title: Muscle wasting and impaired muscle regeneration in a murine model of chronic pulmonary inflammation.
abstract: Muscle wasting and increased circulating levels of inflammatory cytokines, including TNF-alpha, are common features of chronic obstructive pulmonary disease. To investigate whether inflammation of the lung is responsible for systemic inflammation and muscle wasting, we adopted a mouse model of pulmonary inflammation resulting from directed overexpression of a TNF-alpha transgene controlled by the surfactant protein C (SP-C) promoter. Compared with wild-type mice, SP-C/TNF-alpha mice exhibited increased levels of TNF-alpha in the circulation and increased endogenous TNF-alpha expression in skeletal muscle, potentially reflecting an amplificatory response to circulating TNF-alpha. Decreased muscle and body weights observed in SP-C/TNF-alpha mice were indicative of muscle wasting. Further evaluation of the SP-C/TNF-alpha mouse musculature revealed a decreased muscle regenerative capacity, shown by attenuated myoblast proliferation and differentiation in response to reloading of disuse-atrophied muscle, which may contribute to skeletal muscle wasting. Importantly, incubation of cultured myoblasts with TNF-alpha also resulted in elevated TNF-alpha mRNA levels and inhibition of myoblast differentiation. Collectively, our results demonstrate that chronic pulmonary inflammation results in muscle wasting and impaired muscle regeneration in SP-C/TNF-alpha mice, possibly as a consequence of an amplificatory TNF-alpha expression circuit extending from the lung to skeletal muscle.
authors.affiliation: Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands. r.langen@pul.unimaas.nl
authors.forename: Ramon C J
authors.initials: RC
authors.lastname: Langen
authors.forename: Annemie M W J
authors.initials: AM
authors.lastname: Schols
authors.forename: Marco C J M
authors.initials: MC
authors.lastname: Kelders
authors.forename: Jos L J
authors.initials: JL
authors.lastname: van der Velden
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D011014:Pneumonia / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D006657:Histones; D037721:Pulmonary Surfactant-Associated Protein C; D012333:RNA, Messenger; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D018995:Myosin Heavy Chains