期刊
SHOCK
卷 48, 期 2, 页码 227-235出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SHK.0000000000000849
关键词
Alpha7 acetylcholine receptor; burn injury; GTS-21 (DMXB-A); inflammation; interleukin-6; muscle cells
资金
- NIH [P50-GMO21700]
- NIGMS [RO1GM118947]
- Shriners Hospitals for Children Research Philanthropy
- Eleanor and Miles Shore Foundation for Scholars in Medicine
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 (alpha 7AChR) 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 mu M, 100 mM, and 200 mu M) 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 (alpha 7AChR 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-3 beta, 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 alpha 7AChRs 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 WTmice and IL6KO mice, suggesting a potential therapeutic application of alpha 7AChR agonists in the treatment of BI.
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