title: Myosin filament activation in the heart is tuned to the mechanical task.
abstract: The mammalian heart pumps blood through the vessels, maintaining the dynamic equilibrium in a circulatory system driven by two pumps in series. This vital function is based on the fine-tuning of cardiac performance by the Frank-Starling mechanism that relates the pressure exerted by the contracting ventricle (end systolic pressure) to its volume (end systolic volume). At the level of the sarcomere, the structural unit of the cardiac myocytes, the Frank-Starling mechanism consists of the increase in active force with the increase of sarcomere length (length-dependent activation). We combine sarcomere mechanics and micrometer-nanometer-scale X-ray diffraction from synchrotron light in intact ventricular trabeculae from the rat to measure the axial movement of the myosin motors during the diastole-systole cycle under sarcomere length control. We find that the number of myosin motors leaving the off, ATP hydrolysis-unavailable state characteristic of the diastole is adjusted to the sarcomere length-dependent systolic force. This mechanosensing-based regulation of the thick filament makes the energetic cost of the systole rapidly tuned to the mechanical task, revealing a prime aspect of the Frank-Starling mechanism. The regulation is putatively impaired by cardiomyopathy-causing mutations that affect the intramolecular and intermolecular interactions controlling the off state of the motors.
authors.affiliation: PhysioLab, University of Florence, 50019 Florence, Italy.|Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia, Unità di Ricerca di Firenze, 50019 Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Reconditi
authors.affiliation: PhysioLab, University of Florence, 50019 Florence, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Caremani
authors.affiliation: PhysioLab, University of Florence, 50019 Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pinzauti
authors.affiliation: PhysioLab, University of Florence, 50019 Florence, Italy.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Powers
authors.affiliation: European Synchrotron Radiation Facility, F-38043 Grenoble, France.
authors.forename: Theyencheri
authors.initials: T
authors.lastname: Narayanan
authors.affiliation: Department of Physiology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.affiliation: PhysioLab, University of Florence, 50019 Florence, Italy.|Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia, Unità di Ricerca di Firenze, 50019 Florence, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Linari
authors.affiliation: PhysioLab, University of Florence, 50019 Florence, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lombardi
authors.affiliation: PhysioLab, University of Florence, 50019 Florence, Italy; gabriella.piazzesi@unifi.it.
authors.forename: Gabriella
authors.identifier: 0000-0001-9324-2241
authors.initials: G
authors.lastname: Piazzesi
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003971:Diastole; D056966:Excitation Contraction Coupling; D008297:Male; D040542:Mechanotransduction, Cellular; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism*; D051381:Rats; D012518:Sarcomeres / Q000378:metabolism; D013599:Systole; D014961:X-Ray Diffraction
chemical_list: D009218:Myosins; D002118:Calcium
keywords: Frank–Starling mechanism; cardiac muscle; heart regulation; myosin filament mechanosensing; small-angle X-ray diffraction