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 cardiomyopathycausing mutations that affect the intramolecular and intermolecular interactions controlling the off state of the motors. myosin filament mechanosensing | heart regulation | small-angle X-ray diffraction | cardiac muscle | Frank-Starling mechanism I n each sarcomere, the structural unit of the skeletal and cardiac muscles, myosin motors arranged in antiparallel arrays in the two halves of the thick myosin-containing filament work cooperatively, generating force and shortening by cyclic ATPdriven interactions with the interdigitating thin actin-containing filaments. The textbook model for the activation of contraction indicates that the binding to actin of myosin motors from the neighboring thick filament is controlled by a calcium-dependent structural change in the thin filament. However, in these muscles at rest, most of the myosin motors are in the off state and packed into helical tracks with 43-nm periodicity on the surface of the thick filaments (1-4), making them unavailable for binding to the thin filament and ATP hydrolysis (5, 6). Recent X-ray diffraction experiments on single fibers from skeletal muscle showed that, in addition to the canonical thin filament activation system, a thick filament mechanosensing mechanism provides a way for selective unlocking of myosin motors during high load contraction (7). This thick filament-based regulation has not yet been shown in cardiac muscle, in which several regulatory systems are significant. In contrast to skeletal muscle, during heart contraction, the internal concentration of Ca 2+ ([Ca 2+ ] i ) may not reach the full activation level, and thus, the mechanical response depends on both [Ca 2+ ] i and the sensitivity of the filaments to Ca 2+ (8, 9). For a given [Ca 2+ ] i , the maximal force i...

Adaptation of myocardial twist in the remodelled athlete's heart is not related to cardiac output

“…These data strongly complement the LV twist and TwSR responses and are in agreement with recent findings in molecular cardiology (Reconditi et al, 2017). These data strongly complement the LV twist and TwSR responses and are in agreement with recent findings in molecular cardiology (Reconditi et al, 2017).…”

“…Another measurement that supported a consistent pattern of LV systolic muscle function between hearts of different sizes was the similar LV shortening in both study groups. These data strongly complement the LV twist and TwSR responses and are in agreement with recent findings in molecular cardiology (Reconditi et al, 2017).…”

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Contracting striated muscle has a dynamic I‐band spring with an undamped stiffness 100 times larger than the passive stiffness

“…Therefore, the dynamic behaviour of the titin elasticity described here for the skeletal muscle could play a more efficient, specific role in the mechanosensing‐based regulation of the thick filament in the heart (Reconditi et al . ; Piazzesi et al . ).…”

Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function

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