title: Proteasome inhibition improves diaphragm function in an animal model for COPD.
abstract: Diaphragm muscle weakness in patients with chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and mortality. Recent studies indicate that increased contractile protein degradation by the proteasome contributes to diaphragm weakness in patients with COPD. The aim of the present study was to investigate the effect of proteasome inhibition on diaphragm function and contractile protein concentration in an animal model for COPD. Elastase-induced emphysema in hamsters was used as an animal model for COPD; normal hamsters served as controls. Animals were either treated with the proteasome inhibitor Bortezomib (iv) or its vehicle saline. Nine months after induction of emphysema, specific force-generating capacity of diaphragm bundles was measured. Proteolytic activity of the proteasome was assayed spectrofluorometrically. Protein concentrations of proteasome, myosin, and actin were measured by means of Western blotting. Proteasome activity and concentration were significantly higher in the diaphragm of emphysematous hamsters than in normal hamsters. Bortezomib treatment reduced proteasome activity in the diaphragm of emphysematous and normal hamsters. Specific force-generating capacity and myosin concentration of the diaphragm were reduced by ~25% in emphysematous hamsters compared with normal hamsters. Bortezomib treatment of emphysematous hamsters significantly increased diaphragm-specific force-generating capacity and completely restored myosin concentration. Actin concentration was not affected by emphysema, nor by bortezomib treatment. We conclude that treatment with a proteasome inhibitor improves contractile function of the diaphragm in emphysematous hamsters through restoration of myosin concentration. These findings implicate that the proteasome is a potential target of pharmacological intervention on diaphragm weakness in COPD.
authors: Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. h.vanhees@long.umcn.nl
authors: Hieronymus
authors: H
authors: van Hees
authors: Coen
authors: C
authors: Ottenheijm
authors: Leo
authors: L
authors: Ennen
authors: Marianne
authors: M
authors: Linkels
authors: Richard
authors: R
authors: Dekhuijzen
authors: Leo
authors: L
authors: Heunks
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D003285:Contractile Proteins / Q000378:metabolism; D006224:Cricetinae; D003964:Diaphragm / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D004195:Disease Models, Animal; D008297:Male; D009928:Organ Specificity / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000503:physiopathology*; D011656:Pulmonary Emphysema / Q000150:complications / Q000503:physiopathology; D011719:Pyrazines / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; D003285:Contractile Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex