Regulation of PGC-1α Isoform Expression in Skeletal Muscles

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.

Regulation of PPARGC1A gene expression in trained and untrained human skeletal muscle

“…; Popov et al. 2015a). At rest, expression via the canonical promoter is high, while that via the alternative promoter is very low.…”

“…Alternative promoters have the potential to play important roles in generating the complexity of human gene expression, in particular, in regulating gene expression via different promoter in a stimuli-specific manner. In rodent and human skeletal muscle, the PPARGC1A gene can be expressed via the canonical (proximal) and alternative (distal) promoters (Martinez-Redondo et al 2015;Popov et al 2015a). At rest, expression via the canonical promoter is high, while that via the alternative promoter is very low.…”

Increased FXYD1 and PGC‐1α mRNA after blood flow‐restricted running is related to fibre type‐specific AMPK signalling and oxidative stress in human muscle

“…A key determinant of these endurance‐type adaptations is the transcriptional co‐activator, the peroxisome proliferator‐activated receptor‐γ co‐activator 1α (PGC‐1α). It has recently been shown that human muscle contains different PGC‐1α isoforms, and these isoforms may regulate different aspects of the muscle response to exercise . Furthermore, there is evidence for and against some of these isoforms (PGC‐1α1 and PGC‐1α4) responding to different types of exercise.…”

“…It has recently been shown that human muscle contains different PGC-1a isoforms, 18 and these isoforms may regulate different aspects of the muscle response to exercise. 19 Furthermore, there is evidence for 18,20 and against 21,22 some of these isoforms (PGC-1a1 and PGC-1a4) responding to different types of exercise. But like the NKA isoforms, there is limited evidence about the effects of different ergogenic strategies on the regulation of the level of these isoforms in human muscle.…”

PGC‐1α4 gene expression is suppressed by the IL‐6—MEK—ERK 1/2 MAPK signalling axis and altered by resistance exercise, obesity and muscle injury

“…Recent evidence suggests that PGC‐1 α 4 expression may be promoted through β 2 adrenergic receptor signalling to the alternative promoter region (Popov et al . ). Pgc1α4 alternate splicing likely operates through small nuclear proteins assembling upon the pre‐mRNA substrate to excise intron sequences (House & Lynch ).…”