Fig. 4.

A model for the autoregulatory loop regulating the PGC-1α promoter in muscle fiber-type determination. (A) Exercise and subsequently elevated intracellular calcium levels result in an activation of both CaMKIV and CnA in skeletal muscle. Activated CaMKIV can phosphorylate CREB, which then increases transcription of PGC-1α via a conserved CREB-binding site in the proximal promoter. Moreover, CaMKIV and CnA activate the transcriptional activity of MEF2s in part by promoting the dissociation of inhibitory HDACs and Cabin1. MEF2s, potentially in combination with NFAT, bind to at least one MEF2-binding site in the PGC-1α flanking region and increase transcriptional activity. Newly synthesized PGC-1α protein can coactivate MEF2s and thus positively regulate its own transcription. PGC-1α also might compete with the inhibitory HDACs and Cabin 1 for binding to MEF2s. Together, this positive feedback loop may ensure a stable transcription of PGC-1α, leading to muscle fiber-type I determination. (B) Endogenous PGC-1α expression is increased in transgenic mice expressing ectopic PGC-1α in skeletal muscle. Total RNA from wild-type and transgenic skeletal muscle was analyzed for the expression of transgenic and endogenous PGC-1α, GAPDH, myoglobin, and cytochrome c by using real-time PCR. Relative mRNA expression levels were normalized to 18S rRNA levels. nd, not detectable. The values represent the average of three independent experiments, and bars represent SD. *, P < 0.5 between different treatments compared with the untreated control.