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Myosin Filament Activation in the Heart Is Tuned to the Mechanical Task

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Myosin Filament Activation in the Heart Is Tuned to the Mechanical Task Myosin filament activation in the heart is tuned to the mechanical task Massimo Reconditia,b, Marco Caremania, Francesca Pinzautia, Joseph D. Powersa,1, Theyencheri Narayananc, Ger J. M. Stienend, Marco Linaria,b, Vincenzo Lombardia, and Gabriella Piazzesia,2 aPhysioLab, University of Florence, 50019 Florence, Italy; bConsorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia, Unità di Ricerca di Firenze, 50019 Florence, Italy; cEuropean Synchrotron Radiation Facility, F-38043 Grenoble, France; and dDepartment of Physiology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands Edited by James A. Spudich, Stanford University School of Medicine, Stanford, CA, and approved February 13, 2017 (received for review November 25, 2016) The mammalian heart pumps blood through the vessels, maintaining modulated by the degree of phosphorylation of contractile (Myosin the dynamic equilibrium in a circulatory system driven by two pumps Regulatory Light Chain), regulatory [Troponin I on the thin filament in series. This vital function is based on the fine-tuning of cardiac and myosin-binding protein C (MyBP-C) in the thick filament], and performance by the Frank–Starling mechanism that relates the pres- cytoskeletal proteins (14–20). We exploited the nanometer–micro- sure exerted by the contracting ventricle (end systolic pressure) to its meter-scale X-ray diffraction possible at beamline ID02 of the volume (end systolic volume). At the level of the sarcomere, the European Synchrotron Radiation Facility (ESRF) to record the structural unit of the cardiac myocytes, the Frank–Starling mechanism structural changes undergone by the thick filament and the myosin consistsoftheincreaseinactiveforcewiththeincreaseofsarcomere motors during the systole–diastole cycle in intact trabeculae from length (length-dependent activation). We combine sarcomere me- rat cardiac ventricle under SL control. X-ray signals marking the chanics and micrometer–nanometer-scale X-ray diffraction from syn- structure of the thick filament indicate that, in diastole, the myosin chrotron light in intact ventricular trabeculae from the rat to measure motors are in the off state. At the peak of the twitch, the number of the axial movement of the myosin motors during the diastole–systole motors that have been unlocked from the off state is found to be cycle under sarcomere length control. We find that the number of proportional to the SL-dependent systolic force, indicating that thick myosin motors leaving the off, ATP hydrolysis-unavailable state char- filament mechanosensing rapidly tunes the energetic requirements acteristic of the diastole is adjusted to the sarcomere length-dependent to the mechanical task. systolic force. This mechanosensing-based regulation of the thick fila- ment makes the energetic cost of the systole rapidly tuned to the Results mechanical task, revealing a prime aspect of the Frank–Starling mech- SL–Tension Relation Determined with Ultra-Small-Angle X-Ray anism. The regulation is putatively impaired by cardiomyopathy- Diffraction. 2D X-ray diffraction patterns from an intact trabec- causing mutations that affect the intramolecular and intermolecular ula are collected with the detector placed at 30 m from the interactions controlling the off state of the motors. preparation to record the first orders of the sarcomeric reflec- tions (Fig. 1 A and B). The length of the trabecula between the myosin filament mechanosensing | heart regulation | small-angle X-ray transducer levers at rest is set, so that the average SL is ∼2.2 μm diffraction | cardiac muscle | Frank–Starling mechanism [Fig. 1 A, Dia (2.23 μm) and B, blue line]. During force devel- opment in fixed end (FE) conditions, sarcomeres shorten against n each sarcomere, the structural unit of the skeletal and car- the compliance of the attachments, so that, at the peak of force T μ A B Idiac muscles, myosin motors arranged in antiparallel arrays in ( p), SL becomes 1.95 m (13% shorter) (Fig. 1 , FE and , the two halves of the thick myosin-containing filament work cooperatively, generating force and shortening by cyclic ATP- Significance driven interactions with the interdigitating thin actin-containing filaments. The textbook model for the activation of contraction This paper represents a major advance in understanding intrinsic indicates that the binding to actin of myosin motors from the heart beat regulation, because it provides an integrated view of neighboring thick filament is controlled by a calcium-dependent the Frank–Starling law that combines mechanical, structural, and structural change in the thin