NF-kappa B Activation Is Required for the Transition of Pulmonary Inflammation to Muscle Atrophy

R.C.J. Langen, A. Haegens, J.H.J. Vernooy, E.F.M. Wouters, M.P.J. de Winther, H. Carlsen, C. Steele, S.E. Shoelson, A.M.W.J. Schols

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Rationale Disease exacerbations and muscle wasting are negative prognostic factors of COPD. Transient systemic inflammation and malnutrition have been implicated in skeletal muscle wasting following acute exacerbations of COPD. However, the interaction between systemic inflammation and malnutrition in their contribution to muscle atrophy, as well as the molecular basis underlying the transition of systemic inflammation to muscle atrophy remain unresolved.Methods Pulmonary inflammation was induced in mice by intra-tracheal (IT) lipopolysaccharide (LPS) instillation to model acute disease exacerbation. Systemic inflammation, nutritional intake, body and muscle weights were determined. Muscle inflammatory and atrophy signalling were examined, and the effect of muscle specific inactivation of Nuclear Factor kappa B (NF-kB) on muscle atrophy was assessed in genetically modified mice. Results IT-LPS instillation was followed by markedly elevated circulating cytokine levels and NF-kB activation in extra-pulmonary tissues, including skeletal muscle. IT-LPS administration increased the expression of muscle E3 Ub-ligases which govern muscle proteolysis, in particular MuRF1, and caused rapid loss of muscle mass. Reduced food intake only partially accounted for the observed muscle atrophy and did not activate NF-kB in muscle. Rather, plasma transfer experiments revealed the presence of NF-kB- and atrophy-signalling properties in the circulation of IT-LPS treated mice. Genetic inhibition of muscle NF-kB activity suppressed IT-LPS-induced MuRF1 expression and resulted in significant sparing of muscle tissue. Conclusion Systemic inflammation and malnutrition contribute to muscle wasting induced by acute pulmonary inflammation via distinct mechanisms, and muscle NF-kB activation is required for the transition from inflammatory to muscle atrophy signalling.
Original languageEnglish
Pages (from-to)288-297
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume47
Issue number3
DOIs
Publication statusPublished - 1 Jan 2012

Cite this