RT Journal Article SR Electronic T1 Mechanical dysfunction induced by a hypertrophic cardiomyopathy mutation is the primary driver of cellular adaptation JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.05.04.067181 DO 10.1101/2020.05.04.067181 A1 Sarah R. Clippinger A1 Paige E. Cloonan A1 Wei Wang A1 Lina Greenberg A1 W. Tom Stump A1 Paweorn Angsutararux A1 Jeanne M. Nerbonne A1 Michael J. Greenberg YR 2020 UL http://biorxiv.org/content/early/2020/05/05/2020.05.04.067181.abstract AB Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. Here, we examined a HCM mutation in troponin T, R92Q. We demonstrate that the primary molecular insult driving the disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. We demonstrate computationally that these increases in force are direct consequences of the initial molecular insult. This altered cellular contractility causes downstream alterations in gene expression, calcium handling, and electrophysiology. Taken together, our results demonstrate that molecularly driven changes in mechanical tension drive the early disease pathogenesis, leading to activation of adaptive mechanobiological signaling pathways.Competing Interest StatementThe authors have declared no competing interest.