Wang Yanhong, Fusi Luca, Ovejero Jesus G, Hill Cameron, Juma Samina, Cullup Flair Paradine, Ghisleni Andrea, Park-Holohan So-Jin, Ma Weikang, Irving Thomas, Narayanan Theyencheri, Irving Malcolm, Brunello Elisabetta
Randall Centre for Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, King's College London, London, UK.
Centre for Human and Applied Physiological Sciences, King's College London, London, UK.
J Physiol. 2024 Dec;602(24):6889-6907. doi: 10.1113/JP287434. Epub 2024 Nov 17.
Contraction of heart muscle requires activation of both the actin and myosin filaments. The mechanism of myosin filament activation is unknown, but the leading candidate hypothesis is direct mechano-sensing by the filaments. Here, we tested this hypothesis by activating intact trabeculae from rat heart by electrical stimulation under different loads and measuring myosin filament activation by X-ray diffraction. Unexpectedly, we found that the distinct structural changes in the myosin filament associated with activation had different dependences on the load. In early activation, all the structural changes indicated faster activation at higher load, as expected from the mechano-sensing hypothesis, but, at later times, the helical order of the myosin motors characteristic of the inactivated state was lost even at very low load. We conclude that mechano-sensing does operate in heart muscle, but it is supplemented by a previously undescribed mechanism that links myosin filament activation to actin filament activation. KEY POINTS: Myosin filament activation controls the strength and speed of contraction in heart muscle. Early activation of the myosin filament is determined by the filament load. At later times, myosin filament activation is controlled by a load independent pathway. This load independent pathway provides new targets and assays for drug development.
心肌收缩需要肌动蛋白丝和肌球蛋白丝的激活。肌球蛋白丝激活的机制尚不清楚，但主要的候选假说是丝的直接机械传感。在这里，我们通过在不同负荷下对大鼠心脏的完整小梁进行电刺激来激活它，并通过X射线衍射测量肌球蛋白丝的激活，从而检验了这一假说。出乎意料的是，我们发现与激活相关的肌球蛋白丝的明显结构变化对负荷有不同的依赖性。在早期激活时，所有结构变化都表明在较高负荷下激活更快，这正如机械传感假说所预期的那样，但在后期，即使在非常低的负荷下，失活状态下肌球蛋白马达的螺旋顺序也会丧失。我们得出结论，机械传感在心肌中确实起作用，但它由一种以前未描述的机制补充，该机制将肌球蛋白丝的激活与肌动蛋白丝的激活联系起来。要点：肌球蛋白丝的激活控制心肌收缩的强度和速度。肌球蛋白丝的早期激活由丝的负荷决定。在后期，肌球蛋白丝的激活由一条与负荷无关的途径控制。这条与负荷无关的途径为药物开发提供了新的靶点和检测方法。
