High-resolution X-ray diffraction analysis uncovers structural filament pathways modulating cardiac force in rat muscle, suggesting novel molecular targets for therapy.
Regulation of heart function is attributed to a dual filament mechanism: ( i ) the Ca 2+ -dependent structural changes in the regulatory proteins of the thin, actin-containing filament making actin available for myosin motor attachment 1 , and ( ii ) the release of motors from their folded (OFF) state on the surface of the thick filament 2 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 3 , but its molecular basis is still unknown. Here high spatial resolution X-ray diffraction data from electrically paced rat trabeculae and papillary muscles call for a revision of the mechanosensing hypothesis and provide a molecular explanation of the modulation of heart performance also in light of the recent cryo-EM thick filament structure 4, 5 . We find that upon stimulation titin activation 6 triggers structural changes in the thick filament that switch motors ON throughout the filament within ∼½ the maximum systolic force. These structural changes also drive MyBP-C N-terminus to bind actin 7 promoting first motor attachments 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-neighbour cooperative thin filament activation by attached motors 8 . The identification of the roles of MyBP-C, titin, thin and thick filaments in heart regulation enables their targeting for potential therapeutic interventions.
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Morotti et al. (2024) studied this question.
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