The importance of PGC-1α in contractile activity-induced mitochondrial adaptations

Abstract

The transcriptional coactivator PPARγ coactivator-1α (PGC-1α) is a critical regulator of mitochondrial content and function in skeletal muscle. PGC-1α may also mediate mitochondrial adaptations in response to chronic contractile activity (CCA). To characterize the essential role of PGC-1α in organelle biogenesis, C2C12 murine myotubes were transfected with PGC-1α-specific siRNA and subjected to electrical stimulation-evoked CCA. CCA enhanced cytochrome c oxidase (COX) activity along with increases in several nuclear-encoded mitochondrial proteins. Transfection of PGC-1α siRNA decreased protein and mRNA of the coactivator by 60%, resulting in decrements of Tfam and COX-IV proteins. The mRNA expression of the PGC-1 family members PGC-1β and PRC, as well as transcription factors NRF-1/2 and ERRα, did not exhibit compensatory changes in response to PGC-1α depletion. However, phosphorylation of AMPK was enhanced in myotubes with reduced levels of PGC-1α. This suggests the presence of metabolic compensatory stress signals in cells deficient in PGC-1α. Our findings reveal that the CCA-induced increases in COX-IV protein and overall mitochondrial content, using both COX activity and organelle fluorescence, are dependent on PGC-1α. However, this was not the case for all proteins, since decreased levels of the coactivator did not attenuate the increases in Tfam and cytochrome c in response to CCA. These data indicate that PGC-1α is necessary for most of the mitochondrial adaptations that occur with CCA but that there are additional pathways that function in parallel with PGC-1α to mediate the elevated expression of specific nuclear-encoded proteins that are vital for mitochondrial function and cell viability.

Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis

“…Cell Culture and CCA-Embryonic murine skeletal muscle C2C12 myoblasts (ATCC) were differentiated into myotubes and stimulated to induce CCA as described earlier (20). CCA was performed using either one or four successive 3-h bouts (1-and 4-day protocols) of electrical stimulation (5 Hz, 7 V) with an intervening 21-h recovery period following each 3-h bout.…”

“…Mice treated with RSV demonstrate elevations in AMPK activation and PGC-1␣ expression, along with increases in mitochondria in animals fed a high fat diet (19). PGC-1␣ acts as a transcriptional coactivator for nuclear genes encoding mitochondrial proteins (20). As a result, RSV treatment appears to induce a higher aerobic capacity in mice, as shown by increased running time and oxygen consumption in muscle fibers (21).…”

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

“…Yet, whole-body PGC-1α deficiency is not an ideal model to study exercise-induced mitochondrial biogenesis in the skeletal muscle, as it is associated with numerous systemic effects, including hypermetabolism, hyperactivity and reluctance to exercise (Chinsomboon et al, 2009;Lin et al, 2004). Consequently, muscle specific PGC-1α knock-out models have been recently utilised in this line of research, but again with contradictory findings (Geng et al, 2010;Rowe et al, 2012;Uguccioni & Hood, 2011). Indeed, mitochondrial biogenesis has been shown to be impaired following exercise training or chronic electrical stimulation using a PGC-1α gene knock-out model in rodent muscles and culture myotubes, respectively (Geng et al, 2010;Uguccioni & Hood, 2011).…”

“…Consequently, muscle specific PGC-1α knock-out models have been recently utilised in this line of research, but again with contradictory findings (Geng et al, 2010;Rowe et al, 2012;Uguccioni & Hood, 2011). Indeed, mitochondrial biogenesis has been shown to be impaired following exercise training or chronic electrical stimulation using a PGC-1α gene knock-out model in rodent muscles and culture myotubes, respectively (Geng et al, 2010;Uguccioni & Hood, 2011). Conversely, a recent study showed that mitochondrial adaptations following exercise was not impaired in muscle specific PGC-1α knock-out mice (Rowe et al, 2012).…”

“…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).…”