## 4 Skeletal Muscle  
The expression of the FNDC5 gene in SkM cells is differentiated between muscle fiber types. Generally, slow type fibers show a higher expression compared to fast type fibers at rest; PE is able to induce FNDC5 expression in all type of fibers, following an expression pattern regulated by exercise type and duration. For example, in a mouse model, aerobic exercise (i.e., running wheel) induces equal expression of FNDC5 in different muscle fibers [7; 84; 85; 86].  
While the FNDC5 gene is expressed in different tissues, the main sources of circulating irisin are the SkM during PE, and adipose tissue. Therefore, irisin can be considered both a myokine and an adipokine [7; 84]. In the SkM, irisin expression is mainly mediated by PGC-1\(\alpha\) through its interaction with a number of transcription factors implicated in energy requirement [87; 88; 89]. These proteins can induce the expression of FNDC5 in a different manner: [PERSON] et al. (2018) recently suggested in vitro that in C2C12 myotubes the expression of FNDC5 is modulated by the cAMP response element-binding protein (CREB) through its binding with PGC-1\(\alpha\)[90]. It's important to remember that CREB is activated by aerobic exercise and that the signaling of cAMP activates CREB in the SkM during exercise to manage metabolic adaptation [91; 92]. In addition, endurance exercise induces the expression of FNDC5 in the quadriceps via the PGC-1\(\alpha\)/estrogen related receptor alpha (ERRa) pathway [8]. The retinoic acid (RA) is another inductor of FNDC5 expression in muscle. RA is a natural ligand for retinoid X receptor (RXR). This receptor also represents a transcription factor activated by a ligand that binds to RA responsive elements (RARE) in the regulatory sequences of genes regulated by PGC-1\(\alpha\)[93]. The expression of FNDC5 is increased by treatment with RA in differentiated C2C12 myocytes, also in an independent manner from PGC-1\(\alpha\)[94] (Figure 2). During PE, PGC-1\(\alpha\) accelerates mitochondrial biogenesis and regulates the glucose/fatty acid metabolism, favoring the switch from fast to slow fiber contraction. Under this process, the increased expression and activity of PGC-1\(\alpha\) is mediated by the increase of Ca\({}^{2+}\) influx into fibers' cytoplasm [95].  
Conversely, other conditions can inhibit the expression of FNDC5 in SkM. For example, FNDC5 expression is reduced by Myostatin. This myokine exerts a reverse effect to FNDC5, inhibiting the differentiation of myoblast [96], and significantly increasing the mRNA expression levels of PGC-1\(\alpha\) and FNDC5 when it is silenced [97] (Figure 2). Comparably, the expression of PGC-1\(\alpha\) and FNDC5 may be suppressed by the protein Mothers against decapentaplegic homolog 3 (SMAD3) in C2C12 mouse myoblasts, while in knockout Smad3 mice, aerobic exercise increases serum irisin in comparison to wild-type mice [86]. Furthermore, [PERSON] et al. (2016) showed that 48 h of fasting decreased the circulating level of irisin and expression level of FNDC5 in SkM, while the intraperitoneal injection of insulin for 2 weeks has a comparable action on FNDC5/irisin level in plasma and SkM [98].  
Finally, it is worth mentioning the growing interest in the potential use of irisin as a bona fide biomarker and potential target for the complex management of sarcopenia and muscle loss even in subjects after spinal cord injury [80; 99; 100; 101]. Future studies are warranted to investigate the role of irisin as a biological bridge among exercise and muscle metabolism.