Khan Mohammed A S, Khan Mohammed F, Kashiwagi Shizuka, Kem William R, Yasuhara Shingo, Kaneki Masao, Tompkins Ronald G, Martyn Jeevendra A J
*Department of Anesthesiology, Critical Care and Pain Medicine, Shriners Hospitals for Children, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts †Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida ‡Department of Surgery, Shriners Hospitals for Children, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Shock. 2017 Aug;48(2):227-235. doi: 10.1097/SHK.0000000000000849.
The role of interleukin-6 (IL-6) in physiological processes and disease is poorly understood. The hypothesis tested in this study was that selective alpha7 acetylcholine receptor (α7AChR) agonist, GTS-21, releases IL-6 in association with myonuclear accretion and enhances insulin signaling in muscle cells, and improves survival of burn injured (BI) mice. The in vitro effects of GTS-21 were determined in C2C12 myoblasts and 7-day differentiated myotubes (myotubes). The in vivo effects of GTS-21 were tested in BI wild-type (WT) and IL-6 knockout (IL6KO) mice. GTS-21 dose-dependently (0 μM, 100 μM, and 200 μM) significantly increased IL-6 levels in myoblasts and myotubes at 6 and 9 h. GTS-21-induced IL-6 release in myotubes was attenuated by methyllycaconitine (α7AChR antagonist), and by Stat-3 or Stat-5 inhibitors. GTS-21 increased MyoD and Pax7 protein expression, myonuclear accretion, and insulin-induced phosphorylation of Akt, GSK-3β, and Glut4 in myotubes. The glucose levels of burned IL6KO mice receiving GTS-21 decreased significantly compared with sham-burn IL6KO mice. Superimposition of BI on IL6KO mice caused 100% mortality; GTS-21 reduced mortality to 75% in the IL6KO mice. The 75% mortality in burned WT mice was reduced to 0% with GTS-21. The in vitro findings suggest that GTS-21-induced IL-6 release from muscle is mediated via α7AChRs upstream of Stat-3 and -5 pathways and is associated with myonuclear accretion, possibly via MyoD and Pax7 expression. GTS-21 in vivo improves survival in burned WT mice and IL6KO mice, suggesting a potential therapeutic application of α7AChR agonists in the treatment of BI.
白细胞介素-6（IL-6）在生理过程和疾病中的作用尚不清楚。本研究检验的假设是，选择性α7乙酰胆碱受体（α7AChR）激动剂GTS-21与肌核增加相关地释放IL-6，并增强肌肉细胞中的胰岛素信号传导，以及提高烧伤（BI）小鼠的存活率。在C2C12成肌细胞和7天分化的肌管（肌管）中测定GTS-21的体外作用。在BI野生型（WT）和IL-6基因敲除（IL6KO）小鼠中测试GTS-21的体内作用。GTS-21在6小时和9小时时以剂量依赖性方式（0μM、100μM和200μM）显著增加成肌细胞和肌管中的IL-6水平。GTS-21诱导的肌管中IL-6释放被甲基lycaconitine（α7AChR拮抗剂）以及Stat-3或Stat-5抑制剂减弱。GTS-21增加了肌管中MyoD和Pax7蛋白表达、肌核增加以及胰岛素诱导的Akt、GSK-3β和Glut4的磷酸化。与假烧伤IL6KO小鼠相比，接受GTS-21的烧伤IL6KO小鼠的血糖水平显著降低。将BI叠加在IL6KO小鼠上导致100%的死亡率；GTS-21将IL6KO小鼠的死亡率降低到75%。用GTS-21将烧伤WT小鼠75%的死亡率降低到0%。体外研究结果表明GTS-21诱导的肌肉中IL-6释放是通过Stat-3和-Stat-5途径上游的α7AChRs介导的，并且与肌核增加相关，可能是通过MyoD和Pax7表达。GTS-21在体内提高了烧伤WT小鼠和IL6KO小鼠的存活率，表明α7AChR激动剂在BI治疗中具有潜在的治疗应用。
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