Månsson Alf
Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden.
Front Physiol. 2025 Apr 17;16:1576245. doi: 10.3389/fphys.2025.1576245. eCollection 2025.
Small molecular compounds that affect the force, and motion-generating actin-myosin interaction in the heart have emerged as alternatives to treat or alleviate symptoms in severe debilitating conditions, such as cardiomyopathies and heart failure. Omecamtiv mecarbil (OM) is such a compound developed to enhance cardiac contraction. In addition to potential therapeutic use, its effects may help to elucidate myosin energy transduction mechanisms in health and disease and add insights into how the molecular properties govern contraction of large myosin ensembles in cardiac cells. Despite intense studies, the effects of OM are still incompletely understood.
Here we take an approach to elucidate the issue. First, we modify a model, previously used in studies of skeletal muscle, with molecular parameter values for human ventricular β-myosin to make it useful for studies of both myosin mutations and drugs. Repeated tests lead to at a set of parameter values that allow faithful reproduction of range of functional variables of cardiac myocytes. We then apply the model to studies of OM.
The results suggest that major effects of OM such as large reduction of the maximum velocity with more limited effects on maximum isometric force and slowed actin-activated ATPase can be accounted for by two key molecular effects. These encompass a reduced difference in binding free energy between the pre- and post-power-stroke states and greatly increased activation energy for the lever arm swing during the power-stroke. Better quantitative agreement, e.g., isometric force minimally changed from the control value by OM is achieved by additional changes in model parameter values previously suggested by studies of isolated proteins.
影响心脏中产生力量和运动的肌动蛋白-肌球蛋白相互作用的小分子化合物已成为治疗或缓解严重衰弱病症（如心肌病和心力衰竭）症状的替代方法。奥米卡替麦卡比（OM）就是这样一种开发用于增强心脏收缩的化合物。除了潜在的治疗用途外，其作用可能有助于阐明健康和疾病状态下的肌球蛋白能量转导机制，并深入了解分子特性如何控制心脏细胞中大型肌球蛋白集合体的收缩。尽管进行了深入研究，但OM的作用仍未完全了解。
在此，我们采用一种方法来阐明这个问题。首先，我们修改一个先前用于骨骼肌研究的模型，将其分子参数值设定为人心室β-肌球蛋白的参数值，使其可用于肌球蛋白突变和药物研究。反复测试得出一组参数值，这些参数值能够如实再现心肌细胞功能变量的范围。然后，我们将该模型应用于OM的研究。
结果表明，OM的主要作用，如最大速度大幅降低，对最大等长力的影响较有限，以及肌动蛋白激活的ATP酶减慢，可由两个关键分子效应来解释。这包括动力冲程前后结合自由能差异的减小，以及动力冲程期间杠杆臂摆动的活化能大幅增加。通过先前对分离蛋白质研究提出的模型参数值的额外变化，可以实现更好的定量一致性，例如，OM使等长力与对照值相比变化最小。
