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

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.

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.

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.

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.