An autoregulatory loop controls peroxisome proliferator-activated receptor γ coactivator 1α expression in muscle

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Abstract
Skeletal muscle adapts to chronic physical activity by inducing mitochondrial biogenesis and switching proportions of muscle fibers from type II to type I. Several major factors involved in this process have been identified, such as the calcium/calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A (CnA), and the transcriptional component peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Transgenic expression of PGC-1α recently has been shown to dramatically increase the content of type I muscle fibers in skeletal muscle, but the relationship between PGC-1α expression and the key components in calcium signaling is not clear. In this report, we show that the PGC-1α promoter is regulated by both CaMKIV and CnA activity. CaMKIV activates PGC-1α largely through the binding of cAMP response element-binding protein to the PGC-1α promoter. Moreover, we show that a positive feedback loop exists between PGC-1α and members of the myocyte enhancer factor 2 (MEF2) family of transcription factors. MEF2s bind to the PGC-1α promoter and activate it, predominantly when coactivated by PGC-1α. MEF2 activity is stimulated further by CnA signaling. These findings imply a unified pathway, integrating key regulators of calcium signaling with the transcriptional switch PGC-1α. Furthermore, these data suggest an autofeedback loop whereby the calcium-signaling pathway may result in a stable induction of PGC-1α, contributing to the relatively stable nature of muscle fiber-type determination.