The Role of Eif6 in Skeletal Muscle Homeostasis Revealed by Endurance Training Co-expression Networks.
The Role of Eif6 in Skeletal Muscle Homeostasis Revealed by Endurance Training Co-expression Networks.
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DOI：
10.1016/j.celrep.2017.10.040
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发表时间：
2017-11-07
期刊：
影响因子：
8.8
通讯作者：
Falciani F
中科院分区：
文献类型：
--
作者：
Clarke K;Ricciardi S;Pearson T;Bharudin I;Davidsen PK;Bonomo M;Brina D;Scagliola A;Simpson DM;Beynon RJ;Khanim F;Ankers J;Sarzynski MA;Ghosh S;Pisconti A;Rozman J;Hrabe de Angelis M;Bunce C;Stewart C;Egginton S;Caddick M;Jackson M;Bouchard C;Biffo S;Falciani F
定期的耐力训练可以提高肌肉的氧化能力，降低与年龄相关的疾病风险。理解这种现象背后的分子网络至关重要。在这里，通过利用计算模型的力量，我们展示了耐力训练引起基因调控网络的深刻变化，将信号传递和选择性翻译控制与能量代谢和组织重塑联系起来。我们发现，mTOR非依赖因子Eif6的敲除影响线粒体的呼吸效率、ROS产生和运动成绩，我们预测Eif6是这一过程的关键调节因子。我们的工作证明了数据驱动的方法理解肌肉动态平衡的有效性。耐力运动深刻影响基因网络的结构，Eif6是负责肌肉代谢和蛋白质合成的基因网络的枢纽，Eif6+/−小鼠肌肉中线粒体代谢能力发生变化，Eif6单倍体不足导致ROS生成增加，运动能力下降。使用数据驱动的反向工程来揭示Eif6在控制骨骼肌内稳态中的作用。他们通过分析控制骨骼肌适应耐力运动的复杂基因网络，以及对Eif6+/−小鼠的活体研究表明呼吸效率降低，ROS产生增加，运动能力降低，从而实现了这一点。
Regular endurance training improves muscle oxidative capacity and reduces the risk of age-related disorders. Understanding the molecular networks underlying this phenomenon is crucial. Here, by exploiting the power of computational modeling, we show that endurance training induces profound changes in gene regulatory networks linking signaling and selective control of translation to energy metabolism and tissue remodeling. We discovered that knockdown of the mTOR-independent factor Eif6, which we predicted to be a key regulator of this process, affects mitochondrial respiration efficiency, ROS production, and exercise performance. Our work demonstrates the validity of a data-driven approach to understanding muscle homeostasis. Endurance exercise profoundly affects the structure of gene networks Eif6 is a hub in gene networks responsible for muscle metabolism and protein synthesis Mitochondrial metabolic capacity altered in muscle from Eif6+/− mice Eif6 haploinsufficiency increased ROS generation and reduced exercise performance Clarke et al. use data-driven reverse engineering to uncover the role of Eif6 in controlling skeletal muscle homeostasis. They achieve this by analyzing the complex network of genes that controls skeletal muscle adaptation to endurance exercise, together with in vivo studies of eif6+/− mice that show decreased respiration efficiency, increased ROS production, and reduced exercise performance.
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