Molecular aspects of adrenal regulation for circadian glucocorticoid synthesis by chronic voluntary exercise

Chronic voluntary running of mice is known to increase the circadian peak of plasma corticosterone without change in the level of adrenocorticotropic hormone (ACTH). In order to investigate how chronic exercise modulates the circadian HPA axis, we used two weeks of voluntary wheel running of mice and confirmed the significant increase of the circadian peak of plasma corticosterone without alteration in ACTH level. To elucidate the mechanisms of exercise modulation on corticosterone synthesis, we first examined the levels of transcripts involved in corticosterone synthesis of the adrenal gland. Among them, only steroidogenic acute regulatory protein (StAR), the rate-limiting factor that transfers substrate cholesterol into inner mitochondrial membrane, showed significantly higher expression in the exercise group. Since the splanchnic nerve input to the adrenal gland has been reported as a factor involved in the direct modulation of corticosterone synthesis, we next examined the expression levels of enzymes for the catecholamine synthesis as indices of sympatho-adrenomedullary activity. We found that the only rate-limiting enzyme, tyrosine hydroxylase (TH), was significantly higher in the adrenals of exercise group. In addition to the increment of StAR and TH mRNA in response to the chronic exercise, surprisingly, we found only these factors showed the circadian variation in its expression levels that was correlated to the circadian rhythm of corticosterone. Chronic exercise seems to alter the circadian corticosterone synthesis, at least partially via altering the levels of circadian-regulated transcripts, StAR and TH of the adrenal gland.