Ho Richard C, Fujii Nobuharu, Witters Lee A, Hirshman Michael F, Goodyear Laurie J
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Biochem Biophys Res Commun. 2007 Oct 19;362(2):354-9. doi: 10.1016/j.bbrc.2007.07.154. Epub 2007 Aug 7.
AMP-activated protein kinase (AMPK) is widely recognized as an important regulator of glucose transport in skeletal muscle. The p38 mitogen-activated protein kinase (MAPK) has been proposed to be a component of AMPK-mediated signaling. Here we used several different models of altered AMPK activity to determine whether p38 MAPK is a downstream intermediate of AMPK-mediated signaling in skeletal muscle. First, L6 myoblasts and myotubes were treated with AICAR, an AMPK stimulator. AMPK phosphorylation was significantly increased, but there was no change in p38 MAPK phosphorylation. Similarly, AICAR incubation of isolated rat extensor digitorum longus (EDL) muscles did not increase p38 phosphorylation. Next, we used transgenic mice expressing an inactive form of the AMPKalpha2 catalytic subunit in skeletal muscle (AMPKalpha2i TG mice). AMPKalpha2i TG mice did not exhibit any defect in basal or contraction-induced p38 MAPK phosphorylation. We also used transgenic mice expressing an activating mutation in the AMPKgamma1 subunit (gamma1R70Q TG mice). Despite activated AMPK, basal p38 MAPK phosphorylation was not different between wild type and gamma1R70Q TG mice. In addition, muscle contraction-induced p38 MAPK phosphorylation was significantly blunted in the gamma1R70Q TG mice. In conclusion, increasing AMPK activity by AICAR and AMPKgamma1 mutation does not increase p38 MAPK phosphorylation in skeletal muscle. Furthermore, AMPKalpha2i TG mice lacking contraction-stimulated AMPK activity have normal p38 MAPK phosphorylation. These results suggest that p38 MAPK is not a downstream component of AMPK-mediated signaling in skeletal muscle.
AMP激活的蛋白激酶（AMPK）被广泛认为是骨骼肌中葡萄糖转运的重要调节因子。p38丝裂原活化蛋白激酶（MAPK）被认为是AMPK介导信号传导的一个组成部分。在此，我们使用了几种不同的AMPK活性改变模型，以确定p38 MAPK是否是骨骼肌中AMPK介导信号传导的下游中间体。首先，用AMPK刺激剂AICAR处理L6成肌细胞和肌管。AMPK磷酸化显著增加，但p38 MAPK磷酸化没有变化。同样，用AICAR孵育分离的大鼠趾长伸肌（EDL）肌肉也不会增加p38磷酸化。接下来，我们使用了在骨骼肌中表达无活性形式的AMPKalpha2催化亚基的转基因小鼠（AMPKalpha2i TG小鼠）。AMPKalpha2i TG小鼠在基础或收缩诱导的p38 MAPK磷酸化方面没有表现出任何缺陷。我们还使用了在AMPKgamma1亚基中表达激活突变的转基因小鼠（gamma1R70Q TG小鼠）。尽管AMPK被激活，但野生型和gamma1R70Q TG小鼠之间的基础p38 MAPK磷酸化没有差异。此外，在gamma1R70Q TG小鼠中，肌肉收缩诱导的p38 MAPK磷酸化显著减弱。总之，通过AICAR和AMPKgamma1突变增加AMPK活性不会增加骨骼肌中的p38 MAPK磷酸化。此外，缺乏收缩刺激的AMPK活性 的AMPKalpha2i TG小鼠具有正常的p38 MAPK磷酸化。这些结果表明，p38 MAPK不是骨骼肌中AMPK介导信号传导的下游组成部分。
