Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin cardiomyopathy mice [SLAM-IT-seq]. Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin cardiomyopathy mice [SLAM-IT-seq]

Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardiomyocytes of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy. Overall design: SLAM-IT-seq

核被膜（nuclear envelope, NE）破裂是核纤层蛋白相关扩张型心肌病中的新兴观测表型，该疾病为成人起病型，由核纤层组分核纤层蛋白A/C（Lamin A/C）的功能丧失突变所引发。本研究针对一项主流假说展开验证：核被膜破裂可触发病理性cGAS-STING胞质DNA感知通路，实验采用核纤层蛋白心肌病小鼠模型开展研究。结果显示，成年小鼠心肌细胞中核纤层蛋白A/C的表达下调，会导致心肌细胞出现广泛的核被膜破裂，该现象先于炎症转录、纤维化及致死性扩张型心肌病发生。核被膜破裂后伴随DNA损伤积累，但并未引发即刻的心肌细胞死亡。然而，cGAS-STING依赖性炎症信号通路始终处于未激活状态。敲除cGas或Sting基因并未能改善该扩张型心肌病表型。这种cGAS-STING通路激活缺失的原因，大概率是成年心肌细胞在基线状态下几乎不表达cGAS。与之相反，细胞外基质（extracellular matrix, ECM）信号通路被激活，且该通路可能介导了核纤层蛋白表达下调的心肌细胞向成纤维细胞传递的促炎信号。本研究将细胞外基质信号通路（而非cGAS-STING通路）认定为核纤层蛋白心肌病中潜在的炎症介导因素。实验整体设计：SLAM-IT-seq