title: Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis.
abstract: Skeletal muscle catabolism is a co-morbidity of many chronic diseases and is the result of systemic inflammation. Although direct inflammatory cytokine action on muscle promotes atrophy, nonmuscle sites of action for inflammatory mediators are less well described. We demonstrate that central nervous system (CNS)-delimited interleukin 1β (IL-1β) signaling alone can evoke a catabolic program in muscle, rapidly inducing atrophy. This effect is dependent on hypothalamic-pituitary-adrenal (HPA) axis activation, as CNS IL-1β-induced atrophy is abrogated by adrenalectomy. Furthermore, we identified a glucocorticoid-responsive gene expression pattern conserved in models of acute and chronic inflammatory muscle atrophy. In contrast with studies suggesting that the direct action of inflammatory cytokines on muscle is sufficient to induce catabolism, adrenalectomy also blocks the atrophy program in response to systemic inflammation, demonstrating that glucocorticoids are requisite for this process. Additionally, circulating levels of glucocorticoids equivalent to those produced under inflammatory conditions are sufficient to cause profound muscle wasting. Together, these data suggest that a significant component of inflammation-induced muscle catabolism occurs indirectly via a relay in the CNS.
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Braun
authors.forename: Xinxia
authors.initials: X
authors.lastname: Zhu
authors.forename: Marek
authors.initials: M
authors.lastname: Szumowski
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Scott
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Grossberg
authors.forename: Peter R
authors.initials: PR
authors.lastname: Levasseur
authors.forename: Kathryn
authors.initials: K
authors.lastname: Graham
authors.forename: Sheehan
authors.initials: S
authors.lastname: Khan
authors.forename: Sambasivarao
authors.initials: S
authors.lastname: Damaraju
authors.forename: William F
authors.initials: WF
authors.lastname: Colmers
authors.forename: Vickie E
authors.initials: VE
authors.lastname: Baracos
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Marks
mesh_terms: D000315:Adrenalectomy; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D003345:Corticosterone / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000097:blood; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D005938:Glucocorticoids; D053583:Interleukin-1beta; D003345:Corticosterone
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