Prevention of Burn-Induced Inflammatory Responses and Muscle Wasting by GTS-21, a Specific Agonist for ?7 Nicotinic Acetylcholine Receptors.
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ABSTRACT: Muscle wasting (MW) in catabolic conditions (e.g., burn injury [BI]) is a major risk factor affecting prognosis. Activation of interleukin-1? (IL-1?)/nuclear factor-kappa B (NF-?B), interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), and/or forkhead box O transcriptional factor (FOXO)-mediated gene transcription pathways is the pivotal trigger of inflammatory response-induced protein catabolic processes in muscle. The ?7 acetylcholine receptors (?7AChRs) are upregulated in macrophages and peripheral tissues including skeletal muscle during MW conditions. Stimulation of ?7AChRs mitigates inflammatory responses. Hypothesis tested is that attenuation of inflammation by ?7AChR stimulation with specific ?7AChR agonist, GTS-21, will reverse BI-induced body mass and MW by modulating inflammatory and proteolytic signals.Body surface area (30%) BI or sham BI mice were treated with GTS-21 or saline. Tibialis anterior (TA) muscle was harvested at 6?h, day 1 or 3 to examine inflammatory and proteolytic signals.GTS-21 significantly ameliorated the BI-induced increased expression of inflammatory cytokines IL-6, IL-1?, C-X-C motif chemokine ligand 2 (6?h), phosphorylated STAT3, and NF-?B (day 1) in TA muscle. GTS-21 also significantly inhibited BI-induced increase of MuRF1 and FOXO1 (day 1). Consistent with the cytokine and inflammatory mediator changes, BI-induced body weight and TA muscle mass loss at day 3 were mitigated by GTS-21 treatment. The beneficial effect of GTS-21 on BI changes was absent in methyllycaconitine (?7AChR antagonist)-treated wild-type and ?7AChR knockout mice.GTS-21 stimulation of ?7AChRs, by modulating multiple molecular signals related to inflammation and proteolysis, attenuates protein wasting, evidenced by maintenance of body weight and attenuation of distant muscle mass loss after BI. GTS-21 can be a novel, potent therapeutic option for reversal of BI-induced MW.
SUBMITTER: Kashiwagi S
PROVIDER: S-EPMC5167674 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
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