Multiple signaling pathways regulate contractile activity-mediated PGC-1α gene expression and activity in skeletal muscle cells

Abstract

PGC‐1α is an important transcriptional coactivator that plays a key role in mediating mitochondrial biogenesis. Within seconds of the onset of contractile activity, a number of rapid cellular events occur that form part of the initial signaling processes involved in PGC‐1α gene regulation, such as elevations in cytoplasmic calcium, AMPK and p38 activation, and elevated ROS production. We observed that basal levels of PGC‐1α promoter activity were more sensitive to resting Ca2+ levels, compared to ROS, p38 or, AMPK signaling. Moreover, enhanced PGC‐1α transcription and post‐translational activity on DNA were a result of the activation of multiple signal transduction pathways during contractile activity of myotubes. AMPK, ROS, and Ca2+ appear to be necessary for the regulation of contractile activity‐induced PGC‐1α gene expression, governed partly through p38 MAPK and CaMKII activity. Whether these signaling pathways are arranged as a linear sequence of events, or as largely independent pathways during contractile activity, remains to be determined.

Mitochondria, Muscle Health, and Exercise with Advancing Age

“…We subsequently questioned whether this reduced early adaptive response could be a result of disrupted exercise signals to the coactivator in aging muscle. Acute exercise is known to elicit the activation of p38 mitogen-activated protein kinase (MAPK), AMPactivated protein kinase (AMPK), and Ca 2ϩ /calmodulin-dependent protein kinase IV (CAMKIV), which impinge on PGC-1␣ transcription and activity (176). Our studies, and those of others, have revealed that, after acute exercise, aged muscle is less capable of activating these upstream kinases (FIGURE 3) (52, 100, 135).…”

Exercise and the Regulation of Mitochondrial Turnover

“…These studies have implicated cytosolic Ca 2+ in stimulating the expression of a number of mitochondrial genes, 18,19 effects which appear to be mediated, in part, through enhanced signaling by calcium/calmodulindependent protein kinase (CaMK), protein kinase C (PKC), AMPK, and mitogen-activated protein kinases (MAPKs). [18][19][20] Contractile activity-induced signaling by these Ca 2+ -regulated kinases appears to converge on the PGC-1α promoter, 20,21 stimulating an increase in PGC-1α mRNA and protein levels. 20 While the role of PGC-1α as a downstream effector of Ca 2+ in the context of mitochondrial biogenesis has been described, recent work has also highlighted the idea that PGC-1α may also function upstream of Ca 2+ signaling in skeletal muscle, as it controls the expression of variety of proteins which modulate Ca 2+ handling.…”

“…[18][19][20] Contractile activity-induced signaling by these Ca 2+ -regulated kinases appears to converge on the PGC-1α promoter, 20,21 stimulating an increase in PGC-1α mRNA and protein levels. 20 While the role of PGC-1α as a downstream effector of Ca 2+ in the context of mitochondrial biogenesis has been described, recent work has also highlighted the idea that PGC-1α may also function upstream of Ca 2+ signaling in skeletal muscle, as it controls the expression of variety of proteins which modulate Ca 2+ handling. 22 This provides a link for earlier findings, which have described contractile activity as a potent stimulus for inducing alterations in the expression of Ca 2+ handling proteins.…”

“…Furthermore, both promoter activity and PGC-1α protein activity are attenuated during contractile activity if p38 is inhibited. 20 The observed increase in PGC-1α promoter activity may be achieved through the ability of p38 to phosphorylate the TFs, myocyte enhancer factor-2 (MEF2), and activating transcription factor-2 (ATF2), which both bind to promoter elements within the upstream regulatory region of the PGC-1α gene. 26 Therefore, these data suggest that p38 is important for the increase in PGC-1α gene transcription in skeletal muscle with exercise.…”

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

“…While there are many important factors involved in the biosynthesis of the mitochondrion, the transcriptional coactivator, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has been identified as a key regulator involved in this highly complex process Puigserver et al, 1998;Wu et al, 1999). Indeed, there is now good evidence demonstrating that exercise-induced mitochondrial biogenesis is modulated via PGC-1α dependant mechanisms (Calvo et al, 2008;Leick et al, 2010;Leick et al, 2008;Little et al, 2011;Safdar et al, 2011;Uguccioni and Hood, 2011;Zhang et al, 2014). Exercise capacity and performance has shown to be strongly associated with muscle mitochondrial content in both animal and human models (Daussin et al, 2008;Fitts et al, 1975) and is associated with improved risk factors for a variety of chronic diseases (Bishop-Bailey, 2013).…”