## 3 Results and Discussion
### The Signaling Pathways Underlying Satellite Cell Regulation
#### 3.3.3 Alternative Signaling Pathways  
[PERSON] et al. explored the activation of mTOR1 signaling in muscle stem cells in _MyoG_ null zebrafish model. The mechanistic target of the rapamycin (mTOR) signaling pathway is essential for cellular growth and metabolism. It has two distinct complexes, mTOR1 and mTOR2, which interact with various proteins. mTOR1 is activated by nutrients, while mTOR2 is regulated by phosphoinositide 3-kinases (_PI3K_) and growth factor signaling [81; 82]. Adult zebrafish with _MyoG_ loss have reduced muscle bulk, implying a continuous muscle defect in adulthood. MyoG\(-/-\) zebrafish mutants have more abundant muscle stem cells than their siblings, with an over thirteenfold increase in myofiber nuclei. _MyoG_ regulates the adult skeletal muscle growth rate and muscle stem cell dynamics, by affecting their number and deep quiescence state, as well as regulating the expression of mTOR1 signaling genes. The absence of _MyoG_ raised mTOR1 signaling in adult muscle, indicating an alteration in the muscle stem cell niche, and resulted in precocious muscle stem cell activation as assessed by increased _Pax7_ mRNA expression, cell number, and proliferation potential. However, by downregulating the fusogenic genes, _Myomixer_ and _Myomaker_, the stem cells were unable to fuse, and produced improper myofibers with increased size but decreased length, indicating early terminal differentiation. [PERSON] and [PERSON] reported that _TRAF6_ and _Pax7_ are highly expressed in quiescent and activated satellite cells. Satellite-cell specific _TRAF6_ knock-out mice (TRAF6\({}^{\text{cko}}\)) exhibited a decrease in _Pax7_ with the loss of quiescence satellite cell population, as well as upregulation of _MyoD_ expression in cultured myogenic cells, resulting in precocious differentiation. Tumor necrosis factor receptor-associated factor 6 (_TRAF6_) is a protein involved in mediating signal transduction pathways, including extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). _TRAF6_ has a pivotal role in regulating _Pax7_ expression in satellite cells, as observed by a decrease in the number of activated satellite cells, caused by an intrinsic defect. A substantial decrease in quiescent Pax7+ satellite cells in newly isolated fibers of TRAF6\({}^{\text{cko}}\) mice was observed, suggesting its importance for the maintenance of the satellite stem cell pool and function in vivo. TRAF6\({}^{\text{cko}}\) mice had reduced muscle regeneration after injury using a BaCl\({}_{2}\) injection, while defective muscle repair was still observed after weeks post-injury. Using wild-type _TRAF6_ and TRAF6C70A mutant mice, [PERSON] and [PERSON] examined the activity of _TRAF6_ E3 ubiquitin ligase in satellite cell proliferation and self-renewal. It was discovered that the activity of _TRAF6_ E3 ubiquitin ligase is critical for self-renewal, proliferation, and preventing precocious differentiation. Despite the fact that _TRAF6_ is crucial for _AKT_ phosphorylation and translocation, and for response to growth stimuli, no significant difference was observed in _AKT_ phosphorylation or total levels and in its downstream phosphorylation targets. In order to proliferate and self-renew, satellite cells require the ERK1/2 and JNK1/2 signaling activation, while _c-JUN_ regulates _Pax7_ expression by directly binding to the _Pax7_ promoter. _TRAF6_ deficiency caused the E3 ubiquitin ligase to function improperly, resulting in enhanced _c-JUN_ degradation. _TRAF6_ deletion in satellite cells inhibits regeneration and intensifies myopathy, suggesting a post-transcriptional role for the MAPK/c-JUN/AP1 axis in mediating _Pax7_ expression. Increased p38 MAPK expression in TRAF6-deficient cells promotes precocious differentiation, while decreased ERK1/2 and JNK1/2 signaling promote an exit from quiescence and precocious differentiation. [PERSON] et al.