Sex differences in exercise-induced mitochondrial function during viral myocarditis

项目摘要/摘要 据估计，2017年诊断出310万例心肌炎/心肌病。患有疾病的患者 心肌炎有急性心力衰竭导致猝死的风险，心肌炎的发生率和严重程度是 男性高于女性。运动通常改善心脏功能；然而，在病毒性心肌炎期间 运动可导致心力衰竭，导致目前的指南建议患者戒酒 确诊后运动3~6个月。肠道病毒包括柯萨奇病毒B3(CVB3)是一种常见的 美国心肌炎的起因。尽管30年前发表的几项研究发现，锻炼增加了 病毒性心肌炎小鼠的病毒复制和死亡，最近没有研究检查心脏的原因 运动后的失败。我们最近发表了一篇文章，指出在正常健康的小鼠中，运动可以诱导线粒体 通过β1肾上腺素能受体(AR)信号分裂导致线粒体碎裂(即更小、更多 圆形)，与久坐不动的小鼠相比，能量产生增强。此外，我们发现CVB3 需要线粒体分裂才能复制病毒。这项提案的总体目标是确定性行为是否 β-1AR诱导心肌细胞线粒体分裂与运动的差异 心肌炎导致病毒复制增加，线粒体功能障碍，心肌细胞死亡，以及 生物能量衰竭导致心力衰竭。

PROJECT SUMMARY/ABSTRACT An estimated 3.1 million cases of myocarditis/cardiomyopathy were diagnosed in 2017. Patients with myocarditis are at risk of sudden death from acute heart failure and the incidence and severity of myocarditis is higher in men than women. Exercise typically improves cardiac function; however, during viral myocarditis exercise can precipitate heart failure leading to current guidelines recommending that patients abstain from exercise for 3-6 months after diagnosis. Enteroviruses including coxsackievirus B3 (CVB3) are a common cause of myocarditis in the US. Although several studies published 30 years ago found that exercise increased viral replication and death in mice with viral myocarditis, no recent studies have examined the reason for heart failure following exercise. We recently published that in normal, healthy mice exercise induces mitochondrial fission through β1 adrenergic receptor (AR) signaling resulting in fragmented mitochondria (i.e., smaller, more circular) with enhanced energy production compared to sedentary mice. Additionally, we found that CVB3 requires mitochondrial fission for viral replication. The overall goal of this proposal is to determine whether sex differences in β1AR-induced mitochondrial fission with exercise in cardiomyocytes or mice with CVB3 myocarditis lead to increased viral replication, mitochondrial dysfunction, cardiomyocyte cell death, and bioenergetic failure resulting in heart failure.