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. 2015 Jan-Mar;7(1):48-59.

Regulation of PGC-1α Isoform Expression in Skeletal Muscles

D V Popov  1 , E A Lysenko  2 , I V Kuzmin  3 , Vinogradova Vinogradova  1 , A I Grigoriev  1
Affiliations

Regulation of PGC-1α Isoform Expression in Skeletal Muscles

D V Popov et al. Acta Naturae. 2015 Jan-Mar.

Abstract

The coactivator PGC-1α is the key regulator of mitochondrial biogenesis in skeletal muscle. Skeletal muscle expresses several PGC-1α isoforms. This review covers the functional role of PGC-1α isoforms and the regulation of their exercise-associated expression in skeletal muscle. The patterns of PGC-1α mRNA expression may markedly differ at rest and after muscle activity. Different signaling pathways are activated by different physiological stimuli, which regulate the expression of the PGC-1α gene from the canonical and alternative promoters: expression from a canonical (proximal) promoter is regulated by activation of the AMPK; expression from an alternative promoter, via a β2-adrenergic receptor. All transcripts from both promoters are subject to alternative splicing. As a result, truncated isoforms that possess different properties are translated: truncated isoforms are more stable and predominantly activate angiogenesis, whereas full-length isoforms manly regulate mitochondrial biogenesis. The existence of several isoforms partially explains the broad-spectrum function of this protein and allows the organism to adapt to different physiological stimuli. Regulation of the PGC-1α gene expression by different signaling pathways provides ample opportunity for pharmacological influence on the expression of this gene. Those opportunities might be important for the treatment and prevention of various diseases, such as metabolic syndrome and diabetes mellitus. Elucidation of the regulatory mechanisms of the PGC-1α gene expression and their functional role may provide an opportunity to control the expression of different isoforms through exercise and/or pharmacological intervention.

Keywords: PGC-1α; alternative promoter; alternative splicing; gene expression; skeletal muscle.

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Figures

Fig. 1
Fig. 1
The scheme of PGC-1α protein activation and regulation of the PGC-1α gene expression from canonical (proximal) and alternative promoters.AMPK – AMP-activated protein kinase, ATF – activating transcription factor, CaMK – Ca2+/calmodulin-dependent protein kinase, CREB – cAMP response element-binding protein, ERR – estrogen-related receptor, HDAC – class IIa histone deacetylase, MEF – myocyte enhancer factor, NRF – nuclear respiratory factor, OXPHOS – oxidative phosphorylation related genes, p38 MAPK – p38 mitogen-activated protein kinases, PGC – peroxisome proliferator-activated receptor gamma, coactivator, PKA – protein kinase A, PPAR – peroxisome proliferator- activated receptor, SIRT1 – NAD-dependent deacetylase sirtuin-1, TFAM – mitochondrial transcription factor A, TFB1M –mitochondrial transcription factor B1, TFB2M –mitochondrial transcription factor B2, VEGFA –vascular endothelial growth factor A, β2AR –β2-adrenergic receptor
Fig. 2
Fig. 2
A – Different PGC-1α mRNA isoforms are expressed from canonical (PGC-1α-a) and alternative (PGC-1α-b and PGC-1α-c) promoters in mice and encode different amino acid sequences in the first exon. B – Scheme of exons (vertical line) of different isoforms and their genomic DNA locations. The asterisk is a stop-codon. C – Nucleotide and amino acid sequences between exons 6 and 7 in the full-length (PGC-1α) and truncated (NT-PGC-1α) isoforms
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