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

SARS-CoV-2感染后肌痛和疲劳的发病机制

基本信息

批准号：
10709579
负责人：
Sachiko Homma
金额：
$ 14.57万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10709579
关键词：
2019-nCoV ACE2 Ache Acute Address Affect Analgesics Animal Model Animals Atrophic Body Weight decreased COVID-19 COVID-19 long hauler COVID-19 pandemic Cardiopulmonary Chronic Cytokine Gene Development Dyspnea Employment Status Energy Metabolism Environment Enzymes Fatigue Functional disorder Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Transcription Glucose Hamsters Heart Homeostasis Hypoxia Immune Immune response Individual Infection Inflammation Inflammatory Influenza Influenza A virus Injury Interferons Intranasal Administration Invaded Ischemia Lead Locomotion Long COVID Longitudinal Studies Lung Mediating Mesocricetus auratus Mitochondria Modeling Muscle Muscle Fatigue Muscle Fibers Muscle Mitochondria Muscular Atrophy Myalgia Myocardial Infarction Nucleocapsid Proteins Oxygen Pathogenesis Pathogenicity Pathologic Pathology Patients Phase Production Publishing Pulmonary Embolism Quality of life Recovery Regulator Genes Reporting Research Research Personnel SARS-CoV-2 infection Signal Pathway Skeletal Muscle Stroke Symptoms Thrombosis Thrombus Time Up-Regulation Viral Viral Respiratory Tract Infection Virus Virus Diseases acute infection anaerobic glycolysis brain fog common symptom cytokine disabling symptom experience fatty acid metabolism mRNA Expression muscle regeneration post SARS-CoV-2 infection post-COVID-19 receptor respiratory response systemic inflammatory response tissue injury transcriptome sequencing transcriptomics

项目摘要

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.

项目摘要随着COVID-19的大流行的继续，在Covid-19后期管理长途症状已成为下一个水平挑战。持续的骨骼肌酸痛（肌痛）和疲劳是最常见的症状报告的症状超过20周，其症状的症状。肌痛相关与Covid-19一起经常对止痛药的反应不佳。长长的症状，尤其是肌痛，疲劳，呼吸困难和大脑雾，显着影响COVID-19的生活质量和就业状况拖运者。尽管在急性呼吸道病毒感染期间，肌痛和疲劳很常见，但肌肉由SARS-COV-2引起的症状通常比其他呼吸道病毒感染持续更长的时间流感。肌痛和疲劳的发育和持久性的基础的致病机制然而，与COVID-19相关的是，在很大程度上尚不清楚，这使得治疗变得困难。因此，我们提出这项R21探索机制的研究。有四种潜在的机制，包括直接病毒侵袭骨骼肌，微骨和心肺功能障碍的缺血性肌肉损伤，免疫由旺盛的全身性炎症反应造成的介导的肌肉损伤，并改变了肌肉能量稳态。我们建议通过进行探索性纵向来解决这些机制研究以表征骨骼肌对呼吸道SARS-COV-2感染的反应，以确定如何在急性期间和之后，骨骼肌在组织病理学水平和转录水平上受到影响感染，以及肌肉对SARS-COV-2和流感A（IAV）病毒感染的反应是否不同的。通过使用从SARS-COV-2感染的金仓鼠收集的肌肉组织，这是最好的小型小仓鼠之一 Covid-19的动物模型，我们的初步研究发现没有可检测到的SARS-COV-2核素蛋白或炎症暗示直接对肌肉的病毒侵袭。也没有微兽。这些发现带领对于我们的中心假设，即与19与covid相关的肌痛和疲劳可能是由于改变引起的急性SARS-COV-2期间系统性炎症反应和缺氧引起的肌肉能量代谢感染，然后是延长的恢复过程。该假设将由两个具体目标解决。 AIM 1将在SARS-COV-2感染和与IAV感染相比。 AIM 2将表征对SARS-COV-2的肌肉转录反应感染和动态转录随时间变化。我们还将将SARS-COV-2感染与 IAV感染是为了解决最初骨骼肌对SARS-COV-2感染的反应较慢。我们的研究可能会发现组织病理学特征和转录特征可能肌痛和疲劳的基础与Covid-19相关。发现的机制将有助于指导疗法。