## 2 mTORC1 Signaling, Its Regulators, and Ribosome Biogenesis
Upon IGF-1 (insulin-like growth factor 1) axis activation, IRS1 (insulin receptor substrate 1) activates the lipid kinase PI3K (phosphoinositide 3-kinase). PI3K phosphorylates the membrane-bound phospholipid PIP2 (phosphatidylinositol diphosphate) and generates PIP3 (phosphatidylinositol triphosphate), which recruits Akt/PKB (protein kinase B) and PDK1 (phosphoinositide-dependent kinase-1). PDK1 phosphorylates and activates Akt, which then phosphorylates and inactivates TSC1/TSC2 (tuberous sclerosis complex 1/2), a RHEB (Ras homolog enriched in brain) inhibitor. RHEB then activates mTOR (mechanistic/mammalian target of rapamycin). In response to mechanical stimuli, mTOR is also activated by branched-chain amino acids, Vps34 (vacuolar protein sorting 34), DGKn1 (diacylglycerolglycerol kinase eta) and by PA (phosphatidic acid). PA is synthesized by PLD (phospholipase D) and DGK\(\zeta\) (diacylglycerolglycerol kinase zeta) and targets mTOR on its FRB (FKBP-rapamycin-binding) domain to induce its activation. Amino acids promote the recruitment of mTOR to the lysosomal surface, where mTOR is activated by RHEB. ERK1/2 (extracellular signal-regulated kinase 1/2) inhibits TSC1/TSC2 and promotes the transcription of genes involved in muscle growth through Elk1 (ETS-like protein-1), c-Fos, c-Jun and c-Myc. mTOR in association with RICTOR (rapamycin-insensitive companion of mTORR) forms mTOR2 (mechanistic/mammalian target of rapamycin complex 2) and fully activates Akt. mTORC1 (mechanistic/mammalian target of rapamycin complex 1) plays critical roles in mRNA translation, ribosome biogenesis, autophagy inhibition, and perhaps in lipid synthesis in muscle cells. studies showed that diacylglycerolglycerol (DAG) and DAG kinases (DGKs) play an important role in PA accumulation during mechanical stress, especially the zeta isoform of DGK (DGK\(\zeta\)) [45]. In this model, DGK\(\zeta\) stimulates PA biosynthesis through DAG phosphorylation and mTOR activation. PA also binds to the FKBP12-rapamycin binding (FRB) domain of mTOR, promoting the activation of its kinase domain. Moreover, DGK\(\zeta\) represses FOXO03 (forkhead box O3) activity promoting a subsequent inhibition of muscle atrophy F-box (MAFbx)/atropin-1 and muscle ring-finger protein-1 (MuRF1) expressions [46]. Consistent with these data, DGK\(\zeta\), KO (knock-out) muscles show higher levels of MAFbx/atropin-1 and MuRF1 after exercise [46]. Finally, it was found that DGK\(\zeta\) is predominantly increased among DGK isoforms during mechanical overload and that DGK\(\zeta\) is essential for muscle growth [46]. Of note, a recent study highlighted that the eta isozyme of DGK (DGK\(\eta\)) promotes myoblast proliferation through the mTORC1/fatty acid synthase (FASN) pathway [47]. The authors also suggest that mTOR and DGK\(\eta\) are mutually regulated since mTOR knockdown reduces DGK\(\eta\) but also FASN expressions [47]. Muscle growth and hypertrophy are not only reliant on the availability of amino-acids and mRNAs, but are also dependent of the translational activity of ribosomes [118]. Ribosomes regulate cellular protein content by assembling amino acids in a sequence indicated by the mRNA to create polypeptide chains. Ribosome biogenesis starts with ribosomal RNA (rRNA) transcription by RNA polymerase I (Pol I) as a 47S pre-rRNA. This long transcript is then cleaved into 28S, 18S, 5.8S and assembled with ribonuclear proteins [119]. Pol I acts like a primary regulator of ribogenesis, forming a pre-initiation complex (PIC) thanks to the transcription initiation factor IA (TIF-1A), the transcription initiation factor IB (TIF-1B), and the upstream binding factor (UBF) [120; 121; 122]. Of note, transcriptional activity of TIF-1A and UBF mainly depends on cyclins, cyclin-dependent kinases (CDKs), ERK, adenosine monophosphate-activated protein kinase (AMPK), mTORC1, and S6K1 related signaling pathways [120; 123; 124; 125; 126; 127]. Importantly, mTORC1 signaling pathway regulates ribosome biogenesis at several levels (Figure 2).