title: 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.
authors.affiliation: York University, Toronto, ON, Canada.
authors.forename: Giulia
authors.initials: G
authors.lastname: Uguccioni
authors.forename: David A
authors.initials: DA
authors.lastname: Hood
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D015153:Blotting, Western; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000235:genetics; D004558:Electric Stimulation; D003576:Electron Transport Complex IV / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D055785:Gene Knockdown Techniques; D051379:Mice; D008856:Microscopy, Fluorescence; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000502:physiology*; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D014162:Transfection
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D048049:Extracellular Signal-Regulated MAP Kinases