## 2 mTORC1 Signaling, Its Regulators, and Ribosome Biogenesis  
The mammalian/mechanistic target of rapamycin (mTOR) is a 289 kDa serine/threonine kinase [63]. mTOR forms two different multiprotein complexes: mTORC1 and mTORC2 [64]. mTORC1 is sensitive to rapamycin and consists of mTOR, regulatory associated protein of mTOR (RAPTOR) [65; 66], mTOR-associated protein LST8 homolog (mLST8/GBL) [67], DEP domain containing mTOR-interacting protein (DEPTOR) [68], and proline rich Akt substrate of 40 kDa (PRAS40) [69; 70]. mTORC1 was found early in the century to be involved in the regulation of skeletal muscle size and to oppose atrophy [71; 72]. On the other side, mTORC2, which is not sensitive to short-duration rapamycin treatment, is composed of mTOR, rapamycin-insensitive companion of mTOR (RICTOR) [73; 74], mLST8/GBL [74], DEPTOR [68], and mammalian stress-activated protein kinase interacting protein 1 (mSIN1) [75]. Of note, chronic rapamycin treatment inhibits mTOR2 signaling pathway and promotes insulin resistance via the inhibition of this pathway [76; 77]. mTOR2 has been identified as a critical regulator of muscle glucose uptake in response to insulin stimulation and exercise [78]. Importantly, several contractile proteins, actin cytoskeleton regulators, ion-channels, and transcriptional regulators, were suggested as potential substrates of mTOR2 during exercise [78]. mTOR2 is predominantly located at the sarcolemma without modification of this localization in response to feeding and exercise [79]. mTORC1 pathway has been extensively studied in the past few years in skeletal muscle, and particularly during muscle development and growth. In rodent, genetic ablation of mTOR1 components, especially RAPTOR, or pharmacological inhibition of mTORC1, decreases mRNA translation, results in serious muscle dystrophy and prevents overload-induced hypertrophy [71; 80; 81; 82; 83; 84]. Inhibition of mTORC1 in developing muscle causes perinatal death and negatively affects proliferation and fusion of muscle progenitors during regeneration [85]. Nevertheless, a recent study also highlighted that mTORC1 signaling was not essential for the maintenance of adult muscle size and function five months after complete inhibition of this pathway in sedentary rodents [86]. The authors also found that the expression of critical components of the translation machinery and translation rates were decreased despite stable muscle size and function [86]. Other studies previously showed that effective inhibition of mTORC1 with short-term (one or two weeks) and long-term (four to six months) daily treatments or diet based ingestion of rapamycin does not affect fiber size nor muscle mass [87; 88; 89; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 1  
muscle growth [113]. Recently, it was also found that IGF-1/Akt1 regulation is dispensable for activation of mTOR1 signaling and satellite cells following mechanical overload [114]. Furthermore, it was found that mechanical overload induces mTOR1 activation at the early phase thanks to the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (MEK/ERK) pathway through phosphorylation of TSC2 instead of the PI3K/Akt signaling [115]. ERK1/2 pathway is also involved in muscle growth through the regulation of nuclear transcriptional factors (i.e., Elk-1, c-Myc, c-Jun and c-Fos) [116]. Recently, mechanical stimuli were found to activate phospholipase D (PLD) and the lipid second messenger phosphatidic acid (PA) [41]. PA competes with the mTOR1 inhibitor FKBP38 (FK506 binding protein 38), promoting mTOR binding to FKBP12-rapamycin binding (FRB) domain leading to mTOR1 activation [44]. However, none of the IGF-1 and ERK1/2 pathways nor PLD activity modulation appear to be required for mTOR1 activation and skeletal muscle hypertrophy [42; 82; 114; 117]. Nonetheless, recent  
Figure 1: mTORC1 regulates skeletal muscle protein synthesis.