Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy
Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy
复制标题
DOI：
10.1161/circulationaha.119.042339
复制
发表时间：
2020-03-10
期刊：
影响因子：
37.8
通讯作者：
Seidman, Christine E.
中科院分区：
文献类型：
--
作者：
Toepfer, Christopher N.;Garfinkel, Amanda C.;Seidman, Christine E.
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，这些变异引起心脏收缩过度、舒张不良、能量消耗增加，并增加患者心律失常和心力衰竭的风险。最近的研究表明，致病性的错义变体的肌球蛋白，肌节的分子马达，聚集在残基，参与肌节蛋白的动态构象状态。我们假设，这些构象是必不可少的，以适应收缩输出能量守恒和HCM的病理生理学结果从这些conformations.Methods的不稳定：我们测定肌球蛋白ATP结合，以确定在超松弛状态（SRX）的构象或无序松弛状态（DRX）的构象在健康的啮齿动物和人类心脏的肌球蛋白的比例，在基线和响应减少血液动力学需求的冬眠或致病HCM变种。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，我们评估了收缩性，舒张，心肌细胞形态和代谢，有和没有变构调节肌球蛋白ATP酶活性。然后，我们测试是否肌球蛋白变体的位置未知的临床意义，确定在HCM患者，预测功能的后果和协会与心力衰竭和心律失常。结果：肌球蛋白进行生理之间的SRX构象，最大限度地节约能源和DRX构象，使跨桥形成更大的ATP消耗的转变。全身血流动力学要求，肌球蛋白的药理学调节剂，和致病性肌球蛋白错义突变影响这些构象的比例。冬眠增加肌球蛋白的比例在SRX构象，而致病性变体不稳定，这些和增加肌球蛋白的比例在DRX构象，增强心肌细胞的收缩力，但受损的放松和诱发肥厚性重塑与增加能量应激。使用结构位置分层的变体未知的临床意义，我们发现，不稳定的肌球蛋白构象的变体与HCM.Conclusions患者的心力衰竭和心律失常的发生率较高：肌球蛋白构象建立功能平衡，这是必不可少的终身细胞稳态和心脏功能。肌球蛋白能量保存状态的不稳定促进HCM患者的收缩异常、形态和代谢重塑以及不良临床结局。治疗性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局。
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 proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation 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 of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias.Results:Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM.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 patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.