Fediuc S, Gaidhu M P, Ceddia R B
Department of Kinesiology and Health Science, York University, 4700 Keele Street, Toronto, Ontario, Canada N3J 1P3.
Endocrinology. 2006 Nov;147(11):5170-7. doi: 10.1210/en.2006-0480. Epub 2006 Jul 27.
The aim of this study was to investigate the effects of 5-aminoimidasole-4-carboxamide-1-beta-d-ribofuranoside (AICAR)-induced AMP-activated protein kinase activation on glycogen metabolism in soleus (slow twitch, oxidative) and epitrochlearis (fast twitch, glycolytic) skeletal muscles. Isolated soleus and epitrochlearis muscles were incubated in the absence or presence of insulin (100 nM), AICAR (2 mM), and AICAR plus insulin. In soleus muscles exposed to insulin, glycogen synthesis and glycogen content increased 6.4- and 1.3-fold, respectively. AICAR treatment significantly suppressed ( approximately 60%) insulin-stimulated glycogen synthesis and completely prevented the increase in glycogen content induced by insulin. AICAR did not affect either basal or insulin-stimulated glucose uptake but significantly increased insulin-stimulated ( approximately 20%) lactate production in soleus muscles. Interestingly, basal glucose uptake was significantly increased ( approximately 1.4-fold) in the epitrochlearis muscle, even though neither basal nor insulin-stimulated rates of glycogen synthesis, glycogen content, and lactate production were affected by AICAR. We also report the novel evidence that AICAR markedly reduced insulin-induced Akt-Thr308 phosphorylation after 15 and 30 min exposure to insulin, which coincided with a marked reduction in glycogen synthase kinase 3 (GSK)-3alpha/beta phosphorylation. Importantly, phosphorylation of glycogen synthase was increased by AICAR treatment 45 min after insulin stimulation. Our results indicate that AICAR-induced AMP-activated protein kinase activation caused a time-dependent reduction in Akt308 phosphorylation, activation of glycogen synthase kinase-3alpha/beta, and the inactivation of glycogen synthase, which are compatible with the acute reduction in insulin-stimulated glycogen synthesis in oxidative but not glycolytic skeletal muscles.
本研究旨在探讨5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）诱导的AMP激活蛋白激酶激活对比目鱼肌（慢肌纤维，氧化型）和肱三头肌（快肌纤维，糖酵解型）骨骼肌糖原代谢的影响。分离出的比目鱼肌和肱三头肌在无或有胰岛素（100 nM）、AICAR（2 mM）以及AICAR加胰岛素的情况下进行孵育。在暴露于胰岛素的比目鱼肌中，糖原合成和糖原含量分别增加了6.4倍和1.3倍。AICAR处理显著抑制（约60%）胰岛素刺激的糖原合成，并完全阻止了胰岛素诱导的糖原含量增加。AICAR对基础或胰岛素刺激的葡萄糖摄取均无影响，但显著增加了比目鱼肌中胰岛素刺激的（约20%）乳酸生成。有趣的是，肱三头肌的基础葡萄糖摄取显著增加（约1.4倍），尽管AICAR对基础或胰岛素刺激的糖原合成速率、糖原含量及乳酸生成均无影响。我们还报告了新的证据，即AICAR在暴露于胰岛素15分钟和30分钟后显著降低胰岛素诱导的Akt-Thr308磷酸化，这与糖原合成酶激酶3（GSK）-3α/β磷酸化的显著降低相一致。重要的是，胰岛素刺激45分钟后，AICAR处理增加了糖原合成酶的磷酸化。我们的结果表明，AICAR诱导的AMP激活蛋白激酶激活导致Akt308磷酸化随时间依赖性降低、糖原合成酶激酶-3α/β激活以及糖原合成酶失活，这与氧化型而非糖酵解型骨骼肌中胰岛素刺激的糖原合成急性减少相一致。
