Influenza A virus infection induces muscle wasting via IL-6 regulation of the E3 ubiquitin ligase atrogin-1

Kathryn A. Radigan, Trevor T. Nicholson, Lynn C. Welch, Monica Chi, Luciano Amarelle, Martín Angulo, Masahiko Shigemura, Atsuko Shigemura, Constance E. Runyan, Luisa Morales-Nebreda, Harris R Perlman, Ermelinda Ceco, Emilia Lecuona, Laura Dada, Alexander Misharin, Gokhan M. Mutlu, Jacob I Sznajder*, GR Scott Budinger

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 +/2 and atrogin-1 2 / 2 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.

Original languageEnglish (US)
Pages (from-to)484-493
Number of pages10
JournalJournal of Immunology
Volume202
Issue number2
DOIs
StatePublished - Jan 15 2019

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Ubiquitin-Protein Ligases
Influenza A virus
Virus Diseases
Interleukin-6
Human Influenza
Muscles
Adult Respiratory Distress Syndrome
Pneumonia
Morbidity
Muscle Development
Skeletal Muscle Fibers
Up-Regulation
Cytokines
Food
Lung
Infection
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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 R ; Ceco, Ermelinda ; Lecuona, Emilia ; Dada, Laura ; Misharin, Alexander ; Mutlu, Gokhan M. ; Sznajder, Jacob I ; Budinger, GR Scott. / Influenza A virus infection induces muscle wasting via IL-6 regulation of the E3 ubiquitin ligase atrogin-1. In: Journal of Immunology. 2019 ; Vol. 202, No. 2. pp. 484-493.
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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 +/2 and atrogin-1 2 / 2 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.",
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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, HR, Ceco, E, Lecuona, E, Dada, L, Misharin, A, Mutlu, GM, Sznajder, JI & Budinger, GRS 2019, 'Influenza A virus infection induces muscle wasting via IL-6 regulation of the E3 ubiquitin ligase atrogin-1', Journal of Immunology, vol. 202, no. 2, pp. 484-493. https://doi.org/10.4049/jimmunol.1701433

Influenza A virus infection induces muscle wasting via IL-6 regulation of the E3 ubiquitin ligase atrogin-1. / 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 R; Ceco, Ermelinda; Lecuona, Emilia; Dada, Laura; Misharin, Alexander; Mutlu, Gokhan M.; Sznajder, Jacob I; Budinger, GR Scott.

In: Journal of Immunology, Vol. 202, No. 2, 15.01.2019, p. 484-493.

Research output: Contribution to journalArticle

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T1 - Influenza A virus infection induces muscle wasting via IL-6 regulation of the E3 ubiquitin ligase atrogin-1

AU - Radigan, Kathryn A.

AU - Nicholson, Trevor T.

AU - Welch, Lynn C.

AU - Chi, Monica

AU - Amarelle, Luciano

AU - Angulo, Martín

AU - Shigemura, Masahiko

AU - Shigemura, Atsuko

AU - Runyan, Constance E.

AU - Morales-Nebreda, Luisa

AU - Perlman, Harris R

AU - Ceco, Ermelinda

AU - Lecuona, Emilia

AU - Dada, Laura

AU - Misharin, Alexander

AU - Mutlu, Gokhan M.

AU - Sznajder, Jacob I

AU - Budinger, GR Scott

PY - 2019/1/15

Y1 - 2019/1/15

N2 - 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 +/2 and atrogin-1 2 / 2 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.

AB - 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 +/2 and atrogin-1 2 / 2 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.

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