Exercise-induced cardiac adaptation in hypertrophic cardiomyopathy

项目总结 肥厚型心肌病(HCM)每500人中就有1人患病，可导致心力衰竭和心脏骤停 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 突变会导致肌球蛋白构象更加无序，能量效率低下，从而增加ATP 利用，导致代谢功能障碍和过度收缩，并最终导致心肌肥厚和 功能障碍。适度的耐力训练总体上改善了心血管功能和代谢健康， 降低心血管疾病发病率和死亡率的风险。然而，当前的指导方针建议HCM 患者限制运动，导致这一患者群体的体力活动水平减少。与此相反， 最近的证据表明，中强度和大强度耐力训练是安全和 临床上有益于肥厚型心肌炎患者。然而，运动诱发心脏事件背后的机制 HCM的适应情况尚不清楚。这项拟议工作背后的假设是，由 反复耐力运动通过改善肉瘤的致病表型来改善肉瘤的表型 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。要解决这个问题 假设，运动在肥厚性心肌病中的心脏保护作用将在一只健康的小鼠身上进行研究。 在人类肥厚性心肌病患者和患者特定的IPSC来源的心肌细胞中。在目标1中， 确定运动训练是否减缓肥厚性心肌病、深层代谢和收缩的疾病进展 将在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析 老鼠。在目标2中，运动的系统效应是在30分钟的运动后进行评估的，其中 将肥厚型心肌炎患者与健康人进行比较。虽然长期运动训练促进健康，但这是 由单项运动比赛的信号事件驱动。运动前和运动后的血清 接受非靶向代谢组学、半靶向脂质组学和多重细胞因子分析 确定锻炼有益效果的潜在中介因素，并确定 代谢组学对肥厚性心肌炎患者心肺功能的影响。最后，目标3将决定这些是否 运动诱导的系统性因素改善肥厚心肌的收缩和代谢功能障碍；为此， 本研究将以肥厚性心肌病患者的IPSC来源的心肌细胞作为模型系统。此外，活体研究 将在肥厚型心肌炎的小鼠模型中进行。总而言之，锻炼是一种可获得的改善 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。推而广之，我希望这部作品能揭示出 只有缓解症状的药物可用的疾病的治疗目标，结果可能是 鼓励在这些患者群体中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.