The Role of Eif6 in Skeletal Muscle Homeostasis Revealed by Endurance Training Co-expression Networks

Kim Clarke, Sara Ricciardi, Tim Pearson, Izwan Bharudin, Peter K. Davidsen, Michela Bonomo, Daniela Brina, Alessandra Scagliola, Deborah M. Simpson, Robert J. Beynon, Farhat Khanim, John Ankers, Mark A. Sarzynski, Sujoy Ghosh, Addolorata Pisconti, Jan Rozman, Martin Hrabe de Angelis, Chris Bunce, Claire Stewart, Stuart EggintonMark Caddick, Malcolm Jackson, Claude Bouchard, Stefano Biffo, Francesco Falciani

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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. 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.

Original languageEnglish
Pages (from-to)1507-1520
Number of pages14
JournalCell Reports
Volume21
Issue number6
DOIs
StatePublished - 7 Nov 2017
Externally publishedYes

Keywords

  • Eif6
  • exercise
  • metabolism
  • mitochondria
  • network biology
  • skeletal muscle
  • systems biology

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