• Shizuka Kashiwagi, Mohammed A S Khan, Shingo Yasuhara, Takahisa Goto, William R Kem, Ronald G Tompkins, Masao Kaneki, and J A Jeevendra Martyn.
• *Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospital for Children and Harvard Medical School, Boston, Massachusetts†Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan‡Department of Surgery, Massachusetts General Hospital, Shriners Hospital for Children and Harvard Medical School, Boston, Massachusetts§Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida.
• Shock. 2017 Jan 1; 47 (1): 61-69.

IntroductionMuscle wasting (MW) in catabolic conditions (e.g., burn injury [BI]) is a major risk factor affecting prognosis. Activation of interleukin-1β (IL-1β)/nuclear factor-kappa B (NF-κB), 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 α7 acetylcholine receptors (α7AChRs) are upregulated in macrophages and peripheral tissues including skeletal muscle during MW conditions. Stimulation of α7AChRs mitigates inflammatory responses. Hypothesis tested is that attenuation of inflammation by α7AChR stimulation with specific α7AChR agonist, GTS-21, will reverse BI-induced body mass and MW by modulating inflammatory and proteolytic signals.MethodsBody 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.ResultsGTS-21 significantly ameliorated the BI-induced increased expression of inflammatory cytokines IL-6, IL-1β, C-X-C motif chemokine ligand 2 (6 h), phosphorylated STAT3, and NF-κB (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 (α7AChR antagonist)-treated wild-type and α7AChR knockout mice.ConclusionGTS-21 stimulation of α7AChRs, 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.

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