NF-kB activation and polyubiquitin conjugation are required for pulmonary inflammation-induced diaphragm atrophy.

A. Haegens, A.M.W.J. Schols, S.H. Gorissen, A.L. van Essen, F. Snepvangers, D.A. Gray, S.E. Shoelson, R.C.J. Langen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Loss of diaphragm muscle strength in inflammatory lung disease contributes to mortality and is associated with diaphragm fiber atrophy. Ubiquitin (Ub) 26S-proteasome system (UPS) dependent protein breakdown, which mediates muscle atrophy in a number of physiological and pathological conditions, is elevated in diaphragm muscle of patients with chronic obstructive pulmonary disease. Nuclear Factor kappa B (NF-kappaB), an essential regulator of many inflammatory processes, has been implicated in the regulation of poly-Ub conjugation of muscle proteins targeted for proteolysis by the UPS. Here we test if NF-kappaB activation in diaphragm muscle and subsequent protein degradation by the UPS are required for pulmonary inflammation-induced diaphragm atrophy. Acute pulmonary inflammation was induced in mice by intra-tracheal lipopolysaccharide instillation. Fiber cross sectional area, ex vivo tyrosine release, protein poly-Ub conjugation and inflammatory signalling were determined in diaphragm muscle. The contribution of NF-kappaB or the UPS to diaphragm atrophy was assessed in mice with intact or genetically repressed NF-kappaB signalling or attenuated poly-Ub conjugation, respectively. Acute pulmonary inflammation resulted in diaphragm atrophy measured by reduced muscle fiber cross sectional area. This was accompanied by diaphragm NF-kappaB activation, and proteolysis, measured by tyrosine release from the diaphragm. Poly-Ub conjugation was increased in diaphragm; as was the expression of muscle specific E3 Ub-ligases. Genetic suppression of poly-Ub conjugation prevented inflammation-induced diaphragm muscle atrophy as did muscle specific inhibition of NF-kappaB signalling. In conclusion, the present study is the first to demonstrate that diaphragm muscle atrophy resulting from acute pulmonary inflammation requires NF-kappaB activation and UPS-mediated protein degradation.
Original languageEnglish
Pages (from-to)L103-L110
Number of pages8
JournalAmerican Journal of Physiology-Lung Cellular and Molecular Physiology
Volume302
Issue number1
DOIs
Publication statusPublished - 1 Jan 2012

Keywords

  • inspiratory muscle
  • inflammation
  • protein degradation
  • SKELETAL-MUSCLE ATROPHY
  • SYSTEMIC INFLAMMATION
  • MUTANT UBIQUITIN
  • DISEASE
  • DYSFUNCTION
  • MICE
  • LIPOPOLYSACCHARIDE
  • VENTILATION
  • EXPRESSION
  • MORTALITY

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