Gokhan, I.; Li, X.; Sendek, J. M.; Mora Pagan, A. J.; Akar, F. G.; Campbell, S. G.

Background Mutations in DSP, which encodes the protein desmoplakin, lead to cardiomyopathy with unusually high penetrance. Clinical features include ventricular tachyarrhythmias, fibro-fatty infiltration of both ventricles, and ultimately dilated cardiomyopathy. While some data have been gathered to explain the electrophysiological and contractile consequences of desmoplakin cardiomyopathy, a comprehensive mechanism linking DSP mutations to ventricular dilation and heart failure remains elusive. 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 -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.