filament. However, in these muscles energetic aspects of heart performance. We show that mecha- at rest, most of the myosin motors are in the off state and packed nosensing in the myosin filament adjusts the number of myosin into helical tracks with 43-nm periodicity on the surface of the motors recruited from the off, ATP hydrolysis-unavailable state thick filaments (1–4), making them unavailable for binding to the to the systolic force. In this way, the energetic cost of the heart thin filament and ATP hydrolysis (5, 6). Recent X-ray diffraction beat is tuned to the end systolic pressure–volume relation. These experiments on single fibers from skeletal muscle showed that, in results elucidate a plausible mechanistic link between the mu- addition to the canonical thin filament activation system, a thick tations that affect the structure of the myosin filament and filament mechanosensing mechanism provides a way for selective cause hypercontractility and/or loss of contractile efficiency and unlocking of myosin motors during high load contraction (7). dysregulation of the control by the stress-sensing mechanism on This thick filament-based regulation has not yet been shown in the state of the myosin motors. cardiac muscle, in which several regulatory systems are signifi- cant. In contrast to skeletal muscle, during heart contraction, the Author contributions: M.R., M.C., G.J.M.S., M.L., V.L., and G.P. designed research; M.R., 2+ 2+ M.C., F.P., J.D.P., T.N., G.J.M.S., M.L., V.L., and G.P. performed research; M.R., M.C., F.P., internal concentration of Ca ([Ca ]i) may not reach the full J.D.P., T.N., G.J.M.S., M.L., V.L., and G.P. analyzed data; and M.R., G.J.M.S., M.L., V.L., and activation level, and thus, the mechanical response depends on G.P. wrote the paper. 2+ 2+ both [Ca ]i and the sensitivity of the filaments to Ca (8, 9). For The authors declare no conflict of interest. 2+ a given [Ca ]i, the maximal force is larger at longer sarcomere This article is a PNAS Direct Submission. lengths [SLs; length-dependent activation (LDA)], which is the 1Present address: Department of Bioengineering, University of Washington, Seattle, cellular basis of the Frank–Starling law of the heart (10, 11). WA 98105. LDA is the result of a chain of yet undefined events relating a 2To whom correspondence should be addressed. Email: [email protected]. mechanosensor of the SL to the number of force-generating This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. motors and consequently the force (12, 13), and moreover, it is 1073/pnas.1619484114/-/DCSupplemental. 3240–3245 | PNAS | March 21, 2017 | vol. 114 | no. 12 www.pnas.org/cgi/doi/10.1073/pnas.1619484114 Downloaded by guest on September 25, 2021 A Dia C 120 FE 80 40 Force (kPa) 0 LC 0 900 1100 Time (ms) B D 800 125 600 100 75 400 50 nd rd th th 200 2 3 4 5 Force (kPa) Intensity (a.u.) 25 0 0 0.0 0.5 1.0 1.5 2.0 1.8 2.0 2.2 2.4 -1 Reciprocal spacing (µm ) Sarcomere length (µm) Fig. 1. SL measured in a twitching trabecula with ultra-small-angle X-ray diffraction. (A) Meridional slices of 2D diffraction patterns during diastole (Dia) and at the force peak of a systole in either FE or sarcomere LC conditions. Camera length of 30 m; total exposure time of 10 ms for FE and LC and 20 ms for Dia. (B) Meridional intensity profiles from A. Background subtraction starts at ∼0.7 μm−1. Blue, diastole; red, FE twitch; violet, LC twitch. (C) Force of the FE (red) and LC (violet) twitches. Stimulus starts at 775 ms. Gray bars indicate X-ray time windows. (D) Force–SL relations in diastole (triangles) and systole (circles). Black symbols are from ref. 13; blue (Dia), red (FE), and violet (LC) symbols are from four trabeculae used in this work. Graph reprinted with permission from ref. 13. red line). Sarcomere shortening recorded during the force high-angle side (Fig. 2C, blue line), typical of the off state of the development in an FE twitch is used as a feedforward signal to myosin motors (2, 4, 7), and both SM3 (Fig. 2D, blue) and SM6 prevent the sarcomere shortening during the next twitch [length (Fig. 2F, blue) mark a short backbone periodicity. With the pacing clamp (LC) conditions (13, 21)]. In this case, SL at Tp is 6% frequency used here (0.5 Hz), these findings are independent of shorter (2.1 μm) (Fig. 1 A, LC and B, violet line). Tp is larger in whether the trabecula is quiescent or in diastole (Fig. S4). LC (90 kPa) (violet trace in Fig. 1C) than in FE (55 kPa) (red At the peak of twitch force, the intensities of all of the myosin trace in Fig. 1C). In four trabeculae, the SLs are 2.21 ± 0.02 μm meridional reflections (Fig. 2B, red and violet lines) and that of (mean ± SE) in diastole (blue triangle in Fig. 1D), 1.90 ± 0.03 μm the ML1 (Fig. S2 B and C) decrease because of the myosin in FE (red circle in Fig.
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