Caldow M K, Ham D J, Chee A, Trieu J, Naim T, Stapleton D I, Swiderski K, Lynch G S, Koopman R
Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Australia.
Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Australia.
Cytokine. 2017 Aug;96:274-278. doi: 10.1016/j.cyto.2017.05.016. Epub 2017 May 26.
Excessive inflammation reduces skeletal muscle protein synthesis leading to wasting and weakness. The janus kinase/signal transducers and activators of transcription-3 (JAK/STAT3) pathway is important for the regulation of inflammatory signaling. As such, suppressor of cytokine signaling-3 (SOCS3), the negative regulator of JAK/STAT signaling, is thought to be important in the control of muscle homeostasis. We hypothesized that muscle-specific deletion of SOCS3 would impair the anabolic response to leucine during an inflammatory insult. Twelve week old (n=8 per group) SOCS3 muscle-specific knockout mice (SOCS3-MKO) and littermate controls (WT) were injected with lipopolysaccharide (LPS, 1mg/kg) or saline and were studied during fasted conditions or after receiving 0.5g/kg leucine 3h after the injection of LPS. Markers of inflammation, anabolic signaling, and protein synthesis were measured 4h after LPS injection. LPS injection robustly increased mRNA expression of inflammatory molecules (Socs3, Socs1, Il-6, Ccl2, Tnfα and Cd68). In muscles from SOCS3-MKO mice, the Socs3 mRNA response to LPS was significantly blunted (∼6-fold) while STAT3 Tyr705 phosphorylation was exacerbated (18-fold). Leucine administration increased protein synthesis in both WT (∼1.6-fold) and SOCS3-MKO mice (∼1.5-fold) compared to basal levels. LPS administration blunted this effect, but there were no differences between WT and SOCS3-MKO mice. Muscle-specific SOCS3 deletion did not alter the response of AKT, mTOR, S6 or 4EBP1 under any treatment conditions. Therefore, SOCS3 does not appear to mediate the early inflammatory or leucine-induced changes in protein synthesis in skeletal muscle.
过度炎症会降低骨骼肌蛋白质合成，导致肌肉萎缩和无力。Janus激酶/信号转导子和转录激活因子3（JAK/STAT3）通路对炎症信号的调节至关重要。因此，细胞因子信号抑制因子3（SOCS3）作为JAK/STAT信号的负调节因子，被认为在维持肌肉内环境稳定中发挥重要作用。我们推测，在炎症刺激期间，肌肉特异性缺失SOCS3会损害对亮氨酸的合成代谢反应。将12周龄（每组n = 8）的SOCS3肌肉特异性敲除小鼠（SOCS3-MKO）和同窝对照小鼠（WT）注射脂多糖（LPS，1mg/kg）或生理盐水，并在禁食条件下或注射LPS 3小时后给予0.5g/kg亮氨酸后进行研究。在注射LPS 4小时后测量炎症、合成代谢信号和蛋白质合成的标志物。注射LPS后，炎症分子（Socs3、Socs1、Il-6、Ccl2、Tnfα和Cd68）的mRNA表达显著增加。在SOCS3-MKO小鼠的肌肉中，Socs3 mRNA对LPS的反应明显减弱（约6倍），而STAT3 Tyr705磷酸化加剧（18倍）。与基础水平相比，给予亮氨酸后WT小鼠（约1.6倍）和SOCS3-MKO小鼠（约1.5倍）的蛋白质合成均增加。给予LPS减弱了这种作用，但WT小鼠和SOCS3-MKO小鼠之间没有差异。在任何治疗条件下，肌肉特异性缺失SOCS3均未改变AKT、mTOR、S6或4EBP1的反应。因此，SOCS3似乎并未介导骨骼肌中早期炎症或亮氨酸诱导的蛋白质合成变化。
