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

J Immunol. 2019 Jan 15;202(2):484-493. doi: 10.4049/jimmunol.1701433. Epub 2018 Dec 7.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • STAT Transcription Factors / metabolism
  • Signal Transduction
  • Wasting Syndrome / immunology*


  • Forkhead Box Protein O3
  • Interleukin-6
  • Muscle Proteins
  • STAT Transcription Factors
  • FBXO32 protein, human
  • SKP Cullin F-Box Protein Ligases
  • Janus Kinases