Cardiac fibroblasts counterbalance cardiomyocytes in LMNA cardiomyopathy pathogenesis

Genetic cardiomyopathies arising from LMNA gene 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 of LMNA in CFs. Using primary CFs and in vivo mouse models, we found that Lmna mutations 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. Simultaneous Lmna deletion in cardiomyocytes and CFs delayed disease progression, improved cardiac function, and prolonged survival, indicating that Lmna mediate an opposing balance between cardiomyocytes and CFs in driving disease pathogenesis. Our results elucidate previously unexplored roles of LMNA in CFs and suggest that interactions between CFs and cardiomyocytes underlie the rate of progression and the severity of LMNA cardiomyopathy.