1. Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1.
- Author
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Radigan KA, Nicholson TT, Welch LC, Chi M, Amarelle L, Angulo M, Shigemura M, Shigemura A, Runyan CE, Morales-Nebreda L, Perlman H, Ceco E, Lecuona E, Dada LA, Misharin AV, Mutlu GM, Sznajder JI, and Budinger GRS
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Forkhead Box Protein O3 metabolism, Humans, Interleukin-6 genetics, Janus Kinases metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Proteins genetics, SKP Cullin F-Box Protein Ligases genetics, STAT Transcription Factors metabolism, Signal Transduction, Influenza A virus physiology, Influenza, Human immunology, Interleukin-6 metabolism, Lung physiology, Muscle Proteins metabolism, Muscles pathology, Orthomyxoviridae Infections immunology, Pneumonia, Viral immunology, SKP Cullin F-Box Protein Ligases metabolism, Wasting Syndrome immunology
- 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., (Copyright © 2019 by The American Association of Immunologists, Inc.)- Published
- 2019
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