Molecular bases of regulation of cardiac contractility

Regulation of heart contractility is operated by both thin, actin containing filaments, and thick, myosin containing filaments. Ca2+-induced structural changes in the regulatory proteins of the thin filament release the actin sites for interaction with myosin motors. Thick filament mechanosensing adapts to the load the number of motors recruited from the OFF state in which they lie tilted back on their tails unable to interact with actin. In the heartbeat both thin and thick filament activations are under the control of modulatory mechanisms by accessory proteins. Mutations in these proteins cause dysregulation and cardiomyopathy. We use sarcomere-level mechanics and X-ray diffraction on intact and demembranated myocytes of the ventricle of wild type, mutant and transgenic animal models to investigate the mechanisms that control thick filament regulation/dysregulation and test small molecules candidate as therapeutic tools.