Circadian modulation of the cardiac proteome underpins differential adaptation to morning and evening exercise training: an LC-MS/MS analysis.

All living beings on earth are influenced by the circadian rhythm, the rising and the setting of the sun. The ubiquitous effect of exercise is widely believed to maximize health benefits but has not been formally investigated for cardiac responses in the exercise-induced circadian rhythms. We hypothesized that the exercise-related proteome is differentially influenced by circadian rhythm and analyzed the differences between the effects of morning and evening exercise. Twenty-four Sprague-Dawley rats were randomly divided into four groups (n = 6 per group): morning control, morning exercise, evening control, and evening exercise groups. The exercise groups were subjected to 12-week treadmill exercise (5 days/week) performed either during daytime or nighttime. After 12 weeks, the physiological characteristics (e.g., body weight, heart weight, visceral fat, and blood metabolites), cardiovascular capacity (ejection fraction (%) and fractional shortening (%)), circadian gene expression levels (clock, ball1, per1, per2, cry1, and cry2), and the proteomic data were obtained and subjected to univariate and multivariate analysis. The mRNA levels of per1 and cry2 increased in the evening group compared with those in the morning group. We also found that per2 decreased and cry2 increased in the evening exercise groups. The evening exercise groups showed more decreased triacylglycerides and increased blood insulin levels than the morning exercise group. The principal component analysis, partial least squares discriminant analysis, and orthogonal partial least squares discriminant analysis indicated that the circadian rhythm differently influenced the protein networks of the exercise groups. In the morning exercise group, the transcription-translation feedback loop (TTFL) (clock, per1, per2, cry1, and cry2) formed a protein-protein interaction network with Nme2, Hint1, Ddt, Ndufb8, Ldha, and Eef1a2. In contrast, the TTFL group appeared close to Maoa, Hist2h4, and Macrod1 in the evening exercise group. Interestingly, the evening exercise group decreased the mRNA level of per2 but not per1. Per1 and Per2 are known to transport Cry1 and Cry2 into the nucleus. Taken together, we summarized the characteristics of enriched proteins in the aspect of their molecular function, cellular component, and biological process. Our results might provide a better understanding of the circadian effect on exercise-related proteins.

Glucocorticoids and their receptors: insights into specific roles in mitochondria.

Glucocorticoids (GCs) affect most physiological systems and are the most frequently used drugs for multiple disorders and organ transplantation. GC functions depend on a balance between circulating GC and cytoplasmic glucocorticoid receptor II (GR). Mitochondria individually enclose circular, double-stranded DNA that is expressed and replicated in response to nuclear-encoded factors imported from the cytoplasm. Fine-tuning and response to cellular demands should be coordinately regulated by the nucleus and mitochondria; thus mitochondrial-nuclear interaction is vital to optimal mitochondrial function. Elucidation of the direct and indirect effects of steroids, including GCs, on mitochondria is an important and emerging field of research. Mitochondria may also be under GC control because GRs are present in mitochondria, and glucocorticoid response elements (GREs) reside in the mitochondrial genome. Therefore, mitochondrial gene expression can be regulated by GCs via at least two different mechanisms: direct action on mitochondrial DNA and oxidative phosphorylation (OXPHOS) genes, or by an indirect effect through interaction with nuclear genes. In this review, we outline possible mechanisms of regulation of mitochondrial genes in response to GCs in view of translocation of the GR into mitochondria and the possible regulation of OXPHOS genes by GREs in the mitochondrial genome.

Exercise perspective on common cardiac medications.

Medicinal tablets have been used for a long time to treat cardiovascular disease. However, mortality rate is steadily increasing partly because of the patients' sedentary lifestyle and unhealthy diet. By contrast, exercise has been systematically shown to have multiple benefits. Regular exercise training can prevent various diseases in healthy individuals. Combined exercise and cardiac medications may lead to the improvement of heart disease. Numerous exercise training pathways still need further investigations. How exercise can prevent, treat, or attenuate diseases remains somewhat elusive. Thus, this review will discuss cardiac medications in parallel with the mechanism of action of exercise.

Non-genomic effect of glucocorticoids on cardiovascular system.

Glucocorticoids (GCs) are essential steroid hormones for homeostasis, development, metabolism, and cognition and possess anti-inflammatory and immunosuppressive actions. Since glucocorticoid receptor II (GR) is nearly ubiquitous, chronic activation or depletion of GCs leads to dysfunction of diverse organs, including the heart and blood vessels, resulting predominantly from changes in gene expression. Most studies, therefore, have focused on the genomic effects of GC to understand its related pathophysiological manifestations. The nongenomic effects of GCs clearly differ from well-known genomic effects, with the former responding within several minutes without the need for protein synthesis. There is increasing evidence that the nongenomic actions of GCs influence various physiological functions. To develop a GC-mediated therapeutic target for the treatment of cardiovascular disease, understanding the genomic and nongenomic effects of GC on the cardiovascular system is needed. This article reviews our current understanding of the underlying mechanisms of GCs on cardiovascular diseases and stress, as well as how nongenomic GC signaling contributes to these conditions. We suggest that manipulation of GC action based on both GC and GR metabolism, mitochondrial impact, and the action of serum- and glucocorticoid-dependent kinase 1 may provide new information with which to treat cardiovascular diseases.