Significance: Skeletal muscle is a highly plastic tissue. Exercise evokes signaling pathways that strongly modify myofiber metabolism and physiological and contractile properties of skeletal muscle. Regular physical activity is beneficial for health and is highly recommended for the prevention of several chronic conditions. In this review, we have focused our attention on the pathways that are known to mediate physical training-induced plasticity. Recent Advances: An important role for redox signaling has recently been proposed in exercisemediated muscle remodeling and peroxisome proliferator-activated receptor c (PPARc) coactivator-1a (PGC1a) activation. Still more currently, autophagy has also been found to be involved in metabolic adaptation to exercise. Critical Issues: Both redox signaling and autophagy are processes with ambivalent effects; they can be detrimental and beneficial, depending on their delicate balance. As such, understanding their role in the chain of events induced by exercise and leading to skeletal muscle remodeling is a very complicated matter. Moreover, the study of the signaling induced by exercise is made even more difficult by the fact that exercise can be performed with several different modalities, with this having different repercussions on adaptation. Future Directions: Unraveling the complexity of the molecular signaling triggered by exercise on skeletal muscle is crucial in order to define the therapeutic potentiality of physical training and to identify new pharmacological compounds that are able to reproduce some beneficial effects of exercise. In evaluating the effect of new ''exercise mimetics,'' it will also be necessary to take into account the involvement of reactive oxygen species, reactive nitrogen species, and autophagy and their controversial effects. Antioxid. Redox Signal. 21, 154-176.

T ype 2 diabetes mellitus (T2DM) is associated with increased risk of micro and macrovascular complications and ≈2-fold greater risk of mortality when compared with the general population.1,2 Advances in therapy have reduced morbidity and mortality in patients with T2DM. However, cardiovascular risk is far to be eradicated, and mechanism-based therapeutic approaches are needed. 3,4 In patients with diabetes mellitus, high-glucose levels trigger endothelial inflammation, mitochondrial oxidative stress, and reduced availability of nitric oxide, a key effector of vascular health. 3,5 This chain of events favors the development of coronary atherosclerotic lesions, as well as microvascular disease. 4 Although the link between diabetes mellitus and atherosclerosis is well established, a better comprehension of the underlying mechanisms is of utmost importance to identify novel molecular targets. Epigenetic modifications are emerging as key players in cardiovascular disease.6 Acetylation and methylation occurring at DNA/histone complexes significantly alter gene transcription Background-Cellular studies showed that histone methyltransferase Set7 mediates high glucose-induced inflammation via epigenetic regulation of the transcription factor NF-kB. However, the link between Set7 and vascular dysfunction in patients with diabetes mellitus remains unknown. This study was designed to investigate whether Set7 contributes to vascular dysfunction in patients with type 2 diabetes mellitus (T2DM). Methods and Results-Set7-driven epigenetic changes on NF-kB p65 promoter and expression of NF-kB-dependent genes, cyclooxygenase 2 and inducible endothelial nitric oxide synthase, were assessed in peripheral blood mononuclear cells isolated from 68 subjects (44 patients with T2DM and 24 age-matched controls). Brachial artery flow-mediated dilation, 24-hour urinary levels of 8-isoprostaglandin F 2α , and plasma adhesion molecules, intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1, were also determined. Experiments in human aortic endothelial cells exposed to high glucose were performed to elucidate the mechanisms of Set7-driven inflammation and oxidative stress. Set7 expression increased in peripheral blood mononuclear cells from patients with T2DM when compared with controls.Patients with T2DM showed Set7-dependent monomethylation of lysine 4 of histone 3 on NF-kB p65 promoter. This epigenetic signature was associated with upregulation of NF-kB, subsequent transcription of oxidant/inflammatory genes, and increased plasma levels of intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Interestingly, we found that Set7 expression significantly correlated with oxidative marker 8-isoprostaglandin F 2α (r=0.38; P=0.01) and flow-mediated dilation (r=−0.34; P=0.04). In human aortic endothelial cells, silencing of Set7 prevented monomethylation of lysine 4 of histone 3 and abolished NF-kB-dependent oxidant and inflammatory signaling. Conclusions-Set7-induced epigenetic changes contribute to...

Intensive glycemic control (IGC) targeting HbA fails to show an unequivocal reduction of macrovascular complications in type 2 diabetes (T2D); however, the underlying mechanisms remain elusive. Epigenetic changes are emerging as important mediators of cardiovascular damage and may play a role in this setting. This study investigated whether epigenetic regulation of the adaptor protein p66, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA >7.5%) and 24 age- and sex-matched healthy control subjects were consecutively enrolled. IGC was implemented for 6 months in patients with T2D to achieve a target HbA of ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F (8-isoPGF), and epigenetic regulation of p66 were assessed at baseline and follow-up. Continuous glucose monitoring was performed to determine the mean amplitude of glycemic excursion (MAGE) and postprandial incremental area under the curve (AUCpp). At baseline, patients with T2D showed impaired FMD, increased urinary 8-isoPGF, and p66 upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF, and p66 expression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66 promoter of patients with T2D, and IGC did not change such adverse epigenetic remodeling. Persistent downregulation of methyltransferase DNMT3b and deacetylase SIRT1 may explain the observed p66-related epigenetic changes. MAGE and AUCpp but not HbA were independently associated with the altered epigenetic profile on the p66 promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbA levels.

Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kB-induced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes.