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Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Exercise capacity and quality of life are markedly impaired in chronic kidney disease (CKD). Increased plasma uremic toxins such as indoxyl sulfate (IS), which induce oxidative stress, may be involved in this process. An oral adsorbent, AST-120, can reduce circulating IS, however, its effects on skeletal muscle and exercise capacity have not been investigated in CKD., Methods: Subtotal-nephrectomy or sham operation was performed in 8-week-old C57BL/6J mice. They were divided into two groups with or without 8% (w/w) of AST-120 in standard diet for 20 weeks. Sham, Sham + AST-120, CKD and CKD + AST-120 (n = 12, each group) were studied. We also conducted a C2C12 cell culture study to determine the direct effects of IS on oxidative stress., Results: Plasma IS levels were significantly increased in CKD compared with Sham (1.05 ± 0.11 versus 0.21 ± 0.03 mg/dL, P <0.05), which was significantly ameliorated in CKD + AST-120 (0.41 ± 0.06 mg/dL). The running distance to exhaustion determined by treadmill tests was significantly reduced in CKD compared with Sham (267 ± 17 versus 427 ± 36 m, P <0.05), and this reduction was also significantly ameliorated in CKD + AST-120 (407 ± 38 m) without altering skeletal muscle weight. Citrate synthase activity and mitochondrial biogenesis gene were downregulated, and superoxide production was significantly increased in the skeletal muscle from CKD, and these changes were normalized in CKD + AST-120. Incubation of C2C12 cells with IS significantly increased NAD(P)H oxidase activity., Conclusions: The administration of AST-120 improved exercise capacity and mitochondrial biogenesis of skeletal muscle via reducing oxidative stress. AST-120 may be a novel therapeutic agent against exercise intolerance in CKD., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Mitochondria are essential organelles with various functions, and change its network dynamically. The inner mitochondrial membrane (IMM) contains the cristae membrane (CM), which extends into mitochondrial matrix space. A loss of mitofilin, one of the main component of mitochondrial contact site and cristae organizing system (MICOS) complex in the IMM, has known to be unable to preserve CM structure, accompanied with lower membrane potential. And a disruption of mitoNEET, novel protein located in the outer mitochondrial membrane, has been shown to decrease mitochondrial membrane potential, however, the role of mitoNEET in structure of the CM has not been elucidated. Methods and Results: mitoNEET flox/flox mice were generated with lox-P and homologous recombination strategies. Cardiac-specific deletion of mitoNEET (mitoNEET-knockout) was achieved using αMHC-Cre. Transmission electron microscopy showed the mitochondria isolated from mitoNEET-knockout mice reduced number of cristae, loss of the cristae junctions, and accumulation of cristae stack. These mitochondria also exhibited a swollen morphology. ROS production from the mitochondria were higher in mitoNEET-knockout mice. Mitochondrial state 3 respirations were comparable between the groups, however, mitochondrial maximal capacity and reserve capacity in mitoNEET-knockout mice. Mitochondrial membrane potential measured by using cultured cells transfected with CISD1 , encoding mitoNEET, siRNA was decreased in this condition compared to scramble. Mass spectrometry analysis revealed that endogenous mitoNEET coprecipitated with endogenous mitofilin, which is known to be localized in the IMM and involved in CM structure. Echocardiography showed cardiac dysfunction in mitoNEET-knockout mice. Conclusions: The protein-protein interaction between mitoNEET and mitofilin may regulate CM structure through the maintenance of MICOS complex including mitofilin. The lack of this interaction could induce mitochondrial dysfunction, suggesting that mitoNEET play an important role in the regulation of mitochondrial function via mitochondrial morphology. [ABSTRACT FROM AUTHOR]

We have reported that exercise capacity is reduced in high fat diet (HFD)-induced diabetic mice, and that this reduction is associated with impaired mitochondrial function in skeletal muscle (SKM). However, it remains to be clarified whether the treatment of diabetes ameliorates the reduced exercise capacity. Therefore, we examined whether an insulin-sensitizing drug, pioglitazone, could improve exercise capacity in HFD mice. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated with or without pioglitazone (3 mg/kg/day) to yield the following 4 groups: ND+vehicle, ND+pioglitazone, HFD+vehicle, and HFD+pioglitazone ( n =10 each). After 8 weeks, body weight, plasma glucose, and insulin in the HFD+vehicle were significantly increased compared to the ND+vehicle group. Pioglitazone normalized the insulin levels in HFD-fed mice, but did not affect the body weight or plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in the HFD+vehicle, and this reduction was almost completely ameliorated in HFD+pioglitazone mice. ADP-dependent mitochondrial respiration, complex I and III activities, and citrate synthase activity were significantly decreased in the SKM of the HFD+vehicle animals, and these decreases were also attenuated by pioglitazone. NAD(P)H oxidase activity was significantly increased in the HFD+vehicle compared with the ND+vehicle, and this increase was ameliorated in HFD+pioglitazone mice. Pioglitazone improved the exercise capacity in diabetic mice, which was due to the improvement in mitochondrial function and attenuation of oxidative stress in the SKM. Our data suggest that pioglitazone may be useful as an agent for the treatment of diabetes mellitus. [ABSTRACT FROM AUTHOR]

