Abstract
A dual regulation of contraction operates in both skeletal and cardiac muscles. The first mechanism, based on Ca2+-dependent structural changes of the regulatory proteins in the thin filament, makes the actin sites available for binding of the myosin motors. The second recruits the myosin heads from the OFF state, in which they are unable to split ATP and bind to actin, in relation to the force during contraction. Comparison of the relevant X-ray diffraction signals marking the state of the thick filament demonstrates that the force feedback that controls the regulatory state of the thick filament works in the same way in skeletal as in cardiac muscles: even if in an isometric tetanus of skeletal muscle force is under the control of the firing frequency of the motor unit, while in a heartbeat force is controlled by the afterload, the stress-sensor switching the motors ON plays the same role in adapting the energetic cost of the contraction to the force. A new aspect of the Frank-Starling law of the heart emerges: independent of the diastolic filling of the ventricle, the number of myosin motors switched ON during systole, and thus the energetic cost of contraction, are tuned to the arterial pressure. Deterioration of the thick-filament regulation mechanism may explain the hyper-contractility related to hypertrophic cardiomyopathy, an inherited heart disease that in 40% of cases is due to mutations in cardiac myosin.
Highlights
In striated muscles, the contractile machinery is organized in sarcomeres, 2-μm long structural units in which two antiparallel arrays of myosin motors from the thick filament generate steady force and shortening by cyclic ATP-driven interactions with the nearby thin actin-containing filaments originating from the opposite extremities of the sarcomere
Growing evidence that myosin motors in the resting muscle lie along the surface of the thick filament, folded towards the center of the sarcomere, unable to bind actin (Woodhead et al, 2005; Zoghbi et al, 2008) and hydrolyze ATP (Stewart et al, 2010), raised the question of how the motors can sense the state of the thin filament during activation
Using X-ray diffraction on intact myo-cells from skeletal and cardiac muscles at ID02 beamline of the European Synchrotron (ESRF, Grenoble, France) (Narayanan et al, 2017), a second regulatory mechanism, based on thick filament mechanosensing, has been identified, which controls the recruitment of myosin motors from the state at rest in relation to the load (Linari et al, 2015; Reconditi et al, 2017)
Summary
In striated (skeletal and cardiac) muscles, the contractile machinery is organized in sarcomeres, 2-μm long structural units in which two antiparallel arrays of myosin motors from the thick filament generate steady force and shortening by cyclic ATP-driven interactions with the nearby thin actin-containing filaments originating from the opposite extremities of the sarcomere. V0 shortening imposed at the end of the latent period to prevent force development maintains the OFF structure of the thick filament, even if [Ca2+]i is high (Linari et al, 2015). Thick filament regulatory state determines the rate of force development and in turn depends on the force acting on the filament by means of a positive feedback that rapidly adapts the number of available motors to the load
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