Glucocorticoid hormone stimulates mitochondrial biogenesis specifically in skeletal muscle

High levels of circulating glucocorticoid hormone may be important mediators for elevating resting metabolic rate upon severe injury or stress. We therefore investigated the effect of dexamethasone on mitochondrial biogenesis in rats (6 mg/kg daily) as well as in cells in culture (1 microM) over a period of 3 d. A marked stimulation of mitochondrial DNA transcription and increased levels of cytochrome c oxidase activity were found in skeletal muscle of rats and differentiated mouse C2C12 muscle cells, but not in other tissues, myoblasts, or other cell lines. The effect was inhibited by RU486. Therefore, increased occupancy of glucocorticoid receptors is necessary, but not sufficient to increase mitochondrial biogenesis and other, skeletal muscle specific factors are postulated. Expression of the mitochondrial transcription factor A was unchanged, suggesting a possible involvement of the recently described mitochondrial glucocorticoid receptor. Expression of uncoupling protein-3 was also unchanged. In conclusion, our results show that high levels of glucocorticoid hormone are sufficient to stimulate mitochondrial biogenesis; however, only in skeletal muscle. Increased mitochondrial mass in this tissue, without changes of the coupling state of the respiratory chain, might be the molecular basis for the elevated resting metabolic rate observed under high cortisol levels in humans.