Document text
Principal Investigator: Sachiko Homma
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2022
Award: $270,903
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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.
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Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chronic><CoV-2><CoV2><Cricetinae><Cytokine Gene><D-Glucose><Development><Dextrose><Dysfunction><Dyspnea><Employment Status><Energy Expenditure><Energy Metabolism><Environment><Enzyme Gene><Enzymes><Expression Signature><Fatigue><Fatty Acid Metabolism Pathway><Functional disorder><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Gene Transcription><Genes><Genetic Transcription><Glucose><Golden Hamsters><Golden Syrian Hamsters><Grippe><Hamsters><Hamsters Mammals><Heart><Homeostasis><Hypoxia><Hypoxic><IFN><Immune><Immune response><Immunes><Immunological response><Individual><Infection><Inflammation><Inflammatory><Influenza><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Injury><Interferons><Intranasal Administration><Intranasal Drug Administration><Invaded><Investigators><Ischemia><Lack of Energy><Lead><Locomotion><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Longitudinal Studies><Lung><Lung Respiratory System><Mediating><Mesocricetus auratus><Mitochondria><Modeling><Muscle><Muscle Atrophy><Muscle Fatigue><Muscle Fibers><Muscle Mitochondria><Muscle Tissue><Muscle discomfort><Muscle pain><Muscle pain/fibrositis><Muscle sorenesss><Muscular Atrophy><Muscular Fatigue><Myalgia><Myalgic><Myocardial Infarct><Myocardial Infarction><Myodynia><Myoneuralgia><Myosalgia><Myotubes><Nucleocapsid Proteins><O element><O2 element><Orthomyxovirus Type A><Oxygen><Oxygen Deficiency><Pathogenesis><Pathogenicity><Pathologic><Pathology><Patients><Pb element><Phase><Physiological Homeostasis><Physiopathology><Production><Publishing><Pulmonary Embolism><QOL><Quality of life><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Recovery><Regulator Genes><Reporting><Research><Research Personnel><Researchers><Rhabdomyocyte><SARS corona virus 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virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Stroke><Symptoms><Syrian Hamsters><Thrombosis><Time><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcriptional Regulatory Elements><Type A Influenza><Up-Regulation><Upregulation><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus><Virus Diseases><Voluntary Muscle><Weight Loss><Weight Reduction><Wuhan coronavirus><acute infection><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after severe acute respiratory distress syndrome CoV-2 infection><anaerobic glycolysis><angiotensin converting enzyme 2><angiotensin converting enzyme II><base><body weight loss><brain attack><brain fog><cardiac infarct><cerebral vascular accident><cerebrovascular accident><chronic COVID><chronic COVID-19><chronic novel coronavirus disease 2019><common symptom><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronary attack><coronary infarct><coronary infarction><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 detection><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infection><coronavirus disease 2019 long hauler><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus 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haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long hauler><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><long-term study><longitudinal outcome studies><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><longterm study><mRNA Expression><mitochondrial><model of animal><model organism><muscle breakdown><muscle degradation><muscle deterioration><muscle loss><muscle regeneration><muscle wasting><muscular><nCoV2><pain killer><pain medication><pain reliever><painkiller><pathophysiology><post COVID syndrome><post COVID-19 syndrome><post SARS-CoV-2 infection><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-COVID><post-COVID-19><post-acute phases of COVID-19><post-coronavirus disease 2019><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><pulmonary><receptor><regulatory gene><respiratory><response><severe acute respiratory syndrome coronavirus 2 detection><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><systemic inflammation><systemic inflammatory response><thrombotic disease><thrombotic disorder><tissue injury><trans acting element><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptome sequencing><transcriptomics><viral infection><viral respiratory infection><virus infection><virus-induced disease><wt-loss>