An integrated picture of the structural pathways controlling the heart performance

The regulation of heart function is attributed to a dual filament mechanism: (i) the Ca2+-dependent structural changes in the regulatory proteins of the thin, actin-containing filament making actinavailable for myosin motor attachment, and (ii) the release of motors from their folded (OFF) state on the surface of the thick filament allowing them to attach and pull the actin filament. Thick filament mechanosensing is thought to control the number of motors switching ON in relation to the systolic performance, but its molecular basis is still controversial. Here we use high spatial resolution X-ray diffraction data from electrically paced rat trabeculae and papillary muscles to provide a molecular explanation of the modulation of heart performance that calls for a revision of the mechanosensing hypothesis. We find that upon stimulation, titin-mediated structural changes in the thick filament switch motors ON throughout the filament within ~½ the maximum systolic force. These structural changes also drive MyBP-C to promote first motor attachments to actin from the central 1/3 of the half-thick filament. Progression of attachments towards the periphery of half-thick filament with increase in systolic force is carried on by near-neighbor cooperative thin filament activation by attached motors. The identification of the roles of MyBP-C, titin, thin and thick filaments in heart regulation enables their targeting for potential therapeutic interventions.