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Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1

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  • Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1

    J Immunol. 2018 Dec 7. pii: ji1701433. doi: 10.4049/jimmunol.1701433. [Epub ahead of print]
    Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1.

    Radigan KA1, Nicholson TT1, Welch LC1, Chi M1, Amarelle L1,2, Angulo M1,2, Shigemura M1, Shigemura A1, Runyan CE1, Morales-Nebreda L1, Perlman H1, Ceco E1, Lecuona E1, Dada LA1, Misharin AV1, Mutlu GM3, Sznajder JI4, Budinger GRS4.
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    Abstract

    Muscle dysfunction is common in patients with adult respiratory distress syndrome and is associated with morbidity that can persist for years after discharge. In a mouse model of severe influenza A pneumonia, we found the proinflammatory cytokine IL-6 was necessary for the development of muscle dysfunction. Treatment with a Food and Drug Administration-approved Ab antagonist to the IL-6R (tocilizumab) attenuated the severity of influenza A-induced muscle dysfunction. In cultured myotubes, IL-6 promoted muscle degradation via JAK/STAT, FOXO3a, and atrogin-1 upregulation. Consistent with these findings, atrogin-1+/- and atrogin-1-/- mice had attenuated muscle dysfunction following influenza infection. Our data suggest that inflammatory endocrine signals originating from the injured lung activate signaling pathways in the muscle that induce dysfunction. Inhibiting these pathways may limit morbidity in patients with influenza A pneumonia and adult respiratory distress syndrome.


    PMID: 30530483 DOI: 10.4049/jimmunol.1701433
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