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Respiratory SARS-CoV-2 Infection Induces Skeletal Muscle Atrophy and Long-Lasting Energy Metabolism Suppression

ABSTRACT: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacts human health beyond acute infection. Myalgia and fatigue represent two of the most prevalent symptoms in post-COVID-19 syndrome. To determine the mechanisms underlying prolonged muscle symptoms, we characterized longitudinal histopathological and transcriptional changes of skeletal muscle after acute respiratory SARS-CoV-2 infection in a COVID-19 hamster model and compared them with respiratory influenza A virus (IAV) infection. Histopathological and bulk RNA sequencing analyses at 3, 30, and 60 days post infection (dpi) showed no evidence of direct viral invasion, inflammatory cell infiltration, or microthrombi in skeletal muscle, but myofiber atrophy was observed in the SARS-CoV-2 group at 60 dpi, accompanied by downregulation of myofiber genes, atrogenes, and cytoplasmic ribosomal protein genes, and upregulation of autophagy genes. There was persistent downregulation of genes involved in mitochondrial oxidative phosphorylation, fatty acid beta-oxidation, and tricarboxylic acid cycle in the SARS-CoV-2 but not the IAV group. Moreover, TNF-alpha/NF-kB and TGF-beta signaling pathways were differentially regulated in the SARS-CoV-2 group. Our findings suggest that persistent muscle symptoms after COVID-19 may be caused by muscle atrophy and energy metabolism suppression, and that the systemic inflammatory cytokine response may contribute, in part, to the skeletal muscle abnormalities.

ORGANISM(S): Mesocricetus auratus

PROVIDER: GSE231910 | GEO | 2024/06/28

REPOSITORIES: GEO

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Project description:Objectives: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the worldwide COVID-19 pandemic. While SARS-CoV-2 can infect people of all ages and both sexes, senior populations are at greatest risk of severe disease and worse outcomes, and sexual dimorphism has been reported in COVID-19. COVID-19 causes damage to multiple organ systems, including the brain. Neurological symptoms are widely observed in patients with Covid-19, with many survivors suffering from persistent neurological impairment, potentially accelerating Alzheimer’s disease (AD). This study aims to investigate the mechanisms underlying the impact of age, and sex on neuroinflammation due to SARS-CoV-2 infection using mouse models. Methods: Wild-type C57BL/6 mice were subjected to intranasal inoculation of SARS-CoV-2 lineage B.1.351, followed by daily body weight monitoring. At 7 dpi, viral burden and inflammatory cytokine/chemokine responses in the lung and brain were determined by quantitative RT-PCR, followed by immunohistochemical and transcriptomic analyses. Results: Older age, male sex, showed increased lung viral loads and severity of SARS-CoV-2 infection in mice. No viral RNA was detected in the brains of infected mice; however, IL-6 and CCL2 mRNA increased significantly, particularly in brains of old and APOE4 mice. Unbiased brain RNA-seq/transcriptomic analysis showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, and pathway analysis identified innate immunity and defense response to virus and other organisms as the major molecular networks affected in the brain by SARS-CoV-2 infection. Conclusions: Our findings demonstrate that age, and sex, modify the progression and outcome of SARS-CoV-2 infection. SARS-CoV-2 infection triggers neuroinflammatory responses despite the lack of detectable virus in the brain. Changes in molecular networks of innate immunity and defense response to microorganisms underlie the impact of SARS-CoV-2 infection in the brain. These findings in mice mimic epidemiological and clinical observations in humans with Covid-19.

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Respiratory SARS-CoV-2 Infection Induces Skeletal Muscle Atrophy and Long-Lasting Energy Metabolism Suppression

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