Exercise-induced Mitochondrial Biogenesis Begins before the Increase in Muscle PGC-1α Expression

Exercise results in rapid increases in expression of the transcription coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and in mitochondrial biogenesis in skeletal muscle. PGC-1α regulates and coordinates mitochondrial biogenesis, and overexpression of PGC-1α in muscle cells results in increases in mitochondrial content. In this context, it has been proposed that the increase in PGC-1α protein expression mediates the exercise-induced increase in mitochondrial biogenesis. However, we found that mitochondrial proteins with a short half-life increase as rapidly as, or more rapidly than, PGC-1α protein. This finding led us to hypothesize that activation, rather than increased expression, of PGC-1α mediates the initial phase of the exercise-induced increase in mitochondria. In this study, we found that most of the PGC-1α in resting skeletal muscle is in the cytosol. Exercise resulted in activation of p38 MAPK and movement of PGC-1α into the nucleus. In support of our hypothesis, binding of the transcription factor nuclear respiratory factor 1 (NRF-1) to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 promoter increased in response to exercise prior to an increase in PGC-1α protein. Furthermore, exercise-induced increases in the mRNAs of cytochrome c, δ-aminolevulinate synthase, and citrate synthase also occurred before an increase in PGC-1 protein. Thus, it appears that activation of PGC-1α may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in PGC-1α protein sustains and enhances the increase in mitochondrial biogenesis.