## 3 Results and Discussion
### The Signaling Pathways Underlying Satellite Cell Regulation  
#### 3.3.1 Notch  
Notch signaling is a juxtracrine cellular signaling that interacts on the cell surface via ligand-receptor crosstalk. Notch signaling is a multifunctional pathway that is critical in cell fate decisions during muscle development and regeneration. It is also frequently associated with satellite cell proliferation, differentiation, and self-renewal. Notch signaling dysregulation may contribute to various developmental disorders, demonstrating the importance of this signaling in living organisms [61; 62]. [PERSON] et al. and [PERSON] et al. explored the absence of a _PKC\(\theta\)_ and _Sdc3_ in dystrophic muscles respectively, in in vitro and in vivomodels using mice. The absence of \(PKC\theta\) in dystrophic mice increases muscle regeneration, and reduces muscle necrosis and fibrosis, while improving exercise performance without exhaustion of satellite cells, via the activation of Notch signaling and the increase in the Pax7+ quiescent satellite cells. The loss of \(Sdc3\) caused the decrease in Pax7+ cells and inhibited Notch signaling. [PERSON] et al. used a different approach in investigating the Notch signaling pathway in muscular dystrophy, by modulating the parallel expression of \(Notch1\) and \(Notch2\) to maintain the quiescent state of satellite cells after injury. They revealed that \(Notch1\) and \(Notch2\) are essential for muscle regeneration after injury, by tightly regulating \(Pax7\) expression throughout myogenesis. \(Notch1\) and \(Notch2\) cooperate and compensate for one another to control muscle regeneration in adults, hence sustaining the satellite cell pool. [PERSON] et al. investigated the role of Notch signaling in post-fusion myofibers and muscle regeneration using stage-specific activation of Notch1 signaling in mouse strains My11 Cre and MCK-Cre. They discovered that post-differentiation myocytes can de-differentiate back into Pax7+ quiescent satellite cells via Notch1 signaling activation, which is stage-dependent and restricted to mononucleated myofibers, which do not require cytokinesis. Activating Notch signaling in aged and dystrophic mice enhanced muscle function and regeneration; however, it caused severe muscle damage and postnatal mortality, emphasizing the stage-specific nature of \(Notch1\) in maintaining the stem cell niche. A contrasting approach taken by [PERSON] et al. in manipulating Notch signaling expression was shown via the inhibition of overexpressed Notch. The inhibition rescued the induction of myogenic differentiation and improved the function of \( dystrophin/tubulin\) double knockout (dKO) mice muscle progenitor cells (MPC). As a result, Notch overexpression has been shown to negatively regulate muscular dystrophy phenotypes, and re-balancing Notch signaling in dKO mice is critical for modulating pro-inflammatory factors, cell proliferation, and the rate of MPC senescence. Despite the fact that Notch activation facilitates regeneration, [PERSON] et al. 2012 [63] discovered that the ability to increase satellite cells through self-renewal may inhibit muscle regeneration in old mice by delaying myogenic activation. [PERSON] et al. demonstrated the importance of Numb protein, a Notch signaling inhibitor in muscle regenerative myogenesis expressed in activated satellite cells. Numb deficiency in the Pax7-lineage decreased the number of satellite cells in single-fiber culture, resulting in a defective repair response in adult muscle. Numb-deficient cells show no substantial change in the expression levels of \(MyoD\), \(Pax7\), and \(Notch\) ligands, stipulating that Notch signaling is not the major mechanism regulating satellite cell proliferation. Numb regulates skeletal muscle repair, asymmetric satellite cell division, and activation-associated satellite cell progeny proliferative expansion. [PERSON] et al.