## 2 mTORC1 Signaling, Its Regulators, and Ribosome Biogenesis
mTORC1 activates TIF-1A for pre-ribosomal RNA synthesis through Pol I [124]. Moreover, mTOR phosphorylates the human phosphoprotein MAF1 inhibiting RNA polymerase III (Pol III) repression function and leading to subsequent transfer RNA (tRNA) synthesis [128; 129]. mTOR also interacts with the RNA binding protein La-related protein 1 (LARP1) involved with terminal oligopyrimidine (TOP) mRNA translation and subsequently regulates the production of ribosomal proteins, as well as initiation and elongation factors [130; 131; 132]. Finally, mTORC1 regulates the ubiquitous transcription factor c-Myc during chronic resistance training [117]. c-Myc oncoprotein is implicated in the transcription of numerous genes and in the coordination of protein synthesis by upregulated the expression and processing of rRNA and riboproteins components. Transcriptional control of genes required for the initiation of mRNA translation and nuclear export of ribosomal subunits are also modulated by c-Myc [133]. c-Myc is considered as an essential driver of ribosome biogenesis as it regulates the transcription of UBF, TIF-1A, TIF-1B, Pol I, Pol II, and Pol III [133; 134; 135; 136; 137; 138]. Muscle loading, contractile activity, as well as nutrients availability, hormones, and other growth stimuli may impact ribosome biogenesis through the regulation of the aforementioned pathways [124; 139; 140]. During hypertrophy, protein synthesis rate increases, muscle protein pool grows but cell translational capacity (ribosomal density) and efficiency (rate of mRNA translation) could be limiting steps. An increase of total RNA and rRNA content was associated with exercise-induced hypertrophy [58; 141; 142; 143]. In accordance with these observations, the precursor 45S and mature rRNA 18S, 28S and 5.8S transcripts levels were elevated during a resistance training protocol in humans [142]. rRNA content and ribosomal biogenesis are determinant for hypertrophy in human skeletal muscle after a resistance training regimen, and blunted ribosomal production in vitro impedes myotubes hypertrophy [58]. The increase in total RNA and rRNA content seems to be correlated with the muscle growth response [58], suggesting that ribosome biogenesis is a key factor for generating higher hypertrophy in \"super-responder\" subjects. In mice, early increases in rRNA and 45S-pre-rRNA content, as well as expression of c-Myc and its downstream Pol I regulon, were found following functional hypertrophy [144]. Interestingly, chromatin remodeling at the ribosomal DNA (rDNA) promoter was also observed in the same study [144], showing that both transcriptional and epigenetic mechanisms are involved in ribosome biogenesis at the onset of muscle hypertrophy. Finally, [PERSON] and coworkers recently found that both rapamycin-dependent and rapamycin-independent pathways (e.g., myostatin) are involved in ribosome biogenesis in response to resistance training [145]. In summary, mTOR1 signaling pathway is essential for embryonic and adult myogenesis, but not for adult skeletal muscle mass maintenance under normal conditions. mTOR1 stimulates ribosome biogenesis at numerous levels and is critical for hypertrophy in response to mechanical stimuli, even if research on mTOR1-independent mechanisms is still limited. Importantly, among DGK isoforms, DGK\(\zeta\) is now considered as a key regulator of protein biosynthesis during overload. In addition to its role on mTOR1 regulation, DGK\(\zeta\) also prevents protein breakdown by inhibiting FOXO3 pathway. Additional studies are needed to better understand the precise role of DGK\(\zeta\) on catabolic systems  
Figure 2: mTORC1 stimulates ribosome biogenesis. mTOR (mechanistic/mammalian target of rapamycin) modulates the activity of TIF-1A(transcription initiation factor IA) involved in pre-ribosomal RNA synthesis and of the ubiquitous transcription factor c-Myc that controls genes products involved in the transcription and processing of rRNA, in the protein components synthesis, and in the nuclear export of ribosomal subunits.