The role of the transforming growth factor (TGF)-β pathway in myocardial fibrosis is well recognized. However, the precise role of this signaling axis in cardiomyocyte (CM) biology is not defined. In TGF-β signaling, SMAD4 acts as the central intracellular mediator. To investigate the role of TGF-β signaling in CM biology, the authors deleted SMAD4 in adult mouse CMs. We demonstrate that CM-SMAD4-dependent TGF-β signaling is critical for maintaining cardiac function, sarcomere kinetics, ion-channel gene expression, and cardiomyocyte survival. Thus, our findings raise a significant concern regarding the therapeutic approaches that rely on systemic inhibition of the TGF-β pathway for the management of myocardial fibrosis.
Keywords: CM, cardiomyocyte; CSA, cross-sectional area; CTL, control; DCM, dilated cardiomyopathy; KO, knockout; LV, left ventricle/ventricular; MAPK, mitogen-activated protein kinase; MCM, MerCreMer; PI3K, phosphoinositide-3 kinase; RNA-Seq, RNA sequencing; SMAD4; TAK1, transforming growth factor beta–activated kinase 1; TAM, tamoxifen; TGF, transforming growth factor; TGF-β; cMyBP-C, cardiac myosin-binding protein C; cardiomyocyte; cardiomyopathy; fibrosis; heart failure.