[Abstract unavailable

The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and plays a role in mitochondrial biogenesis and oxidative function, in gain- and loss-of function studies. Rev-erb-α-deficiency in skeletal muscle leads to reduced mitochondrial content and oxidative function, resulting in compromised exercise capacity. This phenotype was recapitulated in isolated fibers and in muscle cells upon Rev-erbα knock-down, while Rev-erb-α over-expression increased the number of mitochondria with improved respiratory capacity. Rev-erb-α-deficiency resulted in deactivation of the Stk11–Ampk–Sirt1–Ppargc1-α signaling pathway, whereas autophagy was up-regulated, resulting in both impaired mitochondrial biogenesis and increased clearance. Muscle over-expression or pharmacological activation of Rev-erb-α increased respiration and exercise capacity. This study identifies Rev-erb-α as a pharmacological target which improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.

Wound healing is a well-tuned biological process, which is achieved via consecutive and overlapping phases including hemostasis, inflammatory-related events, cell proliferation and tissue remodeling. Several factors can impair wound healing such as oxygenation defects, aging, and stress as well as deleterious health conditions such as infection, diabetes, alcohol overuse, smoking and impaired nutritional status. Growing evidence suggests that reactive oxygen species (ROS) are crucial regulators of several phases of healing processes. ROS are centrally involved in all wound healing processes as low concentrations of ROS generation are required for the fight against invading microorganisms and cell survival signaling. Excessive production of ROS or impaired ROS detoxification causes oxidative damage, which is the main cause of non-healing chronic wounds. In this context, experimental and clinical studies have revealed that antioxidant and anti-inflammatory strategies have proven beneficial in the non-healing state. Among available antioxidant strategies, treatments using mitochondrial-targeted antioxidants are of particular interest. Specifically, mitochondrial-targeted peptides such as elamipretide have the potential to mitigate mitochondrial dysfunction and aberrant inflammatory response through activation of nucleotide-binding oligomerization domain (NOD)-like family receptors, such as the pyrin domain containing 3 (NLRP3) inflammasome, nuclear factor-kappa B (NF-κB) signaling pathway inhibition, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2).

Physiological functions of tau remain ill defined. In the present study, Marciniak et al. uncover a novel function of tau in its ability to regulate brain insulin signaling and discuss the pathophysiological implications of these findings for Alzheimer’s disease and tauopathies.

In studies of Nr1d1 mice and human macrophages with pharmacologic activation of NR1D1, we found NR1D1 to regulate the timing of NLRP3 expression and production of inflammatory cytokines by macrophages. Activation of NR1D1 reduced the severity of peritoneal inflammation and fulminant hepatitis in mice.

Use of metal carbonyl-based compounds capable of releasing carbon monoxide (CO) in biological systems have emerged as a potential adjunctive therapy for sepsis via their antioxidant, anti-inflammatory, and antiapoptotic effects. The role of CO in regulation of mitochondrial dysfunction and biogenesis associated with sepsis has not been investigated. In the present study, we employed a ruthenium-based water-soluble CO carrier, tricarbonylchoro(glycinato)ruthenium (II) (CORM-3), one of the novel CO-releasing molecules (CO-RMs), to test whether CO can improve cardiac mitochondrial dysfunction and survival in peritonitis-induced sepsis. Peritonitis was performed in mice by cecal ligation and perforation. Tumor necrosis factor-␣, interleukin-10, and nitrite/nitrate plasma levels were tested to evaluate the systemic inflammatory response. Functional mitochondrial studies included determination of membrane potential, respiration, and redox status. Oxidative stress was evaluated by measurements of mitochondrial hydrogen peroxide, carbonyl protein and GSH levels. Mitochondrial biogenesis was assessed by peroxisome proliferator-activated receptor ␥ coactivator (PGC)-1␣ protein expression and mitochondrial DNA (mtDNA) copy number. The systemic inflammatory response elicited by peritonitis was accompanied by mitochondrial energetic metabolism deterioration and reduced PGC-1␣ protein expression. CORM-3 treatment in septic mice restored the deleterious effects of sepsis on mitochondrial membrane potential, respiratory control ratio, and energetics. It is interesting that administration of CORM-3 during sepsis elicited a mild oxidative stress response that stimulated mitochondrial biogenesis with PGC-1␣ protein expression and mtDNA copy number increases. Our results reveal that delivery of controlled amounts of CO dramatically reduced mortality in septic mice, indicating that CO-RMs could be used therapeutically to prevent organ dysfunction and death in sepsis.

Nitroxyl (HNO) exerts inotropic and lusitropic effects in myocardium, in part via activation of SERCA (sarcoplasmic reticulum calcium ATPase). To elucidate the molecular mechanism, adult rat ventricular myocytes were exposed to HNO derived from Angeli's salt. HNO increased the maximal rate of thapsigargin-sensitive Ca 2؉ uptake mediated by SERCA in sarcoplasmic vesicles and caused reversible oxidative modification of SERCA thiols. HNO increased the S-glutathiolation of SERCA, and adenoviral overexpression of glutaredoxin-1 prevented both the HNO-stimulated oxidative modification of SERCA and its activation, as did overexpression of a mutated SERCA in which cysteine 674 was replaced with serine. Thus, HNO increases the maximal activation of SERCA via S-glutathiolation at cysteine 674. N itroxyl (HNO), the 1-electron reduced and protonated form of nitric oxide (NO), exerts a bioactivity profile that differs markedly from NO 1,2 and other reactive nitrogen species such as peroxynitrite. 3 In the cardiovascular system, HNO derived from Angeli's salt (AS) exerts inotropic and lusitropic effects in the myocardium 4 and causes relaxation of vascular smooth muscle. 5,6 These observations have raised the possibility that HNO is involved in cardiovascular regulation and/or may have therapeutic potential.In cardiac myocytes, HNO increases calcium cycling in association with increasing the activities of SERCA (sarcoplasmic reticulum ATPase) and the calcium release channel (CRC). 1 In vascular smooth muscle cells SERCA activity can be increased by NO-induced S-glutathiolation. 7 Accordingly, we hypothesized that in cardiac myocytes HNO can activate SERCA via S-glutathiolation. Materials and MethodsIn all experiments, adult rat ventricular myocytes (ARVMs) 8 were exposed for 15 minutes to 500 mol/L AS dissolved in 10 mmol/L NaOH. Detailed methods are provided in the online supplement at http://circres.ahajournals.org. Results and Discussion HNO Activation of SERCA Involves Reversible, Oxidative Thiol ModificationAS increased myocyte shortening (Ϸ2-fold) and accelerated relaxation ( Figure I in the online data supplement), confirming the findings of Tocchetti et al. 1 In the absence of dithiothreitol (DTT), AS (500 mol/L; 15 minutes) increased maximal SERCA activity Ϸ3-fold ( Figure 1A). In the pres-

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