Infection and chronic disease activate a systemic brain-muscle signaling axis

  1. Shuo Yang
  2. Meijie Tian
  3. Yulong Dai
  4. Rong Wang
  5. Shigehiro Yamada
  6. Shengyong Feng
  7. Yunyun Wang
  8. Deepak Chhangani
  9. Tiffany Ou
  10. Wenle Li
  11. Xuan Guo
  12. Jennifer McAdow
  13. Diego E. Rincon-Limas
  14. Xin Yin
  15. Wanbo Tai
  16. Gong Cheng
  17. Aaron Johnson

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.

Article activity feed

  1. Version published to 10.1126/sciimmunol.adm7908
  2. ScreenIT

    SciScore for 10.1101/2020.12.20.423533: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableFlies were crossed at 25°C for two days; the progeny were raised at 29°C, and female adults were collected at day 3 post eclosure.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Immunohistochemistry and imaging: Antibodies used include anti-SARS-CoV-2-ORF3a (1:200, 101AP, FabGennix International Inc), anti-Tropomyosin (1:600, MAC141, Abcam).
    anti-SARS-CoV-2-ORF3a
    suggested: None
    anti-Tropomyosin
    suggested: (DSHB Cat# BB5/37.1, RRID:AB_2889799)
    Experimental Models: Cell Lines
    SentencesResources
    For LysoTracker staining, Hela cells were seeded in 6-well plates with cover slips and grown to 50% confluency at 37°C with 5%CO2 in Dulbecco’s modified Eagle’s medium (12430047, Invitrogen) supplemented with 10% heat-inactivated FBS (A4766801, Invitrogen).
    Hela
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Drosophila genetics: The Gal4 stocks used to express SARS-CoV-2 ORF3a in brain, eye, and muscle included P(GAL4-elav.L) (Bloomington Stock Center, 8760), P(GAL4-ninaE.
    P(GAL4-elav.L)
    suggested: None
    GMR) (Bloomington Stock Center, 1104), and P(Mef2-GAL4.247) (Bloomington Stock Center, 50742).
    GMR)
    suggested: None
    P(Mef2-GAL4.247)
    suggested: None
    Transgenic Flies: UAS-SARS-CoV-2-ORF3a transgenic flies were generated by PCR-mediated subcloning of the SARS-CoV-2-ORF3a coding sequence (pDONR207 SARS-CoV-2 ORF3A, #141271, Addgene) into pUASt-Attb (EcoRI/XbaI).
    UAS-SARS-CoV-2-ORF3a
    suggested: None
    For Drosophila eye imaging, UAS-ORF3a/TM3, Sb flies were crossed with GMR-gal4 virgin flies to direct expression of ORF3a in eyes.
    UAS-ORF3a/TM3
    suggested: None
    For wild type control, w1118 flies were crossed with GMR-gal4 virgin flies.
    w1118
    suggested: None
    Software and Algorithms
    SentencesResources
    Projected in-focus images were produced with the Montage Multifocus module of the Zen Pro Software.
    Zen
    suggested: None
    Western blots were performed by standard method using precast gels (#456-1096, BioRad), and imaged with the ChemiDoc XRS+ system (BioRad).
    BioRad
    suggested: None
    Kaplan-Meier survival curves were generated, and statistical analysis was performed using log-rank analysis (Prism9, GraphPad Software).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    All statistical analyses were performed with GraphPad Prism 9 software.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.12.20.423533 on bioRxiv