Essential role of the PGC‐1α/PPARβ axis in Ucp3 gene induction

Abstract

Key points We report that the peroxisome proliferator‐activated receptor (PPAR)γ coactivator 1‐α (PGC‐1α)/PPARβ axis is a crucial mediator of uncoupling protein 3 (UCP3) expression in skeletal muscle cells via the transactivativation of a distal PPAR response element at the Ucp3 gene promoter. This mechanism is activated during the myogenic process and by high concentrations of fatty acids independent of PGC‐1α protein levels. Ucp3 is essential for PGC‐1α‐induced oxidative capacity and the adaptive mitochondrial response to fatty acid exposure. These findings provide further evidence for the broad spectrum of the coactivator action in mitochondrial homeostasis, positioning the PGC‐1ɑ/PPARβ axis as an essential component of the molecular regulation of Ucp3 gene in skeletal muscle cells. Abstract Uncoupling protein 3 (UCP3) has an essential role in fatty acid metabolism and mitochondrial redox regulation in skeletal muscle. However, the molecular mechanisms involved in the expression of Ucp3 are poorly known. In the present study, we show that the peroxisome proliferator‐activated receptor (PPAR)γ coactivator 1‐α (PGC‐1α)/PPARβ axis is a crucial mediator of Ucp3 expression in skeletal muscle cells. In silico analysis of the UCP3 promoter and quantitative chromatin immunoprecipitation experiments revealed that the induction of the UCP3 transcript is mediated by the transactivation of a distal PPAR response element at the Ucp3 gene promoter by the coactivator PGC‐1α. This mechanism is activated during myogenesis and during metabolic stress induced by fatty acids independent of PGC‐1α protein levels. We also provide evidence that Ucp3 is essential for PGC‐1α‐induced oxidative capacity. Taken together, our results highlight PGC‐1ɑ/PPARβ as an essential component of the molecular regulation of Ucp3 gene in skeletal muscle cells.

Cooperative control of oxidative metabolism by PGC‐1α and PPARβ: implications for exercise‐induced mitochondrial remodelling in skeletal muscle

“…Because NRF-1 is also a transcription factor for CaMKKβ, the NRF-1-mediated increase in CaMKKβ expression may further stimulate the PGC-1α/PPARβ axis via enhanced AMPK phosphorylation by CaMKKβ (Koh et al 2017). Concurrently, given that PPARβ stabilizes existing PGC-1α protein (Koh et al 2017) and that metabolic stress enriches the presence of PGC-1α at PPREs (Lima et al 2019), is it plausible that exercise enhances PGC-1α's coactivation of PPARβ-mediated transcription on the promoters of key mitochondrial biogenic genes (e.g. NRF-1 and PGC-1α).…”

“…fatty acid exposure, exercise) thereby facilitating the induction of oxidative gene expression (Yamamoto et al 2011), the contribution of transcriptional de-repression in the control of mitochondrial biogenesis by PGC-1α/PPARβ provides an important avenue for future research in exercised human skeletal muscle. Lima et al's (2019) observation of a dissociation between PGC-1α activity and protein/mRNA content in response to cellular stressors (i.e. myogenesis and chronic palmitate exposure) has widespread implications for the field of exercise physiology.…”

“…In the current issue of The Journal of Physiology, Lima and colleagues (Lima et al 2019) employed in silico and in vitro models to investigate the potential involvement of the PGC-1α/PPARβ axis in the transcriptional control of uncoupling protein 3 (UCP3) expression in skeletal muscle. First, the authors used public ChIPseq datasets to demonstrate that the UCP3 promoter contains putative PPREs that overlap with binding sites for PGC-1α.…”

“…First, the authors used public ChIPseq datasets to demonstrate that the UCP3 promoter contains putative PPREs that overlap with binding sites for PGC-1α. Second, Lima et al (2019) examined UCP3 mRNA levels and PGC-1α interactions at the UCP3 promoter during myogenesis. Coincident with an increase in UCP3 mRNA levels, myogenesis increased the presence of PGC-1α at a binding site on the UCP3 promoter that overlapped with a known PPRE.…”

“…In their article, Lima et al (2019) provide an interesting discussion on the interactions between the PGC-1α/PPARβ axis and UCP3 expression in response to myogenesis and fatty acid exposure. In an attempt to the extend the authors' discussion, we consider the implications of their findings within the context of exercise-induced mitochondrial biogenesis in skeletal muscle.…”