title: Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle.
abstract: Cachexia is a wasting condition defined by skeletal muscle atrophy in the setting of systemic inflammation. To explore the site at which inflammatory mediators act to produce atrophy in vivo, we utilized mice with a conditional deletion of the inflammatory adaptor protein myeloid differentiation factor 88 (MyD88). Although whole-body MyD88-knockout (wbMyD88KO) mice resist skeletal muscle atrophy in response to LPS, muscle-specific deletion of MyD88 is not protective. Furthermore, selective reexpression of MyD88 in the muscle of wbMyD88KO mice via electroporation fails to restore atrophy gene induction by LPS. To evaluate the role of glucocorticoids as the inflammation-induced mediator of atrophy in vivo, we generated mice with targeted deletion of the glucocorticoid receptor in muscle (mGRKO mice). Muscle-specific deletion of the glucocorticoid receptor affords a 71% protection against LPS-induced atrophy compared to control animals. Furthermore, mGRKO mice exhibit 77% less skeletal muscle atrophy than control animals in response to tumor growth. These data demonstrate that glucocorticoids are a major determinant of inflammation-induced atrophy in vivo and play a critical role in the pathogenesis of endotoxemic and cancer cachexia.
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Mail Code L-481, Portland, OR 97239, USA.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Braun
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Grossberg
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Krasnow
authors.forename: Peter R
authors.initials: PR
authors.lastname: Levasseur
authors.forename: Marek
authors.initials: M
authors.lastname: Szumowski
authors.forename: Xin Xia
authors.initials: XX
authors.lastname: Zhu
authors.forename: Julia E
authors.initials: JE
authors.lastname: Maxson
authors.forename: J Gabriel
authors.initials: JG
authors.lastname: Knoll
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Barnes
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Marks
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000209:etiology* / Q000378:metabolism*; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005938:Glucocorticoids / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018836:Inflammation Mediators / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D011965:Receptors, Glucocorticoid
keywords: MyD88; adenocarcinoma; atrophy; corticosterone; inflammation; lipopolysaccharide; sickness behavior