Pathogenesis of myalgia and fatigue after SARS-CoV-2 infection

项目总结 随着新冠肺炎疫情的持续，管理后的新冠肺炎远程症状成为下一个 水平挑战。持续性骨骼肌疼痛(肌痛)和疲劳是最常见的 症状超过20周的新冠肺炎长途运输者报告的症状。伴发的肌痛 新冠肺炎对止痛药的反应通常很差。长期的冠状病毒症状，特别是肌肉疼痛， 疲劳、呼吸困难、脑雾等，明显影响新冠肺炎龙的生活质量和就业状况 搬运工。虽然肌肉酸痛和疲劳在急性呼吸道病毒感染期间很常见，但肌肉 SARS-CoV-2引起的症状通常比其他呼吸道病毒感染持续的时间长得多，包括 流行性感冒。肌痛和疲劳发生和持续的致病机制 然而，与新冠肺炎相关的药物在很大程度上是未知的，这使得治疗变得困难。因此，我们建议 本研究拟对R21的作用机制进行探讨。有四种可能的机制，包括病毒的直接入侵 对于骨骼肌，微血栓造成的缺血性肌肉损伤和心肺功能障碍，免疫- 由活跃的全身炎症反应和改变的肌肉引起的肌肉损伤 能量平衡。我们建议通过进行纵向的探索性研究来解决这些机制 研究骨骼肌对呼吸道SARS-CoV-2感染的反应以确定如何 骨骼肌在急性发作期间和之后在组织病理水平和转录水平受到影响 感染，以及肌肉对SARS-CoV-2和甲型流感病毒(IAV)感染的反应是否 不一样。通过使用从感染SARS-CoV-2的金黄仓鼠身上收集的肌肉组织，最好的小型仓鼠之一 对于新冠肺炎的动物模型，我们的初步研究没有发现可检测到的SARS-CoV-2核蛋白或 发炎提示病毒直接侵入肌肉。也没有微血栓形成。这些发现导致了 我们的中心假设是与新冠肺炎相关的肌肉疼痛和疲劳可能是由改变引起的 急性SARS-CoV-2期间全身炎症反应和缺氧所致的肌肉能量代谢 感染，随后是一个漫长的康复疗程。这一假设将通过两个具体目标来解决。 目的1确定SARS-CoV-2感染后不同阶段肌肉的组织病理学变化 与IAV感染比较。目的2将表征肌肉对SARS-CoV-2的转录反应 感染和动态转录随时间的变化。我们还将比较SARS-CoV-2感染与 解决IAV感染能否恢复骨骼肌对SARS-CoV-2感染的初步反应 是比较慢的。我们的研究可能会确定组织病理学特征和转录签名，这些特征可能 与新冠肺炎相关的肌肉疼痛和疲劳是其潜在原因。已发现的机制将有助于指导治疗。

PROJECT SUMMARY As the COVID-19 pandemic continues, managing post COVID-19 long-haul symptoms have become the next level challenge. Persistent skeletal muscle aches (myalgia) and fatigue are among the most common symptoms reported by COVID-19 long haulers who have symptoms beyond 20 weeks. The myalgia associated with COVID-19 often responds poorly to pain medications. The long-COVID symptoms, especially myalgia, fatigue, dyspnea, and brain fog, significantly affect the quality of life and employment status of COVID-19 long haulers. Although myalgia and fatigue are common during acute respiratory viral infection, the muscle symptoms caused by SARS-CoV-2 often last much longer than other respiratory viral infections including influenza. The pathogenic mechanisms underlying the development and persistence of myalgia and fatigue associated with COVID-19, however, is largely unknown, which makes the treatment difficult. We thus propose this R21 study to explore the mechanisms. There are four potential mechanisms, including direct viral invasion to skeletal muscle, ischemic muscle injury from microthrombi and cardiopulmonary dysfunction, immune- mediated muscle damage caused by an exuberant systemic inflammatory response, and altered muscle energy homeostasis. We propose to address these mechanisms by conducting an exploratory longitudinal study to characterize the skeletal muscle response to respiratory SARS-CoV-2 infection to determine how skeletal muscle is affected at the histopathological level and transcriptional level during and after acute infection, and whether the muscle responses to SARS-CoV-2 and influenza A (IAV) viral infections are different. By using muscle tissues collected from SARS-CoV-2-infected golden hamsters, one of the best small animal models for COVID-19, our preliminary study found no detectable SARS-CoV-2 nucleocapsid protein or inflammation to suggest direct viral invasion to muscle. There were no microthrombi either. These findings lead to our central hypothesis that myalgia and fatigue associated with COVID-19 are likely caused by altered muscle energy metabolism due to a systemic inflammatory response and hypoxia during acute SARS-CoV-2 infection, followed by a prolonged recovery course. This hypothesis will be addressed by two specific aims. Aim 1 will identify muscle histopathological changes at different stages after SARS-CoV-2 infection and compare with IAV infection. Aim 2 will characterize the muscle transcriptional response to SARS-CoV-2 infection and the dynamic transcriptional changes with time. We will also compare SARS-CoV-2 infection with IAV infection to address whether the recovery of the initial skeletal muscle response to SARS-CoV-2 infection is slower. Our study will likely identify histopathological features and transcriptional signatures that may underlie myalgia and fatigue associated with COVID-19. The mechanisms uncovered will help guide therapies.