Hoshino Daisuke, Kawata Kentaro, Kunida Katsuyuki, Hatano Atsushi, Yugi Katsuyuki, Wada Takumi, Fujii Masashi, Sano Takanori, Ito Yuki, Furuichi Yasuro, Manabe Yasuko, Suzuki Yutaka, Fujii Nobuharu L, Soga Tomoyoshi, Kuroda Shinya
Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Bioscience and Technology Program, Department of Engineering Science, University of Electro-Communications, Tokyo 182-8585, Japan.
iScience. 2020 Sep 12;23(10):101558. doi: 10.1016/j.isci.2020.101558. eCollection 2020 Oct 23.
Skeletal muscle adaptation is mediated by cooperative regulation of metabolism, signal transduction, and gene expression. However, the global regulatory mechanism remains unclear. To address this issue, we performed electrical pulse stimulation (EPS) in differentiated C2C12 myotubes at low and high frequency, carried out metabolome and transcriptome analyses, and investigated phosphorylation status of signaling molecules. EPS triggered extensive and specific changes in metabolites, signaling phosphorylation, and gene expression during and after EPS in a frequency-dependent manner. We constructed trans-omic network by integrating these data and found selective activation of the pentose phosphate pathway including metabolites, upstream signaling molecules, and gene expression of metabolic enzymes after high-frequency EPS. We experimentally validated that activation of these molecules after high-frequency EPS was dependent on reactive oxygen species (ROS). Thus, the trans-omic analysis revealed ROS-dependent activation in signal transduction, metabolome, and transcriptome after high-frequency EPS in C2C12 myotubes, shedding light on possible mechanisms of muscle adaptation.
骨骼肌适应是由代谢、信号转导和基因表达的协同调节介导的。然而，整体调节机制仍不清楚。为了解决这个问题，我们在分化的C2C12肌管中进行了低频和高频电脉冲刺激（EPS），进行了代谢组和转录组分析，并研究了信号分子的磷酸化状态。EPS在刺激期间和之后以频率依赖的方式引发了代谢物、信号磷酸化和基因表达的广泛而特异性的变化。我们通过整合这些数据构建了跨组学网络，发现高频EPS后磷酸戊糖途径包括代谢物、上游信号分子和代谢酶基因表达的选择性激活。我们通过实验验证了高频EPS后这些分子的激活依赖于活性氧（ROS）。因此，跨组学分析揭示了C2C12肌管中高频EPS后信号转导、代谢组和转录组中ROS依赖性激活，为肌肉适应的可能机制提供了线索。
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