Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation

Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in people younger than 30 yr. HCM is characterized by hypertrophy of the left ventricular wall and interventricular septum, myocyte disarray, fibrosis, and diastolic dysfunction. HCM is also associated with marked alterations in cardiomyocyte function, including changes in electrophysiology, contractility, and calcium handling (Harvey and Leinwand, 2011). Large-scale sequencing of families has revealed that 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. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. Computational modeling shows that the increased cellular force is consistent with the molecular mechanism. These changes in cellular contractility cause 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 of familial HCM, leading to activation of adaptive mechanobiological signaling pathways.

Automated summary

Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in sarcomeric proteins and is the leading cause of sudden cardiac death in individuals under 30 years of age. The complex pathogenesis of HCM involves changes in molecular, cellular, and tissue levels of function. Research suggests that molecularly driven changes in mechanical tension are the primary driver of early disease progression in familial HCM.