Exercise-induced cardiac adaptation in hypertrophic cardiomyopathy

项目摘要 肥厚型心肌病（HCM）影响500人中的1人，可导致心力衰竭和突发性心脏病。 死亡编码肌节蛋白的基因突变是大多数HCM病例的原因。这些 突变诱导更无序，能量效率低下的肌球蛋白构象，增加ATP 利用，导致代谢功能障碍和过度收缩，并最终导致心脏肥大， 功能障碍适度的耐力训练可以改善心血管功能和整体代谢健康， 降低心血管疾病发病率和死亡率的风险。然而，目前的指南建议HCM 患者限制运动，导致该患者群体中身体活动水平降低。与此相反， 最近的证据表明，中等强度和高强度的耐力运动训练是安全的， 对HCM患者有益。然而，运动诱导的心脏 HCM的适应性尚不清楚。这项工作背后的假设是， 反复耐力运动通过改善肌节型HCM的病理表型， 能量低效的肌球蛋白结构和相关的心肌细胞代谢功能障碍。为了解决这个 假设，HCM中运动的心脏保护作用将在良好建立的小鼠中进行研究 在人HCM患者和患者特异性iPSC衍生的心肌细胞中，对HCM模型进行了研究。目标1： 确定运动训练是否能减缓HCM的疾病进展， 将在来自训练和未训练的心脏组织和分离的心室肌细胞中进行表型分型 小鼠在目标2中，响应于30分钟的运动回合来评估运动的全身效应，其中 将HCM患者与健康个体进行比较。虽然长期运动训练促进健康，但这是 由来自个体锻炼回合的信号事件驱动。运动前后的血清将 进行非靶向代谢组学、半靶向脂质组学和多重细胞因子测定分析， 确定运动有益效果的潜在介质，并确定 代谢组学用于HCM患者的心肺适应性。最后，目标3将确定这些 运动诱发的全身因素改善了HCM的收缩和代谢功能障碍;为此， 来自HCM患者的iPSC衍生的心肌细胞将用作模型系统。此外，体内研究 将在HCM小鼠模型中进行。总而言之，运动是一种可以改善 健康和整体生活质量，通过这些创新的实验，我希望描绘出 运动改善HCM健康的机制。通过扩展，我希望这项工作揭示小说 治疗目标的疾病，只有减轻疾病的药物是可用的，结果可以是 以鼓励该患者人群进行促进健康的运动。

PROJECT SUMMARY Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and can lead to heart failure and sudden cardiac death. Mutations in genes encoding sarcomere proteins are responsible for a majority of HCM cases. These mutations induce a more disordered, energetically inefficient myosin conformation, which increases ATP utilization, leading to metabolic dysfunction and hypercontractility, and eventually, cardiac hypertrophy and dysfunction. Moderate endurance training improves cardiovascular function and metabolic health overall, reducing the risk for cardiovascular morbidity and mortality. However, current guidelines recommend that HCM patients limit exercise, leading to reduced levels of physical activity in this patient population. Contrary to this, recent evidence demonstrates that moderate and high-intensity endurance exercise training is safe and clinically beneficial for patients with HCM. However, the mechanisms behind exercise-induced cardiac adaptation in HCM are unknown. The hypothesis behind the proposed work is that systemic factors induced by repeated endurance exercise ameliorate the pathogenic phenotype in sarcomeric HCM by improving the energetically inefficient myosin structure and associated cardiomyocyte metabolic dysfunction. To address this hypothesis, the cardioprotective effects of exercise in HCM will be investigated in a well-established mouse model of HCM, in human HCM patients and in patient-specific iPSC-derived cardiomyocytes. In Aim 1, to determine if exercise training decelerates disease progression in HCM, deep metabolic and contractile phenotyping will be performed in cardiac tissue and isolated ventricular myocytes from trained and untrained mice. In Aim 2, the systemic effects of exercise are evaluated in response to a 30 min bout of exercise, where HCM patients are compared to healthy individuals. While long-term exercise training promotes health, this is driven by signalling events from individual exercise bouts. Serum from before and after exercise will be subjected to untargeted metabolomics, semi-targeted lipidomics and a multiplex cytokine assay analysis to identify potential mediators of the beneficial effects of exercise and determine the predictive power of metabolomics for cardiorespiratory fitness in HCM patients. Finally, Aim 3 will determine whether these exercise-induced systemic factors ameliorate the contractile and metabolic dysfunction of HCM; for this, iPSC-derived cardiomyocytes from HCM patients will be used as a model system. In addition, in vivo studies will be conducted in a mouse model of HCM. Altogether, exercise is an accessible intervention to improve health and overall quality of life, and through these innovative experiments I expect to delineate the mechanisms by which exercise improves health in HCM. By extension, I expect this work to reveal novel therapeutic targets for a disease where only symptom-alleviating drugs are available, and the results can be leveraged to encourage health-promoting exercise in this patient population.