Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle.
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.
['Braun|Theodore P|TP|', 'Grossberg|Aaron J|AJ|', 'Krasnow|Stephanie M|SM|', 'Levasseur|Peter R|PR|', 'Szumowski|Marek|M|', 'Zhu|Xin Xia|XX|', 'Maxson|Julia E|JE|', 'Knoll|J Gabriel|JG|', 'Barnes|Anthony P|AP|', 'Marks|Daniel L|DL|']
D000818:Animals D015153:Blotting, Western D002100:Cachexia D018827:Carcinoma, Lewis Lung D005938:Glucocorticoids D007150:Immunohistochemistry D017403:In Situ Hybridization D018836:Inflammation Mediators D008070:Lipopolysaccharides D051379:Mice D018345:Mice, Knockout D018482:Muscle, Skeletal D009133:Muscular Atrophy D053594:Myeloid Differentiation Factor 88 D060888:Real-Time Polymerase Chain Reaction D011965:Receptors, Glucocorticoid D015398:Signal Transduction
atrophy inflammation MyD88 adenocarcinoma corticosterone lipopolysaccharide sickness behavior