PT  - JOURNAL ARTICLE
AU  - Sarah R. Clippinger
AU  - Paige E. Cloonan
AU  - Lina Greenberg
AU  - Melanie Ernst
AU  - W. Tom Stump
AU  - Michael J. Greenberg
TI  - Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy
AID  - 10.1101/555391
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 555391
4099  - http://biorxiv.org/content/early/2019/02/21/555391.short
4100  - http://biorxiv.org/content/early/2019/02/21/555391.full
AB  - 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, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, ΔK210. We determined the molecular mechanism of ΔK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that ΔK210 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 alterations in mechanosensing as an important factor in the development of DCM.