Cardiac fibroblasts counterbalance cardiomyocytes inLMNAcardiomyopathy pathogenesis

Genetic cardiomyopathies arising fromLMNAgene mutations display variable age of onset, severity, and fibrosis development despite being monogenic in nature. This variability suggests a fundamental element in disease pathogenesis that has yet to be elucidated. Given the central role cardiac fibroblasts (CFs) play in fibrosis, we studied the relevance ofLMNAin CFs. Using primary CFs andin vivomouse models, we found thatLmnamutations impact various aspects of CF function. Both knockdown and point-mutant models impaired CF proliferation and contraction whereas other functions appear to be mutation-dependent. SimultaneousLmnadeletion in cardiomyocytes and CFs delayed disease progression, improved cardiac function, and prolonged survival, indicating thatLmnamediate an opposing balance between cardiomyocytes and CFs in driving disease pathogenesis. Our results elucidate previously unexplored roles ofLMNAin CFs and suggest that interactions between CFs and cardiomyocytes underlie the rate of progression and the severity ofLMNAcardiomyopathy.