Coordination of mitochondrial biogenesis by PGC-1α in human skeletal muscle: A re-evaluation

The transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1α) is proposed to coordinate skeletal muscle mitochondrial biogenesis through the integrated induction of nuclear- and mitochondrial-encoded gene transcription. This paradigm is based largely on experiments demonstrating PGC-1α's ability to co-activate various nuclear transcription factors that increase the expression of mitochondrial genes, as well as PGC-1α's direct interaction with mitochondrial transcription factor A within mitochondria to increase the transcription of mitochondrial DNA. While this paradigm is supported by evidence from cellular and transgenic animal models, as well as acute exercise studies involving animals, the up-regulation of nuclear- and mitochondrial-encoded genes in response to exercise does not appear to occur in a coordinated fashion in human skeletal muscle. This review re-evaluates our current understanding of this phenomenon by highlighting evidence from recent studies examining the exercise-induced expression of nuclear- and mitochondrial-encoded genes targeted by PGC-1α. We also highlight several possible theories that may explain the apparent inability of PGC-1α to coordinately up-regulate the expression of genes required for mitochondrial biogenesis in human skeletal muscle, and provide directions for future work exploring mitochondrial biogenic gene expression following exercise.