Desmoplakin loss leads to PKC-dependent insertion of series sarcomeres and contractile dysfunction in cardiomyocytes.

Background: Mutations in Methods: We use iPSC-derived engineered heart tissue (EHT) bearing a functional desmoplakin haploinsufficiency to model the heart failure phenotype that occurs in desmoplakin cardiomyopathy. Functional haploinsufficiency is secondary to a missense mutation, R451G, that results in proteolytic degradation of desmoplakin with no detectable protein. We complement functional data obtained in tissue-engineered constructs with cell biology assays in 2D cardiomyocytes to glean insights into the mechanism and mechanobiology of desmoplakin cardiomyopathy. Results: Engineered heart tissues harboring a desmoplakin insufficiency recapitulate a patient phenotype notable for hypocontractility and ventricular dilation. Surprisingly, DSP-mutant tissues exhibited a shortened resting sarcomere length that was dependent on protein kinase C activity. Concurrently, mechanical load on α-catenin was increased, suggesting a mechanism by which desmosomal insufficiency redistributes force to adherens junctions. Excessive loading on adherens junctions may act as a stimulus for avid insertion of series sarcomeres, shortening the length per sarcomere, and resulting in a contractile deficit. PKC inhibition rescues shortened sarcomere length in DSP-mutant tissues, suggesting that it could be a target for future molecular therapies. Conclusions: Our study uncovers a novel mechanism underlying systolic dysfunction in desmoplakin cardiomyopathy. We not only recapitulate the disease phenotype, but we identify sarcomere length regulation through altered force transmission at the intercalated disc as a previously-unrecognized mechanism.