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.

坏死性凋亡是程序性细胞死亡的一种形式，其特征在于膜完整性的丧失和细胞内内容物的释放，其执行取决于混合谱系激酶结构域样蛋白 (MLK​​L) 磷酸化后的膜破坏活性。在这里，我们发现肌纤维在肌肉损伤后发生 MLKL 依赖性坏死。对坏死性凋亡上游激酶受体相互作用蛋白激酶 1 (RIPK1) 的药理学抑制或肌纤维中 MLKL 表达的基因消融导致显着的肌肉再生缺陷。通过将因子释放到肌肉干细胞 (MuSC) 微环境中，坏死性肌纤维促进了肌肉再生。发现由坏死性肌纤维释放的 Tenascin-C (TNC) 对 MuSC 增殖至关重要。TNC 在肌纤维中的临时表达受到坏死性凋亡的严格控制；TNC 的细胞外释放依赖于坏死性细胞膜破裂。TNC 通过其 N 端组装域和 EGF 样域直接激活 MuSC 中的 EGF 受体 (EGFR) 信号通路。这些发现表明，坏死性凋亡在促进 MuSC 增殖以促进肌肉再生方面起着关键作用。