Resveratrol and dexamethasone have cell-specific effects on the circadian clock but not on the rhythm of mitochondrial function in the fetal heart

Proper development of the heart during the fetal period is a prerequisite for health in later life. It was shown that maternal supplementation with stilbenoid resveratrol (RES) is beneficial for cardiovascular function. Synthetic glucocorticoid dexamethasone (DEX) is commonly used in the prenatal treatment of respiratory distress syndrome. RES affects the circadian clock in various tissues but its effect on the fetal heart has not been studied. We hypothetized that RES may affect the the circadian clock via modulation of the glucocorticoid signaling and/or mitochondrial function. Therefore, we tested the effects of different concentrations of RES and synthetic glucocorticoid dexamethasone (DEX) on the circadian clock, energy metabolism and mitochondrial function in fetal cardiomyocytes (CMCs) and cardiac fibroblasts (FBs). We found that RES affects the clock in both CMCs and FBs by increasing the stability of the clock protein PER2. In CMCs, the effect was mediated via the adenylyl cyclase signaling pathway. RES modulated DEX-induced effects on the circadian clock in CMCs and FBs. We were able to detect a circadian rhythm in mitochondrial function in fetal heart cells, which was confirmed by ATP and resazurin assays as well as visualization of the mitochondrial network and reactive oxygen species (ROS). Interestingly, we found that both drugs shifted the phase of fetal heart clock, but had no effect on the phase of mitochondrial rhythmicity, indicating a possible uncoupling of circadian and mitochondrial rhythms in fetal CMCs and FBs. Overall, our data revealed fetal heart-specific effects of RES on the circadian clock through the stabilization of PER2 protein and its ability to modulate DEX-induced effects on the clock.