The cGAS-STING pathway is dispensable in a mouse model ofLMNA-cardiomyopathy despite nuclear envelope rupture

Abstract

ABSTRACTMutations in the nuclear Lamin A/C gene (LMNA) cause diverse degenerative disorders, including malignant dilated cardiomyopathy in adults. A prevailing hypothesis postulates thatLMNAmutations cause nuclear envelope ruptures that trigger pathogenic inflammatory signaling via the cGAS-STING cytosolic DNA-sensing pathway. Here, we provide evidence against this hypothesis, using a mouse model ofLMNA-related cardiomyopathy that mimics Lamin A/C protein reduction observed in patient cardiomyocytes. We observed that pervasive nuclear envelope ruptures preceded the onset of cardiac transcriptional modulation and dilated cardiomyopathy. Nuclear ruptures activated DNA damage response without causing immediate cardiomyocyte death. However, cGAS-STING downstream cytokine genes remained inactive in the mutant cardiomyocytes. DeletingcGasorStingdid not alleviate cardiomyopathy. Instead, extracellular matrix signaling was predicted to emanate from Lamin A/C-reduced cardiomyocytes to communicate with fibroblasts in the heart. These findings suggest that cGAS-STING is not a major pathogenetic contributor toLMNA-related dilated cardiomyopathy in adult humans.