In rodents and humans, it has been demonstrated that peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a key regulator of the exercise-induced changes of muscle fibers towards a slow phenotype, as well as in the protection from muscle atrophy [
108,
112,
113]. Several studies have shown that PGC-1α is upregulated after high-intensity training [
114,
115,
116,
117,
118]. Activation of PGC-1α is likely to occur by phosphorylation of the PGC-1α protein by p38 MAPK together with NF-κB [
119], both of which are known to be activated by ROS [
91,
92]. PGC-1α has been demonstrated to regulate lipid and carbohydrate metabolism, and to improve the oxidative capacity of the muscle fibers by increasing the amount and activity of mitochondria through upregulation of nuclear respiratory factors (NRF-1, 2) and mitochondrial transcription factor A (TFAM) [
120,
121]. Furthermore, PGC-1α regulates genes involved in the determination of muscle fiber type. Overexpression of PGC-1α increases the proportion of oxidative type I fibers [
122] while PGC-1α knock-out (KO) mice exhibit a shift from oxidative type I and IIA toward glycolytic type IID/X and IIB fibers [
123]. This regulatory diversity of PGC-1α is enabled by its broad binding capacity to transcription factors in various signaling pathways. PGC-1α has multiple binding sites for the interactions with diverse coactivators. A domain between amino acids 200 and 400 interacts with the nuclear receptors PPARγ and NRF-1 [
124], which are considered as master regulators of mitochondrial biogenesis [
125]. PGC-1α binds to and activates the transcriptional function of NRF-1 on the promoter for TFAM, a direct regulator of mitochondrial DNA replication and transcription [
120]. Another domain that predominantly binds to nuclear hormone receptors such as ERR-α, PPARs, RXR, glucocorticoid receptor, HNF4, and probably others, is an LXXLL sequence in the N-terminal region of PGC-1α [
124]. This sequence is necessary for the coactivation of the nuclear receptor liver x receptor α (LXRα) [
126]. The transcription complex of LXRα and PGC-1α then activates fatty acid synthase (FAS), a multifunctional enzyme that catalyzes all reactions required for the
de novo biosynthesis of lipid [
127]. The binding site of the nuclear receptor estrogen-related receptor α (ERR-α) is also in the LXXLL region of PGC-1α [
124]. The transcription complex formed by ERR-α and PGC-1α induces the expression of vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis [
128,
129]. Between amino acids 400 to 500 of the PGC-1α protein is the binding site for myocyte enhancer factor 2 (MEF2). This transcription factor is a key regulator of slow muscle identity [
130]. MEF2 proteins are activated through the calcium-regulated calcineurin signaling pathway [
130,
131]. When overexpressed, MEF2C promotes the formation of slow fibers, thus enhancing running endurance in mice [
132]. Genetic deletion of
Mef2c has been shown to block activity-dependent (exercise-induced) fast-to-slow fiber type transition [
132]. This is in line with the proposed role of PGC-1α in such transitions. Muscle-specific overexpression of PGC-1α has been shown to evoke a transition of glycolytic type II in oxidative type I fibers [
122]. This shift is initiated by the formation of a PGC-1α/MEF2 transcription complex, which then activates the expression of slow muscle genes [
133]. Handschin
et al. [
123] have shown that PGC-1α deficient mice display a significant shift from slow oxidative type I and fast oxidative IIA toward fast glycolytic type IIX and IIB fibers, resulting in a reduced endurance capacity.