Effect of contractile activity on PGC-1α transcription in young and aged skeletal muscle

Abstract

Mitochondrial impairments are often noted in aged skeletal muscle. The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is integral to maintaining mitochondria, and its expression declines in aged muscle. It remains unknown whether this is due to a transcriptional deficit during aging. Our study examined PGC-1α transcription in muscle from young and old F344BN rats. Using a rat PGC-1α promoter-reporter construct, we found that PGC-1α transcription was reduced by ∼65% in aged TA muscle, accompanied by decreases in PGC-1α mRNA and transcript stability. Altered expression patterns in PGC-1α transcription regulatory factors, including nuclear respiratory factor 2, upstream transcription factor 1, activating transcription factor 2, and yin yang 1, were noted in aged muscle. Acute contractile activity (CA) followed by recovery was employed to examine whether PGC-1α transcription could be activated in aged muscle similar to that observed in young muscle. AMPK and p38 signaling was attenuated in aged muscle. CA evoked an upregulation of PGC-1α transcription in both young and aged groups, whereas mRNAs encoding PGC-1α and cytochrome oxidase subunit IV were induced during the recovery period. Global DNA methylation, an inhibitory event for transcription, was enhanced in aged muscle, likely a result of elevated methyltransferase enzyme Dnmt3b in aged muscle. Successive bouts of CA for 7 days to evaluate longer-term consequences resulted in a rescue of PGC-1α and downstream mRNAs in aged muscle. Our data indicate that diminished mitochondria in aged muscle is due partly to a deficit in PGC-1α transcription, a result of attenuated upstream signaling. Contractile activity is an appropriate countermeasure to restore PGC-1α expression and mitochondrial content in aged muscle. NEW & NOTEWORTHY PGC-1α is a regulator of mitochondrial biogenesis in muscle. We demonstrate that PGC-1α expression is reduced in aging muscle due to decreases in transcriptional and posttranscriptional mechanisms. The transcriptional deficit is due to alterations in transcription factor expression, reduced signaling, and DNA methylation. Acute exercise can initiate signaling to reverse the transcriptional defect, restoring PGC-1α expression toward young values, suggesting a mechanism whereby aged muscle can respond to exercise for the promotion of mitochondrial biogenesis.

Autophagy and mitophagy flux in young and aged skeletal muscle following chronic contractile activity

“…Although this remains controversial, recent work has indicated that aged muscle can increase the transcription of PGC‐1α in response to contractile activity (Carter et al . ), as well as enhance its translational capacity in response to a training regime (Robinson et al . ).…”

“…Additionally, following exercise training protocols, aged muscle appears to harbour a lower capacity for the generation of new, healthy organelles than younger counterparts (Hood et al 2016). Although this remains controversial, recent work has indicated that aged muscle can increase the transcription of PGC-1α in response to contractile activity (Carter et al 2018), as well as enhance its translational capacity in response to a training regime (Robinson et al 2017). Nonetheless, little research has focused on the selective removal of organelles through mitophagy, a process also critical to maintaining organelle and muscle integrity.…”

“…), impaired transcription of PGC‐1α (Carter et al . ), altered synthesis of mitochondrial proteins (Rooyackers et al . ; Miller et al .…”

“…Although controversial, ageing muscle often presents with a population of compromised mitochondria. Observed impairments include reduced organelle content (Chabi et al 2008;O'Leary et al 2013;St-Jean-Pelletier et al 2017), impaired transcription of PGC-1α (Carter et al 2018), altered synthesis of mitochondrial proteins (Rooyackers et al 1996;Miller et al 2012), poor respiratory function (Conley et al 2000;), higher reactive oxygen species (ROS) emission (Chabi et al 2008;), loss of mitochondrial membrane potential ( m ; Chabi et al 2008), decreased calcium retention (Gouspillou et al 2014), increased mtDNA mutational load (Melov et al 1995) and greater release of pro-apoptotic proteins (Chabi et al 2008;Gouspillou et al 2014). These changes may potentially contribute to the observed decline in muscle performance with ageing, but it remains unclear if these changes are due solely to ageing or are a product of changes in physical activity (Kent-Braun & Ng, 2000;Picard et al 2011;Joseph et al 2012;Hepple, 2014;Leduc-Gaudet et al 2015;St-Jean-Pelletier et al 2017).…”

Redox Signaling from Mitochondria: Signal Propagation and Its Targets

“…Mitochondrial redox signaling activates guanosine triphosphatase (GTPase) RhoA, which subsequently triggers accumulation of F-actin, beneficial for the repair of local injury. A self-standing field beyond the scope of this article represents studies of aged skeletal muscle and relations to a sedentary life-style [32]. We should at least note that overexpression of PGC1α in aging muscle led to a reversal of the observed age-related changes [33].…”