Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle

Theodore P. Braun, Aaron Grossberg, Stephanie Krasnow, Peter R. Levasseur, Marek Szumowski, Xin Xia Zhu, Julia Maxson, J. Gabriel Knoll, Anthony Barnes, Daniel Marks

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.-Braun, T. P., Grossberg, A. J., Krasnow, S. M., Levasseur, P. R., Szumowski, M., Zhu, X. X., Maxson, J. E., Knoll, J. G., Barnes, A. P., and Marks, D. L. Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle.

Original languageEnglish (US)
Pages (from-to)3572-3582
Number of pages11
JournalFASEB Journal
Volume27
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

Cachexia
Myeloid Differentiation Factor 88
Endotoxins
Glucocorticoids
Atrophy
Muscle
Skeletal Muscle
Muscular Atrophy
Muscles
Glucocorticoid Receptors
Neoplasms
Knockout Mice
Inflammation
Inflammation Mediators
Electroporation
Animals
Tumors
Growth
Genes
Proteins

Keywords

  • Adenocarcinoma
  • Atrophy
  • Corticosterone
  • Inflammation
  • Lipopolysaccharide
  • MyD88
  • Sickness behavior

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle. / Braun, Theodore P.; Grossberg, Aaron; Krasnow, Stephanie; Levasseur, Peter R.; Szumowski, Marek; Zhu, Xin Xia; Maxson, Julia; Knoll, J. Gabriel; Barnes, Anthony; Marks, Daniel.

In: FASEB Journal, Vol. 27, No. 9, 09.2013, p. 3572-3582.

Research output: Contribution to journalArticle

Braun, Theodore P. ; Grossberg, Aaron ; Krasnow, Stephanie ; Levasseur, Peter R. ; Szumowski, Marek ; Zhu, Xin Xia ; Maxson, Julia ; Knoll, J. Gabriel ; Barnes, Anthony ; Marks, Daniel. / Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle. In: FASEB Journal. 2013 ; Vol. 27, No. 9. pp. 3572-3582.
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