# PERM1--An Emerging Transcriptional Regulator of Mitochondrial Biogenesis: A Systematic Review
## 4 Discussion
### PERM1 and Skeletal Muscle
#### 4.1.2 Signaling/Gene Induction  
An overview of the PERM1 signaling pathway in skeletal muscle is provided in Figure 3. The pioneering study by [PERSON] et al. (2013) characterized PERM1 in C2C12 myotubes, revealing that PERM1 acts downstream of PGC-1\(\alpha\) and ERRs and is involved in the regulation of muscle-selective pathways of energy metabolism and in the regulation of the contractile function [12]. Overexpression of PGC-1\(\alpha\), PGC-1\(\beta\), ERR\(\alpha\), ERR\(\beta\), and ERR\(\gamma\) in C2C12 myotubes induce _PERM1_ expression, with PGC-1\(\alpha\) and ERR\(\alpha\) leading to a more pronounced increase in _PERM1_[12]. Interestingly, MetaMEx reveals that _PGC-1\(\alpha\)_ and _PERM1_ expression is strongly correlated in human muscles [20]. Additionally, CaMKII (calcium/calmodulin-dependent protein kinase II) interacts with PERM1 forming a regulatory feed-forward loop where PERM1 promotes the activation of CaMKII, and the activation of CaMKII increases the expression and activity of _PERM1_[13]. In GLUT-4 mutated mouse skeletal muscle, PERM1 phosphorylation is increased, suggesting that PERM1 may work in collaboration with AMPK and CaMK signaling [30].  
Activation of _PERM1_ induces the expression of a gene set affecting a diverse range of cellular processes including energy metabolism homeostasis, mitochondrial biogenesis, lipid and glucose uptake, and contractile activity. Overexpression of PERM1 in C2C12 myotubes induces _PGC-1\(\alpha\)_ and _ERR_ target genes, including _CKMT2, GLUT4_, and _TNN13_, while PERM1 suppression increases _PDK4_ mRNA, indicating its negative regulation by _PERM1_[12]. Additionally, specific _PGC-1\(\alpha\)/ERR/PERM1_-regulated genes (see Figure 3) rely predominantly on _PERM1_ for an efficient response to _PGC-1\(\alpha\)_[12]. PERM1 overexpression has been shown to increase p-p38 MAPK protein levels in both the primary myotubes and the tibialis anterior muscle of mice, while upregulating other proteins and genes involved in the regulation of mitochondrial biogenesis and of lipid and glucose metabolism (see Figure 4) [11].  
Findings from PERM1 loss-of-function studies have also contributed to the elucidation of PERM1's downstream network. Muscle-specific PERM1 knockdown in mice has been found to reduce acute exercise-mediated increases in p-CaMKII and p-p38 MAPK protein expression, attenuate induction of exercise-responsive genes associated with oxidative capacity, and increase exercise-responsive genes associated with cellular stress (see Figure 3) [13]. Additionally, PERM1 knockdown in mice performing 4 weeks of voluntary wheel running has been shown to decrease the protein levels of all OxPhos complexes and PGC-1\(\alpha\), abolish training-induced increases in myoglobin, CKMT2, and CPT1B, and increase ERR\(\alpha\) and SIRT3 [13]. Similarly, PERM1 knockdown in mice has been shown to decrease expression of proteins associated with the OxPhos function, the MIB complex, oxidative stress signaling, mitochondrial energy metabolism, and apoptosis (see Figure 3) [26].