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

Uguccioni G, Hood DA. The importance of PGC-1 alpha in contractile activity-induced mitochondrial adaptations. Am J Physiol Endocrinol Metab 300: E361-E371, 2011. First published November 16, 2010; doi: 10.1152/ajpendo.00292.2010.-The transcriptional coactivator PPAR gamma coactivator-1 alpha (PGC-1 alpha) is a critical regulator of mitochondrial content and function in skeletal muscle. PGC-1 alpha may also mediate mitochondrial adaptations in response to chronic contractile activity (CCA). To characterize the essential role of PGC-1 alpha in organelle biogenesis, C2C12 murine myotubes were transfected with PGC-1 alpha-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-1 alpha 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-1 beta and PRC, as well as transcription factors NRF-1/2 and ERR alpha, did not exhibit compensatory changes in response to PGC-1 alpha depletion. However, phosphorylation of AMPK was enhanced in myotubes with reduced levels of PGC-1 alpha. This suggests the presence of metabolic compensatory stress signals in cells deficient in PGC-1 alpha. 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-1 alpha. 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-1 alpha is necessary for most of the mitochondrial adaptations that occur with CCA but that there are additional pathways that function in parallel with PGC-1 alpha to mediate the elevated expression of specific nuclear-encoded proteins that are vital for mitochondrial function and cell viability.