Eukaryotic initiation factor 2B epsilon induces cap‐dependent translation and skeletal muscle hypertrophy

Abstract

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 eIF2Bε. Follow up studies determined that eIF2Bε 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 2Bε (eIF2Bε) 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 eIF2Bε 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 eIF2Bε 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 eIF2Bε abundance to skeletal myofibre hypertrophy, and indicate that eIF2Bε abundance may at least partially underlie the widely divergent hypertrophic phenotypes in human skeletal muscle exposed to mechanical stimuli.

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

“…sActRIIB-Fc also increased the phosphorylation of 4E-BP1, a protein less responsive to rapamycin (12), and eIF2Bε protein. eIF2Bε is required for translation initiation, and its overexpression has induced ϳ20% hypertrophy of myofibers in mice (38). In contrast, the phosphorylation of Akt at Ser 473 increased after only 2 wk, when muscle mass was already increased, and at Thr 308 it remained unchanged.…”

Small‐molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia

“…This included an up‐regulation of eIF2B (subunit δ) and down‐regulation of BAX, which we later confirmed by immunoblotting. The eIF2B pathway is a known translational regulator of protein synthesis, with evidence showing that its content can directly influence fibre size 31. The direct targeting of elF2B by MuRF1 appears plausible because our previous yeast two‐hybrid screens identified elF2B as a MuRF1 interacting factor, linking MuRF1 as a negative regulator of protein synthesis 32.…”

Heterogeneity in resistance training-induced muscle strength and mass responses in men and women of different ages

“…In previous studies with healthy human subjects, e.g., several genetic variations (Riechman et al 2004;Devaney et al 2009;Walsh et al 2012;Van Deveire et al 2012), differences in skeletal muscle gene Raue et al 2012;Phillips et al 2013) and microRNA expression (Davidsen et al 2011), phosphorylation status of signaling proteins (Mayhew et al 2011;Mitchell et al 2013), androgen receptor concentrations (Ahtiainen et al 2011;Mitchell et al 2013), and satellite cell count (Petrella et al 2008) have been suggested to segregate high and low responders to RTinduced muscle hypertrophy. The physiological aspects of individual variation in phenotype responses to RT are apparently very complex phenomena and more studies specifically focused on high and low responders are required to reveal unambiguously the mechanisms of individual differences in RT-induced adaptations.…”