Peroxisome Proliferator-activated Receptor γ Coactivator-1 α Isoforms Selectively Regulate Multiple Splicing Events on Target Genes

Abstract

Endurance and resistance exercise training induces specific and profound changes in the skeletal muscle transcriptome. Peroxisome proliferator-activated receptor ␥ coactivator-1 ␣ (PGC-1␣) coactivators are not only among the genes differentially induced by distinct training methods, but they also participate in the ensuing signaling cascades that allow skeletal muscle to adapt to each type of exercise. Although endurance training preferentially induces PGC-1␣1 expression, resistance exercise activates the expression of PGC-1␣2, -␣3, and -␣4. These three alternative PGC-1␣ isoforms lack the arginine/serine-rich (RS) and RNA recognition motifs characteristic of PGC-1␣1. Discrete functions for PGC-1␣1 and -␣4 have been described, but the biological role of PGC-1␣2 and -␣3 remains elusive. Here we show that different PGC-1␣ variants can affect target gene splicing through diverse mechanisms, including alternative promoter usage. By analyzing the exon structure of the target transcripts for each PGC-1␣ isoform, we were able to identify a large number of previously unknown PGC-1␣2 and -␣3 target genes and pathways in skeletal muscle. In particular, PGC-1␣2 seems to mediate a decrease in the levels of cholesterol synthesis genes. Our results suggest that the conservation of the N-terminal activation and repression domains (and not the RS/RNA recognition motif) is what determines the gene programs and splicing options modulated by each PGC-1␣ isoform. By using skeletal muscle-specific transgenic mice for PGC-1␣1 and -␣4, we could validate, in vivo, splicing events observed in in vitro studies. These results show that alternative PGC-1␣ variants can affect target gene expression both quantitatively and qualitatively and identify novel biological pathways under the control of this system of coactivators.

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

“…We provide the first evidence that acute exercise was successful at eliciting significant elevations in full-length SMN transcript levels. Collectively, the present results support our earlier speculation (Ng et al 2018;Dial et al 2018b) that the mechanism(s) responsible for exercise-induced SMN expression include enhanced SMN transcriptional activation downstream of AKT and ERK/ELK1 signalling (Biondi et al 2015), PGC-1α-driven pre-mRNA SMN splicing corrections (Monsalve et al 2000;Martínez-Redondo et al 2016), as well as p38-mediated SMN mRNA stabilization (Farooq et al 2009(Farooq et al , 2013. Furthermore, our data demonstrate that physiological AMPK stimulation is associated with increased SMN expression (r = 0.45, R 2 = 0.20, P < 0.05; data not shown), which extends an earlier proof-of-concept report that observed some benefits to pharmacological AMPK activation in severe SMA-like mice (Cerveró et al 2016).…”

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

“…Here we observed that mito-TEMPO decelerates IPF-LF senescence in vitro, and in pre-clinical studies for asthma and kidney disease, mitoTEMPO exhibits antifibrotic activity. 1,45,46 In this study, the expression of PGC-1α was increased in IPF-LFs 48 These splice variants are regulated differently to PGC-1α1 and evoke distinct biological programs. 49 In this study, we provide evidence that an auto-feedback loop exists between dysfunctional mitochondrial and senescence in LFs, involving increases in mitochondrial superoxide and mTORC1 activation.…”

“…Here, the predominant form of PGC‐1α detected in LFs had a lower apparent MW, between 50 and 75 kDa. While PGC‐1α1 is the most widely characterised PGC‐1α isoform, there are numerous lower MW versions, including PGC‐1α2 and PGC‐1α3, both of which are closer to 50 kDa in size . These splice variants are regulated differently to PGC‐1α1 and evoke distinct biological programs .…”

Mitochondria Initiate and Regulate Sarcopenia

“…PGC-1α2, PGC-1α3, and PGC-1α4, have been shown to stimulate protein synthesis and attenuate UPS activity in cultured myotubes and mouse skeletal muscle (87, 119). Furthermore, PGC-1α reduces muscle protein degradation by the UPS via blocking nuclear factor κB (NF-κB) and FoxO3 activity (16, 124).…”