show here that OSM potently inhibited myoblast differentiation mainly by activating the JAK1/STAT1/STAT3 pathway. OSM downregulated myocyte enhancer-binding factor 2A (MEF2A), upregulated the expression of Id1 and Id2, and inhibited the transcriptional activity of MyoD and MEF2. In addition, OSM also enhanced the expression of STAT3 and OSM receptor, which constituted a positive feedback loop to further amplify OSM-induced signaling. Moreover, we found that STAT1 physically associated with MEF2 and repressed its transcriptional activity, which could account for the OSM-mediated repression of MEF2. Although undetectable in normal muscles in vivo, OSM was rapidly induced on muscle injury and then promptly downregulated just before the majority of myoblasts differentiate. Prolonged expression of OSM in muscles compromised the regeneration process without affecting myoblast proliferation, suggesting that OSM functions to prevent proliferating myoblasts from premature differentiation during the early phase of muscle regeneration.
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Acknowledgements
We thank Dr Toru Ouchi for the STAT1c construct, and other members of the Wu laboratory for technical help and discussions. This project was supported by grants from Hong Kong Research Grant Council (N_HKUST621/08, HKUST6496/06M, 663308, HKUST1/06C to ZW) and an Area of Excellence Scheme (AoE/B-15/01) of the University Grants Council.
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Supplementary information, Figure S1
Simultaneous inhibition of JAK1 and ERK reduced myoblast proliferation (PDF 130 kb)
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OSM treatment did not alter the stability of Id proteins. (PDF 37 kb)
Supplementary information, Figure S3
STAT1 interacted with and repressed MEF2 (PDF 80 kb)
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Xiao, F., Wang, H., Fu, X. et al. Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration. Cell Res 21, 350–364 (2011). https://doi.org/10.1038/cr.2010.144
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DOI: https://doi.org/10.1038/cr.2010.144
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