Konig Stéphane, Hinard Valérie, Arnaudeau Serge, Holzer Nicolas, Potter Gaël, Bader Charles R, Bernheim Laurent
Département de Physiologie, Centre Médical Universitaire, Hôpital Cantonal Universitaire, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
J Biol Chem. 2004 Jul 2;279(27):28187-96. doi: 10.1074/jbc.M313932200. Epub 2004 Apr 14.
It is widely thought that myogenin is one of the earliest detectable markers of skeletal muscle differentiation. Here we show that, during human myoblast differentiation, an inward rectifier K(+) channel (Kir2.1) and its associated hyperpolarization trigger expression and activity of the myogenic transcription factors, myogenin and myocyte enhancer factor-2 (MEF2). Furthermore, Kir2.1 current precedes and is required for the developmental increase in expression/activity of myogenin and MEF2. Drugs or antisense reducing Kir2.1 current diminished or suppressed fusion as well as expression/activity of myogenin and MEF2. In contrast, LY294002, an inhibitor of phosphatidylinositol 3-kinase (a pathway controlling initiation of the myogenic program) that inhibited both myogenin/MEF2 expression and fusion, did not affect Kir2.1 current. This non-blockade by LY294002 indicates that Kir2.1 acts upstream of myogenin and MEF2. We propose that Kir2.1 channel activation is a required key early event that initiates myogenesis by turning on myogenin and MEF2 transcription factors via a hyperpolarization-activated Ca(2+)-dependent pathway.
人们普遍认为，肌细胞生成素是骨骼肌分化最早可检测到的标志物之一。在此我们表明，在人类成肌细胞分化过程中，内向整流钾通道（Kir2.1）及其相关的超极化触发了肌源性转录因子肌细胞生成素和肌细胞增强因子2（MEF2）的表达和活性。此外，Kir2.1电流先于肌细胞生成素和MEF2表达/活性的发育性增加出现且是其必需条件。降低Kir2.1电流的药物或反义寡核苷酸会减少或抑制融合以及肌细胞生成素和MEF2的表达/活性。相反，磷脂酰肌醇3激酶抑制剂LY294002（一种控制肌源性程序起始的信号通路）抑制了肌细胞生成素/MEF2的表达和融合，但不影响Kir2.1电流。LY294002的这种非阻断作用表明Kir2.1在肌细胞生成素和MEF2的上游起作用。我们提出，Kir2.1通道激活是一个必需的关键早期事件，它通过超极化激活的钙依赖途径开启肌细胞生成素和MEF2转录因子，从而启动肌生成。
