Journal
CELL RESEARCH
Volume 30, Issue 12, Pages 1063-1077Publisher
SPRINGERNATURE
DOI: 10.1038/s41422-020-00393-6
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Funding
- Strategic Priority Research Program of the Chinese Academy of Science [XDA16020400]
- NSFC [31622035]
- Ministry of Science and Technology of China [2017YFA002700]
- National Natural Science Foundation of China [31622035, 91649104, 31671536, 31871304]
- National Basic Research Program of China 973 Program [2015CB943400]
- CAS-Youth Innovation Program Association [2016246]
- Space Medical Experiment Project of China Manned Space Program [HYZHXM01017]
- Science and Technology of Commission of Shanghai Municipal [17JC1400901, 18ZR1446300]
- Peak Disciplines (Type IV) of Institution of High Learning in Shanghai
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Necroptosis, a form of programmed cell death, is characterized by the loss of membrane integrity and release of intracellular contents, the execution of which depends on the membrane-disrupting activity of the Mixed Lineage Kinase Domain-Like protein (MLKL) upon its phosphorylation. Here we found myofibers committed MLKL-dependent necroptosis after muscle injury. Either pharmacological inhibition of the necroptosis upstream kinase Receptor Interacting Protein Kinases 1 (RIPK1) or genetic ablation of MLKL expression in myofibers led to significant muscle regeneration defects. By releasing factors into the muscle stem cell (MuSC) microenvironment, necroptotic myofibers facilitated muscle regeneration. Tenascin-C (TNC), released by necroptotic myofibers, was found to be critical for MuSC proliferation. The temporary expression of TNC in myofibers is tightly controlled by necroptosis; the extracellular release of TNC depends on necroptotic membrane rupture. TNC directly activated EGF receptor (EGFR) signaling pathway in MuSCs through its N-terminus assembly domain together with the EGF-like domain. These findings indicate that necroptosis plays a key role in promoting MuSC proliferation to facilitate muscle regeneration.
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