The truncated splice variants, NT -PGC -1α and PGC -1α4 , increase with both endurance and resistance exercise in human skeletal muscle

Abstract

Recently, a truncated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant, PGC-1α4, that originates from the alternative promoter was shown to be induced by resistance exercise and to elicit muscle hypertrophy without coactivation of “classical” PGC-1α targets involved in mitochondrial biogenesis and angiogenesis. In order to test if distinct physiological adaptations are characterized by divergent induction of PGC-1α splice variants, we investigated the expression of truncated and nontruncated PGC-1α splice variants and PGC-1α transcripts originating from the alternative and the proximal promoter, in human skeletal muscle in response to endurance and resistance exercise. Both total PGC-1α and truncated PGC-1α mRNA expression were increased 2 h after endurance (P < 0.01) and resistance exercise (P < 0.01), with greater increases after endurance exercise (P < 0.05). Expression of nontruncated PGC-1α increased significantly in both exercise groups (P < 0.01 for both groups) without any significant differences between the groups. Both endurance and resistance exercise induced truncated as well as nontruncated PGC-1α transcripts from both the alternative and the proximal promoter. Further challenging the hypothesis that induction of distinct PGC-1α splice variants controls exercise adaptation, both nontruncated and truncated PGC-1α transcripts were induced in AICAR-treated human myotubes (P < 0.05). Thus, contrary to our hypothesis, resistance exercise did not specifically induce the truncated forms of PGC-1α. Induction of truncated PGC-1α splice variants does not appear to underlie distinct adaptations to resistance versus endurance exercise. Further studies on the existence of numerous splice variants originating from different promoters are needed.

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…In addition, a 12-week progressive weight lifting programme specifically induces isoforms Pgc-1α2, Pgc-1α3 and Pgc-1α4 from the novel promoter [37]. However, other research shows that both promoters can be activated independent of the exercise intervention [60,61]. PGC-1α isoform expression patterns display distinct temporal dynamics [55] and until we understand the mechanisms behind these different expression profiles it is important to unify experimental procedures such as exercise intervention, sampling and gene expression analysis techniques.…”

Is muscle hypertrophy following resistance exercise regulated by truncated splice variants of PGC-1α?

“…Adding to the discrepant findings, specific truncated splice variants were suggested to be regulated distinctly by two different promoters (Ruas et al 2012), whereas reports focusing on human skeletal muscle demonstrated both exercise modalities upregulate truncated splice variants from both promoters (Norrbom et al 2011, Ydfors et al 2013. It was suggested that the disparate findings might be traced to the use of primers in the Ruas study that do not distinguish between both promoters (discussed in Ydfors et al 2013).…”

“…The similar responses of splice variants to acute (Ydfors et al 2013, Lundberg et al 2014) and chronic (Lundberg et al 2014) exercise of both modalities in human skeletal muscle challenge this idea of splice variant-specific regulation of adaptation to exercise. Hence, these studies offer two different perspectives.…”

“…It was suggested that the disparate findings might be traced to the use of primers in the Ruas study that do not distinguish between both promoters (discussed in Ydfors et al 2013). The Lundberg and Ydfors studies used primers that capture pooled truncated transcripts from both promoters, whilst the Ruas study may not have been able to distinguish between either promoter for PGC-1a (discussed in Ydfors et al 2013).…”

PGC-1α Mediated Muscle Aerobic Adaptations to Exercise, Heat and Cold Exposure

“…Recent studies have identified several PGC-1α isoforms (Popov et al, 2014;Tadaishi et al, 2011;Ydfors et al, 2013) which are mostly exercise sensitive and collectively contribute to the overall increase in skeletal muscle PGC-1α mRNA observed following exercise (Baar et al, 2002;McGee & Hargreaves, 2004;Pilegaard et al, 2003;Russell et al, 2005). However, PGC-1α protein content may (Mathai et al, 2008) or may not (McGee & Hargreaves, 2004) be up-regulated following acute exercise, indicating that initial increases in PGC-1α mRNA do not necessarily lead to increased protein expression.…”