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

• DOI: 10.1161/res.125.suppl_1.904
• Publication Date: 2019-10-16T17:53:59Z
• Authors: Michael J Greenberg; Sarah R Clippinger; Paige E Cloonan; Melanie Ernst; Tom Stump; Lina Greenberg
• Keywords: Dilated Cardiomyopathy; Contractility; Desmin; Proteostasis; Haploinsufficiency

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