Eukaryotic initiation factor 2B epsilon induces cap-dependent translation and skeletal muscle hypertrophy
Article first published online: 14 JUN 2011
© 2011 The Authors. Journal compilation © 2011 The Physiological Society
The Journal of Physiology
Volume 589, Issue 12, pages 3023–3037, June 2011
How to Cite
Mayhew, D. L., Hornberger, T. A., Lincoln, H. C. and Bamman, M. M. (2011), Eukaryotic initiation factor 2B epsilon induces cap-dependent translation and skeletal muscle hypertrophy. The Journal of Physiology, 589: 3023–3037. doi: 10.1113/jphysiol.2010.202432
- Issue published online: 14 JUN 2011
- Article first published online: 14 JUN 2011
- (Received 12 November 2010; accepted after revision 7 April 2011; first published online 11 April 2011)
Non-technical summary Skeletal muscle comprises ∼40% of total body mass, and the control of muscle mass has significant effects on overall health. Skeletal muscle mass is determined by the balance of protein synthesis and degradation within muscle cells. We sought to determine which cellular proteins that control protein synthesis within muscle cells are associated with muscle growth after resistance exercise, a potent growth stimulus. We identified two proteins that were associated with muscle growth in humans: p70S6K and eIF2Bɛ. Follow up studies determined that eIF2Bɛ alone is sufficient to induce muscle growth. This is the first study to determine that this protein can induce skeletal muscle growth. These results further our understanding of how skeletal muscle responds to resistance exercise.
Abstract The purpose of this study was to identify signalling components known to control mRNA translation initiation in skeletal muscle that are responsive to mechanical load and may be partly responsible for myofibre hypertrophy. To accomplish this, we first utilized a human cluster model in which skeletal muscle samples from subjects with widely divergent hypertrophic responses to resistance training were used for the identification of signalling proteins associated with the degree myofibre hypertrophy. We found that of 11 translational signalling molecules examined, the response of p(T421/S424)-p70S6K phosphorylation and total eukaryotic initiation factor 2Bɛ (eIF2Bɛ) protein abundance after a single bout of unaccustomed resistance exercise was associated with myofibre hypertrophy following 16 weeks of training. Follow up studies revealed that overexpression of eIF2Bɛ alone was sufficient to induce an 87% increase in cap-dependent translation in L6 myoblasts in vitro and 21% hypertrophy of myofibres in mouse skeletal muscle in vivo (P < 0.05). However, genetically altering p70S6K activity had no impact on eIF2Bɛ protein abundance in mouse skeletal muscle in vivo or multiple cell lines in vitro (P > 0.05), suggesting that the two phenomena were not directly related. These are the first data that mechanistically link eIF2Bɛ abundance to skeletal myofibre hypertrophy, and indicate that eIF2Bɛ abundance may at least partially underlie the widely divergent hypertrophic phenotypes in human skeletal muscle exposed to mechanical stimuli.