心肌肌球蛋白丝活化的负荷依赖性

IF 4.7 2区医学 Q1 NEUROSCIENCES

Journal of Physiology-London Pub Date : 2024-11-17 DOI:10.1113/JP287434

Yanhong Wang, Luca Fusi, Jesus G. Ovejero, Cameron Hill, Samina Juma, Flair Paradine Cullup, Andrea Ghisleni, So-Jin Park-Holohan, Weikang Ma, Thomas Irving, Theyencheri Narayanan, Malcolm Irving, Elisabetta Brunello

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引用次数: 0

摘要

心肌收缩需要激活肌动蛋白丝和肌球蛋白丝。肌球蛋白丝活化的机制尚不清楚，但主要的候选假设是肌球蛋白丝的直接机械感应。在此，我们在不同负荷下通过电刺激激活大鼠心脏的完整小梁，并通过 X 射线衍射测量肌球蛋白丝的激活情况，从而验证了这一假设。出乎意料的是，我们发现肌球蛋白丝与活化相关的不同结构变化对负荷有着不同的依赖性。在早期激活过程中，所有结构变化都表明在较高载荷下激活速度更快，正如机械感应假说所预期的那样；但在后期，即使在很低的载荷下，肌球蛋白马达也会失去失活状态特有的螺旋顺序。我们的结论是，机械传感确实在心肌中起作用，但它得到了一种以前未曾描述过的机制的补充，这种机制将肌球蛋白丝的激活与肌动蛋白丝的激活联系在一起。要点：肌球蛋白丝活化控制着心肌收缩的强度和速度。肌球蛋白丝的早期激活由肌球蛋白丝负荷决定。在后期，肌球蛋白丝的活化受独立于负荷的途径控制。这种与负荷无关的途径为药物开发提供了新的目标和检测方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Load-dependence of the activation of myosin filaments in heart muscle

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Load-dependence of the activation of myosin filaments in heart muscle

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.

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来源期刊

Journal of Physiology-London 医学-神经科学

CiteScore

9.70

自引率

7.30%

发文量

817

审稿时长

2 months

期刊介绍： The Journal of Physiology publishes full-length original Research Papers and Techniques for Physiology, which are short papers aimed at disseminating new techniques for physiological research. Articles solicited by the Editorial Board include Perspectives, Symposium Reports and Topical Reviews, which highlight areas of special physiological interest. CrossTalk articles are short editorial-style invited articles framing a debate between experts in the field on controversial topics. Letters to the Editor and Journal Club articles are also published. All categories of papers are subjected to peer reivew. The Journal of Physiology welcomes submitted research papers in all areas of physiology. Authors should present original work that illustrates new physiological principles or mechanisms. Papers on work at the molecular level, at the level of the cell membrane, single cells, tissues or organs and on systems physiology are all acceptable. Theoretical papers and papers that use computational models to further our understanding of physiological processes will be considered if based on experimentally derived data and if the hypothesis advanced is directly amenable to experimental testing. While emphasis is on human and mammalian physiology, work on lower vertebrate or invertebrate preparations may be suitable if it furthers the understanding of the functioning of other organisms including mammals.