## 3 eIF3f and mTOR in Skeletal Muscle Function
In recent years, the physiological role of eIF3f has been more extensively investigated in skeletal muscle. It was found that the E3 ubiquitin ligase MAFbx/atrogin-1 targets the Mov34 motif of eIF3f during atrophy for polyubiquitination and subsequent degradation by the proteasome [40,166,167]. A series of studies highlighted that eIF3f expression is essential to maintain skeletal muscle mass and that expression of a mutant (eIF3f K5-10R, where six lysine residues on the C-terminal have been mutated) insensitive to MAFbx/atrogin-1 targeting protects against starvation-induced muscle atrophy [39,40,151,167]. eIF3f K5-10R overexpression also promotes enhanced protein synthesis and hypertrophy in normal conditions compared to wild type protein, suggesting a role of eIF3f in muscle growth [40,151]. Of note, a subset of microRNAs (miRNAsA) in the delta-like homolog 1 and the type III iodothyronine deiodinase (DIk1-Dio3) cluster showed an anti-atrophic effect, probably by limiting the degradation of eIF3f by MAFbx/atrogin-1 [168]. Importantly, it was found that mice carrying a null mutation of the _eIF3f_ gene failed to develop and died at the early embryonic stage [39]. One candidate explaining the development impairment could be the Notch pathway known to be positively regulated through eIF3f deubiquitinase activity [169]. Because Notch is essential for post-implantation development [170], a possible defect of this pathway in eIF3f null mice could contribute to failed development. However, heterozygous mice (eIF3f+/ mice) live but show a lower skeletal muscle mass associated with a lower mTOR1 pathway activation, polysome content and protein synthesis flux [39]. Noteworthy, muscle atrophy (i.e., muscle mass  
Figure 3: mTORC1 regulates eIF3f in skeletal muscle protein translation. RHEB (Ras homolog enriched in brain) activates mTORC1 (mechanistic/mammalian target of rapamycin complex 1), which binds to the scaffold protein eIF3f (eukaryotic initiation factor 3f) through a TOS (TOR signaling) motif and modulates mRNA translation by phosphorylating eIF3f bound-S6K1 (S6 kinase 1) and 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1). S6K1-mediated regulation of translation occurs, in part, through phosphorylation of rpS6 (ribosomal protein S6), eIF4B (eukaryotic translation initiation factor 4B), and eEF2k (eukaryotic elongation factor-2 kinase). eEF2k inhibits eEF2 (eukaryotic elongation factor-2) to promotes mRNA translation. Phosphorylation of 4E-BP1 by mTOR (mechanistic/mammalian target of rapamycin) promotes its dissociation from eIF4E (eukaryotic initiation factor 4E) and allows for the assembly of the preinitiation complex. During muscle wasting, eIF3f is targeted by MAFbx (muscle atrophy F-box) at Mov34 motif to promote eIF3f proteasomal degradation. Resistance training and amino acids enable the migration of the mTORC1/eIF3f complex at the lysosome surface and at the cell membrane near to peripheral nuclei and blood capillaries. Of note, CDK1 (phosphoinositide-dependent kinase-1) phosphorylates S6K1 for full activation. and CSA) was found to be exacerbated in heterozygous mice compared to control during immobilization [39]. Of note, no impact of partial deletion of eIF3f was found on both the ubiquitination levels of muscle proteins and numerous markers of autophagy pathway, including markers of mitophagy (i.e., the specific degradation of mitochondria through autophagy) [39]. Thus, eIF3f plays a critical role in embryonic development and adult skeletal muscle mass maintenance, with a role essentially focused on protein synthesis pathways rather than proteolysis. Furthermore, a role of eIF3f in adaptations to exercise was recently suggested. Mechanical overload enhances eIF3f expression and, interestingly, this effect is blunted in DGK\(\zeta\) KO muscles [46]. Thus, inhibition of FOXOO3 pathway by DGK\(\zeta\) could play a role in MAFbx/atropin-1-induced eIF3f degradation and mRNA translation.