Background: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. Methods: We assayed myosin ATP binding to define the proportions of myosin in SRX or DRX conformations in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants with unknown clinical significance (VUS) that were identified in HCM patients, predicted functional consequences and associations with heart failure and arrhythmias. Results: Myosins undergo physiologic shifts between SRX conformations that maximized energy-conservation and active states (DRX) that enable cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacologic modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased SRX conformations while pathogenic variants destabilized these and increased the proportion of DRX myosins, which enhanced cardiomyocyte contractility but impaired relaxation, and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify VUS, we showed that variants that unbalanced myosin conformations were associated with higher rates of heart failure and arrhythmias in HCM patients. Conclusions: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy conserving states promotes contractile abnormalities, morphological and metabolic remodeling and adverse clinical outcomes in HCM patients. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in HCM patients.

中文翻译：

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肌球蛋白隔离调节肌节功能、心肌细胞能量和代谢，了解肥厚型心肌病的发病机制。


背景：肥厚型心肌病 (HCM) 是由肌节蛋白基因的致病性变异引起的，这些变异会引起心脏收缩过度、松弛不良、心脏能量消耗增加，并增加患者发生心律失常和心力衰竭的风险。最近的研究表明，肌球蛋白（肌节的分子马达）中的致病性错义变异聚集在参与肌节蛋白动态构象状态的残基中。我们假设这些构象对于调整收缩输出以实现能量守恒至关重要，并且 HCM 的病理生理学是由这些构象的不稳定造成的。方法：我们测定了肌球蛋白 ATP 结合，以确定健康啮齿动物和人类心脏中肌球蛋白在基线时的 SRX 或 DRX 构象比例，以及响应冬眠或致病性 HCM 变异降低的血流动力学需求。为了确定肌球蛋白构象、肌节功能和细胞生物学之间的关系，我们评估了肌球蛋白 ATP 酶活性的变构调节剂的收缩性、舒张性以及心肌细胞的形态和代谢。然后，我们测试了在 HCM 患者中发现的临床意义未知的肌球蛋白变异 (VUS) 的位置是否可以预测功能后果以及与心力衰竭和心律失常的关联。结果：肌球蛋白在 SRX 构象和活性状态 (DRX) 之间经历生理转变，从而最大限度地提高能量守恒，从而以更大的 ATP 消耗实现跨桥形成。全身血流动力学要求、肌球蛋白的药理调节剂和致病性肌球蛋白错义突变影响这些构象的比例。 冬眠增加了 SRX 构象，而致病性变异则破坏了这些构象的稳定性，并增加了 DRX 肌球蛋白的比例，从而增强了心肌细胞的收缩力，但损害了舒张性，并随着能量应激的增加而诱发肥厚性重塑。使用结构位置对 VUS 进行分层，我们发现肌球蛋白构象不平衡的变异与 HCM 患者心力衰竭和心律失常的较高发生率相关。结论：肌球蛋白构象建立了工作能量平衡，这对于终生细胞稳态和心脏功能至关重要。肌球蛋白能量守恒状态的不稳定会促进 HCM 患者的收缩异常、形态和代谢重塑以及不良的临床结果。治疗再稳定可纠正细胞收缩和代谢表型，并可能限制 HCM 患者的这些不良临床结果。