Introduction: Reduced exercise capacity is an independent predictor of poor prognosis in heart failure (HF) patients and is closely associated with skeletal muscle abnormalities including impaired mitochondrial dysfunction. We showed that mitochondrial function is impaired in skeletal muscle from HF mice at the chronic phase. This abnormality is known to be caused by increased reactive oxygen species (ROS) in HF. The pathogenic mechanism of mitochondrial dysfunction in association with increased ROS in skeletal muscle from HF is unclear. Xanthine oxidase (XO) was reported to be an important mediator of ROS overproduction in ischemic tissue because XO activates by hypoxia. Here we examined the role of XO-derived ROS in the regulation of mitochondrial function in skeletal muscle from mice with HF after myocardial infarction (MI). Methods and Results: MI was created in male C57BL/6J mice by ligating the left coronary artery, and a sham operation was also performed in survivors (n=8/group). Cardiac function measured by echocardiography was significantly decreased in the MI mice compared to the sham mice. We first examined whether XO-derived ROS evaluated by hydrogen peroxide production in skeletal muscle was increased in HF mice post-MI. The production of XO-derived ROS was significantly increased in the MI mice from 1 to 7 days post-surgery, whereas it did not differ between both groups at 14 and 28 days. Next, we divided mice into three groups in survivors (n=8/group): sham+vehicle, MI+vehicle, and MI+Feb (febuxostat, an XO inhibitor, 5 mg/kg body weight/day). Feb or vehicle was administered by oral gavage at 1 and 24 h before and once-daily on days 1 to 7 post-MI or sham surgery. At day 28 post-surgery, exercise capacity as evaluated by treadmill testing and the mitochondrial respiration in skeletal muscle fibers shown by high-resolution respirometry were significantly decreased in the MI mice compared to the sham mice, and these were preserved in the MI+Feb mice in association with decreased XO-derived ROS. The chronic (28-day) administration of Feb did not preserve these favorable outcomes. Conclusion: XO inhibition during increased XO-derived ROS in the acute phase can preserve mitochondrial function in skeletal muscle and exercise capacity in HF mice. [ABSTRACT FROM AUTHOR]

Introduction: Mitochondrial dysfunction and oxidative stress play a crucial role in the development of heart failure. However, the role of reactive oxygen species (ROS) originating from peripheral blood mononuclear cell (PBMC) mitochondria in chronic heart failure (HF) is unknown. Hypothesis: Mitochondrial ROS emission from PBMCs is increased in symptomatic HF patients, which is linked to systemic oxidative stress, HF severity, and exercise intolerance. Methods: We enrolled 36 patients with chronic HF (62 ± 13 years, New York Heart Association [NYHA] functional class I-III) and the patients were divided into two groups; NYHA I-II group (n=17) and NYHA III group (n=19). To assess exercise capacity, we performed cardiopulmonary exercise testing with bicycle ergometer. We measured mitochondrial respiratory capacity and mitochondrial ROS emission in permeabilized PBMCs with the use of high-resolution respirometry and spectrofluorometry. We also measured urine 8-OHdG as a marker of systemic oxidative stress. Results: Plasma levels of B-type natriuretic peptide (BNP), a biomarker for severity of HF, were significantly higher in NYHA III group than in NYHA I-II group (286.0±251.0 vs. 93.4±101.2 pg/mL, P <0.01). HF patients with NYHA III had a lowered peak oxygen uptake (VO2) compared to HF patients with NYHA I-II (14.4±4.1 vs. 19.7±4.5 mL/kg/min, P <0.01). Mitochondrial oxidative phosphorylation capacities with complex I, complex II, or complex I+II-linked substrates in PBMCs were comparable between groups, however, maximal capacity of mitochondrial electron transfer system with complex II-linked substrates in PBMCs was significantly reduced in NYHA III group in association with the lowered peak VO2. Notably, HF patients with NYHA III had a significantly higher mitochondrial ROS emission from PBMCs, and this was closely correlated with the elevated urine 8-OHdG levels, the increased plasma levels of BNP, and the lowered peak VO2, respectively. Conclusions: Increased mitochondrial ROS emission in circulating PBMCs is associated with systemic oxidative stress, HF severity, and exercise intolerance in patients with chronic HF. [ABSTRACT FROM AUTHOR]