Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in...

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 tested a prevailing hypothesis that NE ruptures trigger pathological cGAS-STING cytosolic DNA-sensing pathway, using a mouse model of Lamin-cardiomyopathy. Reduction of Lamin A/C in cardiomyocytes of adult mice caused pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures were followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remained inactive. Deleting cGas or Sting did not rescue cardiomyopathy. The lack of cGAS-STING activation was likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling was 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.