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

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 dysf...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2019-01, Vol.202 (2), p.484-493
Main Authors: Radigan, Kathryn A, Nicholson, Trevor T, Welch, Lynn C, Chi, Monica, Amarelle, Luciano, Angulo, Martín, Shigemura, Masahiko, Shigemura, Atsuko, Runyan, Constance E, Morales-Nebreda, Luisa, Perlman, Harris, Ceco, Ermelinda, Lecuona, Emilia, Dada, Laura A, Misharin, Alexander V, Mutlu, Gokhan M, Sznajder, Jacob I, Budinger, G R Scott
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Disease Models, Animal
Forkhead Box Protein O3 - metabolism
Humans
Influenza A virus - physiology
Influenza, Human - immunology
Interleukin-6 - genetics
Interleukin-6 - metabolism
Janus Kinases - metabolism
Lung - physiology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle Proteins - genetics
Muscle Proteins - metabolism
Muscles - pathology
Orthomyxoviridae Infections - immunology
Pneumonia, Viral - immunology
Signal Transduction
SKP Cullin F-Box Protein Ligases - genetics
SKP Cullin F-Box Protein Ligases - metabolism
STAT Transcription Factors - metabolism
Wasting Syndrome - immunology
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Summary: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, and 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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1701433