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

Mitochondria undergo robust morphological and functional changes in response to a number of environmental conditions. For instance, physical exercise, myogenesis and cold exposure are known to induce mitochondrial biogenesis in skeletal muscle. The transcriptional co-activator peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 alpha (PGC-1α) is an established regulator of skeletal muscle mitochondrial biogenesis, though recent evidence (reviewed in Islam et al. 2019) has also identified additional protein with important roles in mitochondrial remodelling, including the nuclear hormone receptor PPAR-beta (PPARβ). PPARβ heterodimerizes with the retinoic acid receptor to bind specific DNA sequences known as PPAR response elements (PPREs), which are present on the promoters of various genes involved in oxidative metabolism. In the absence of a ligand (e.g. free-fatty acids), PPARβ’s association with corepressors (e.g. nuclear receptor corepressor-1; NCoR1) inhibits its transcriptional activity, whereas ligand-binding and/or post-translational modification leads to the recruitment of coactivators (e.g. PGC-1α) that increase PPARβ’s transcriptional activity at PPREs. Importantly, PPARβ promotes mitochondrial biogenesis through a dual mechanism involving enhanced expression of the nuclear respiratory factor 1 (NRF-1) and stabilization of existing PGC-1α protein (Koh et al. 2017). Given that both PGC-1α and PPARβ are involved in the transcriptional control of mitochondrial biogenesis (Islam et al. 2019), a functional interaction between these two regulatory protein (Koh et al. 2017) implicates the PGC-1α/PPARβ axis as an important mediator of exercise-induced mitochondrial remodelling in skeletal muscle. 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. 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. Supporting the co-involvement of PGC-1α and PPARβ in the regulation of UCP3 gene expression in skeletal muscle cells, silencing PGC-1α abolished the increase in UCP3 mRNA following treatment with a PPARβ ligand. Third, chronic treatment of myotubes with palmitate enriched the presence of PGC-1α at the PPRE on the UCP3 promoter, activated PPRE-driven gene transcription, and increased UCP3 mRNA levels. Moreover, UCP3 knockdown in myoblasts overexpressing PGC-1α abolished the palmitate-induced increase in mitochondrial respiratory function, highlighting UCP3 as an essential mediator of PGC-1α’s ability to enhance mitochondrial function in response to metabolic overload. Collectively, these findings exemplify the importance of the PGC-1α/PPARβ axis in the induction of UCP3 gene expression. An additional noteworthy observation was the increase in PGC-1α activity despite reductions in PGC-1α mRNA/protein levels during myogenesis and/or in response to chronic palmitate exposure. Importantly, this observation demonstrates that PGC-1α’s activity can dissociate from changes in its mRNA/protein content under conditions of increased metabolic stress. 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. Specifically, we discuss (1) the importance of the PGC-1α/PPARβ axis in the transcriptional control of exercise-induced mitochondrial biogenesis and (2) the implications of the dissociation between PGC-1α activity and its mRNA/protein content.