## 3 Results and Discussion
### The Signaling Pathways Underlying Satellite Cell Regulation
#### 3.3.2 Wnt
In contrast to aged skeletal muscle, triggering exercise-dependent canonical Wnt/\(\beta\)-catenin signaling did not cause fibrosis in adult skeletal muscle, was associated with satellite cell activation, and promoted myogenic proliferation. In young mice, voluntary exercise significantly restored _Pax7_ expression in satellite cells, whereas in adult mice the decrease in _Pax7_ due to aging was primarily restored by the activated Pax7 cell population. Interestingly, [PERSON] et al. proposed that Wnt/\(\beta\)-catenin signaling must be silenced during adult muscle regeneration, because transiently active Wnt/\(\beta\)-catenin signaling is not required for regeneration and \(\beta\)-catenin downregulation is necessary to restrict the regenerative response, but does not participate in self-renewal of the satellite cell. MyoD+ cell expansion and proliferation were unaffected by \(\beta\)-_catenin_ deletion in the adult mice model, indicating that satellite cells could self-renew, as assessed by Pax7+ cell number in the basal lamina. _Klotho_ is a Wnt signaling negative regulator that is often associated with aging [71; 72]. _Klotho_ deficiency in mice has been linked to muscle weakness, sarcopenia, and compromised skeletal muscle regeneration [73; 74; 75]. Additionally, studies suggest that _Klotho_ plays a role in modulating autophagy in different type of tissues [76]. [PERSON] et al. discovered that _Klotho_ expression in muscle is reduced in mdx dystrophic mice at the onset of pathology and during aging. The dramatic production of pro-inflammatory cytokines like tumor-necrosis factor \(\alpha\) (_TNF\(\alpha\)_) and interferon gamma (_IFN\(\gamma\)_) in mdx mice reduced _Klotho_ expression in mdx dystrophic muscle, while elevating _Klotho_ expression in macrophages by 50% in each case, suggesting it may regulate cytokine expression in dystrophic muscle. _Klotho_ regulates satellite cell numbers and muscle fiber growth in vivo, as exhibited by mdx mice that received the _Klotho_ transgenic bone marrow cells (BMCs). The increased muscle fiber size and quantification of Pax7+ satellite cells in recipient mice compared to the mdx control, suggested an increase in the number of macrophages that promote muscle regeneration. [PERSON] et al. suggested that _Klotho_ enhances the regenerative capacity of dystrophic muscle driven by _TNF\(\alpha\)_. _Klotho_ suppression is an adaptive trait that shields macrophages from oxidative stress damage. M2 macrophages can be beneficial or harmful in muscular dystrophy, but administrating _Klotho_ to dystrophic muscle can reduce the expression of pro-fibrotic transcripts and prevent the connective tissue accumulation. [PERSON] et al. used a different strategy to understand differentiation regulator factor change within Wnt signaling by profiling commonly dysregulated miRNAs in a zebrafish dystrophic model (sapje zebrafish) and human DMD. They revealed that several muscle-enriched miRNAs, including miR-199a-5p, were more highly expressed in sapje zebrafish at 5 days post fertilization (dpf) than at 30 dpf, indicating that dysregulated miRNAs in zebrafish dystrophic disease may arise early in development. They also discovered that miR-199a-5p level were elevated in human dystrophic muscles. Serum response factor (SRF) is a miRNAs repressor, and its transcriptional co-factors myocardium-related transcription factor (MRTF) were used in this research to identify dysregulated miRNA transcripts. They are known to control myogenic fusion, differentiation, regeneration, and dystrophic disease pathogenesis [77; 78; 79]. MiR-199a-5p expression is SRF-dependent and targets several regulatory factors within Wnt signaling pathways including _Wnt2_, Frizzled-4 (_FZD4_), and Jagged1 (_JAG1_) which are involved in human myoblast differentiation, regulation of _Pax7/MyoD_ expression, and proliferation.