Molecular bases of regulation of cardiac contractility

Regulation of heart contractility is operated by thin and thick filaments. Ca2+-induced structural changes in the regulatory proteins of the thin filament release the actin sites for interaction with myosin motors. Titin mediated thick filament mechanosensing recruits motors from their OFF state, starting from the distal region of the half thick filament (htf) and attains saturation at ~40 kPa, while first motor attachment to actin occurs from the central region of the htf, likely promoted by MyBP-C. High systolic forces (>40 kPa) are explained by attachment of motors from progressively more peripheral region for the near-neighbor cooperative activation of the thin filament by attached motors. Mutations in these proteins cause cardiomyopathy. In the planned visit we will combine mechanics and X-ray diffraction on trabeculae of rats carrying a RBM20 mutation responsible for the development of a Dilated Cardiomyopathy, likely related to preferential expression of a longer I-band titin.