Abstract 904: Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy

Abstract

Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, one of the outstanding challenges in the field has been connecting mutation-induced changes in molecular function with the phenotype seen in cardiomyocytes. Many of the DCM mutation-induced changes in contractility at the molecular scale are subtle, begging the question of what other factors could link molecular-scale changes in contractile proteins with the cellular phenotype. We hypothesized that disease-causing mutations of sarcomeric proteins would likely affect not only contraction, but also how cardiomyocytes sense and respond to changes in their mechanical environment associated with aging and disease. To test this hypothesis, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, deltaK210. We determined the molecular mechanism of deltaK210 using biochemical and biophysical tools, and then we used computational modeling to predict that the mutation should reduce the force per sarcomere in cells. In mutant human stem cell derived cardiomyocytes, we found that deltaK210 not only reduces contractility, but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results link the molecular and cellular phenotypes and implicate impaired mechanosensing as an under-appreciated mechanism in the pathogenesis and progression of dilated cardiomyopathies. These results also have important implications for our understanding of multiple heart diseases and the design of precision therapeutics.