Prevention of Mechanics-Induced Hyperproliferative Fibroblast States Alleviates Dilated Cardiomyopathy
Cardiomyocyte hypocontractility underlies inherited dilated cardiomyopathy (DCM), but the fibroblasts' impact on DCM phenotypes is poorly understood despite its regulation of fibrosis, which is a strong predictor of disease severity. DCM mice with an I61Q variant of cardiac troponin c (cTnC)  had elevated diastolic tension sensation at fibroblast focal adhesions and matrix-integrin receptor interactions that initiated de novo  formation of hyperproliferative-mechanosensitized states and doubled the population . These fibroblast adaptations drove fibrosis-independent myocardial stiffening and subsequent cardiomyocyte dilation. Genetically disabling mechanotransduction arrested the fibroblast response, which in turn prevented dilated myocyte remodeling and drastically improved myocyte hypocontractility and myocardial function. In conclusion, noncanonical  fibroblast-dependent stiffening of the myocardium proved essential to the DCM phenotype, marking a potential  cellular target for therapeutic intervention. Overall design: Single nucleus RNA sequencing of cardiac ventricles from mice of WT, I61Q mutant, or I61Q mutant and fibroblast-specific p38 knockout mice (I61Q-p38).