Attenuated Epigenetic Suppression of Muscle Stem Cell Necroptosis Is Required for Efficient Regeneration of Dystrophic Muscles

Somatic stem cells expand massively during tissue regeneration, which might require control of cell fitness, allowing elimination of non-competitive, potentially harmful cells. How or if such cells are removed to restore organ function is not fully understood. Here, we show that a substantial fraction of muscle stem cells (MuSCs) undergo necroptosis because of epigenetic rewiring during chronic skeletal muscle regeneration, which is required for efficient regeneration of dystrophic muscles. Inhibition of necroptosis strongly enhances suppression of MuSC expansion in a non-cell-autonomous manner. Prevention of necroptosis in MuSCs of healthy muscles is mediated by the chromatin remodeler CHD4, which directly represses the necroptotic effector Ripk3, while CHD4-dependent Ripk3 repression is dramatically attenuated in dystrophic muscles. Loss of Ripk3 repression by inactivation of Chd4 causes massive necroptosis of MuSCs, abolishing regeneration. Our study demonstrates how programmed cell death in MuSCs is tightly controlled to achieve optimal tissue regeneration. [Display omitted] •Necroptotic cell death of MuSCs is essential for efficient muscle regeneration•Inhibition of necroptosis exacerbates adverse crosstalk among mdx muscle stem cells•The CHD4/NuRD complex directly represses Ripk3-dependent necroptosis•Attenuated recruitment of CHD4 to Ripk3 locus lowers necroptosis threshold in dystrophy Sreenivasan et al. describe the necessity to remove a subpopulation of muscle stem cells by necroptosis for efficient regeneration of chronically damaged skeletal muscles. Muscle stem cells acquire a lowered threshold for necroptosis by attenuating recruitment of the repressive CHD4/NuRD complex to the Ripk3 promotor.