title: NF-κB activation and polyubiquitin conjugation are required for pulmonary inflammation-induced diaphragm atrophy.
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-κB), 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-κB 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 intratracheal lipopolysaccharide instillation. Fiber cross-sectional area, ex vivo tyrosine release, protein poly-Ub conjugation, and inflammatory signaling were determined in diaphragm muscle. The contribution of NF-κB or the UPS to diaphragm atrophy was assessed in mice with intact or genetically repressed NF-κB signaling 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-κB 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-κB signaling. In conclusion, the present study is the first to demonstrate that diaphragm muscle atrophy, resulting from acute pulmonary inflammation, requires NF-κB activation and UPS-mediated protein degradation.
authors: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors: Astrid
authors: A
authors: Haegens
authors: Annemie M
authors: AM
authors: Schols
authors: Stefan H
authors: SH
authors: Gorissen
authors: Anon L
authors: AL
authors: van Essen
authors: Frank
authors: F
authors: Snepvangers
authors: Douglas A
authors: DA
authors: Gray
authors: Steven E
authors: SE
authors: Shoelson
authors: Ramon C
authors: RC
authors: Langen
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016328:NF-kappa B; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease