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Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as New York Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.

Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n = 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

Aims: Exercise capacity is reduced in heart failure (HF) patients, due mostly to skeletal muscle abnormalities including impaired energy metabolism, mitochondrial dysfunction, fibre type transition, and atrophy. Glucagon-like peptide-1 (GLP-1) has been shown to improve exercise capacity in HF patients. We investigated the effects of the administration of a dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and skeletal muscle abnormalities in an HF mouse model 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 performed in other mice. The mice were then divided into two groups according to the treatment with or without a DPP-4 inhibitor, MK-0626 [1 mg/kg body weight (BW)/day] provided in the diet. Four weeks later, the exercise capacity evaluated by treadmill test was revealed to be limited in the MI mice, and it was ameliorated in the MI + MK-0626 group without affecting the infarct size or cardiac function. The citrate synthase activity, mitochondrial oxidative phosphorylation capacity, supercomplex formation, and their quantity were reduced in the skeletal muscle from the MI mice, and these decreases were normalized in the MI + MK-0626 group, in association with the improvement of mitochondrial biogenesis. Immunohistochemical staining also revealed that a shift toward the fast-twitch fibre type in the MI mice was also reversed by MK-0626. Favourable effects of MK-0626 were significantly inhibited by treatment of GLP-1 antagonist, Exendin-(9-39) (150 pmol/kg BW/min, subcutaneous osmotic pumps) in MI + MK-0626 mice. Similarly, exercise capacity and mitochondrial function were significantly improved by treatment of GLP-1 agonist, Exendin-4 (1 nmol/kg/BW/h, subcutaneous osmotic pumps)., Conclusions: A DPP-4 inhibitor may be a novel therapeutic agent against the exercise intolerance seen in HF patients by improving the mitochondrial biogenesis in their skeletal muscle., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

New Findings: What is the central question of this study? Does angiotensin II directly induce skeletal muscle abnormalities? What is the main finding and its importance? Angiotensin II induces skeletal muscle abnormalities and reduced exercise capacity. Mitochondrial dysfunction and a decreased number of oxidative fibres are manifest early, while muscle atrophy is seen later. Thus, angiotensin II may play an important role in the skeletal muscle abnormalities observed in a wide variety of diseases. Skeletal muscle abnormalities, such as mitochondrial dysfunction, a decreased percentage of oxidative fibres and atrophy, are the main cause of reduced exercise capacity observed in ageing and various diseases, including heart failure. The renin-angiotensin system, particularly angiotensin II (Ang II), is activated in the skeletal muscle in these conditions. Here, we examined whether Ang II could directly induce these skeletal muscle abnormalities and investigated their time course. Angiotensin II (1000 ng kg(-1)  min(-1) ) or vehicle was administered to male C57BL/6J mice (10-12 weeks of age) via subcutaneously implanted osmotic minipumps for 1 or 4 weeks. Angiotensin II significantly decreased body and hindlimb skeletal muscle weights compared with vehicle at 4 weeks. In parallel, muscle cross-sectional area was also decreased in the skeletal muscle at 4 weeks. Muscle RING finger-1 and atrogin-1 were significantly increased in the skeletal muscle from mice treated with Ang II. In addition, cleaved caspase-3 and terminal deoxynucleotidyl trasferase-mediated dUTP nick-positive nuclei were significantly increased in mice treated with Ang II at 1 and 4 weeks, respectively. Mitochondrial oxidative enzymes, such as citrate synthase, complex I and complex III activities were significantly decreased in the skeletal muscle from mice treated Ang II at 1 and 4 weeks. NAD(P)H oxidase-derived superoxide production was increased. NADH staining revealed that type I fibres were decreased and type IIb fibres increased in mice treated with Ang II at 1 week. The work and running distance evaluated by a treadmill test were significantly decreased in mice treated with Ang II at 4 weeks. Thus, Ang II could directly induce the abnormalities in skeletal muscle function and structure., (© 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.)

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart, whereas antioxidant enzyme activities are preserved as normal. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target of oxidant-induced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive cardiac remodeling and failure. Therefore, mitochondrial oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of mitochondrial transcription factor A (TFAM) could ameliorate the decline in mtDNA copy number and preserve it at a normal level in failing hearts. Consistent with alterations in mtDNA, the decrease in oxidative capacities was also prevented. Therefore, the activation of TFAM expression could ameliorate the pathophysiologic processes seen in myocardial failure. Inhibition of mitochondrial oxidative stress and mtDNA damage could be novel and potentially very effective treatment strategies for heart failure.

Systemic inflammation underlies the association between obesity and nonalcoholic fatty liver disease (NAFLD). Here, we investigated functional changes in leukocytes' mitochondria in obese individuals and their associations with NAFLD. We analyzed 14 obese male Japanese university students whose body mass index was > 30 kg/m2 and 15 healthy age- and sex-matched lean university students as controls. We observed that the mitochondrial oxidative phosphorylation (OXPHOS) capacity with complex I + II-linked substrates in peripheral blood mononuclear cells (PBMCs), which was measured using a high-resolution respirometry, was significantly higher in the obese group versus the controls. The PBMCs' mitochondrial complex IV capacity was also higher in the obese subjects. All of the obese subjects had hepatic steatosis defined by a fatty liver index (FLI) score ≥ 60, and there was a positive correlation between their FLI scores and their PBMCs' mitochondrial OXPHOS capacity. The increased PBMCs' mitochondrial OXPHOS capacity was associated with insulin resistance, systemic inflammation, and higher serum levels of interleukin-6 in the entire series of subjects. Our results suggest that the mitochondrial respiratory capacity is increased in the PBMCs at the early stage of obesity, and the enhanced PBMCs' mitochondrial oxidative metabolism is associated with hepatic steatosis in obese young adults. [ABSTRACT FROM AUTHOR]

Mitochondrial function is reduced in skeletal muscles of many patients with systemic diseases and it is difficult to deliver medicinal substances to mitochondria in such tissue. In this study, we report on attempts to develop liposome-based carriers for mitochondrial delivery using mouse myoblasts (C2C12) by varying the lipid composition of the carriers. We found that a liposome that contains an optimal lipid modified with the KALA peptide (a cellular uptake and mitochondrial targeting device) was the most effective nanocarrier for achieving mitochondrial delivery in C2C12 cells. We also report on successful mitochondrial transgene expression using the carriers encapsulating a mitochondrial DNA vector as we previously reported. • We succeeded in developing a nano carrier for mitochondrial delivery using myoblasts. • We also report on successful mitochondrial transgene expression using this carrier. • A KALA peptide modification to a liposome was effective for mitochondrial delivery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense, has been shown to play an important role in the pathophysiology of cardiac remodeling and heart failure (HF). It induces subtle changes in intracellular pathways, redox signaling, at lower levels, but causes cellular dysfunction and damage at higher levels. ROS are derived from several intracellular sources, including mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. The production of ROS is increased within the mitochondria from failing hearts, whereas normal antioxidant enzyme activities are preserved. Chronic increases in ROS production in the mitochondria lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further ROS generation, and cellular injury. ROS directly impair contractile function by modifying proteins central to excitation-contraction coupling. Moreover, ROS activate a broad variety of hypertrophy signaling kinases and transcription factors and mediate apoptosis. They also stimulate cardiac fibroblast proliferation and activate the matrix metalloproteinases, leading to the extracellular matrix remodeling. These cellular events are involved in the development and progression of maladaptive myocardial remodeling and failure. Oxidative stress is also involved in the skeletal muscle dysfunction, which may be associated with exercise intolerance and insulin resistance in HF. Therefore, oxidative stress is involved in the pathophysiology of HF in the heart as well as in the skeletal muscle. A better understanding of these mechanisms may enable the development of novel and effective therapeutic strategies against HF. [ABSTRACT FROM AUTHOR]

The article focuses on the role of renin–angiotensin system (RAS) activation in angiotensin II (Ang II) and skeletal muscle abnormalities. Topics discussed include role of various skeletal muscle abnormalities like impairment of skeletal muscle energy metabolism that declines the exercise capacity, role of Ang II in the development of skeletal muscle abnormalities, and impact of skeletal muscle abnormalities in various chronic diseases like cardiovascular disease and metabolic disease.

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]

Decreased exercise capacity, which is an independent predictor of the poor prognosis of patients with heart failure (HF), is attributed to markedly impaired skeletal muscle mitochondrial function and fatty acid oxidation. Previous studies reported that the administration of an inhibitor of sodium-glucose cotransporter 2 (SGLT2) increases ketone body production and fat utilization in type 2 diabetic mice. In this study, we investigated the effects of SGLT2 inhibitor administration on exercise endurance and skeletal muscle mitochondrial function with fatty acid oxidation in a murine model of HF after the induction of myocardial infarction (MI). Two weeks post-MI, HF mice were divided into 2 groups, i.e., with or without treatment with the SGLT2 inhibitor empagliflozin (Empa, 300 mg/kg of food). Consistent with previous studies, urinary glucose and blood beta-hydroxybutyrate levels were increased in the HF+Empa mice compared with the sham and HF mice 4 weeks after the start of Empa administration. Exercise endurance capacity was limited in the HF mice but was ameliorated in the HF+Empa mice, without any effects on cardiac function, food intake, spontaneous physical activity, skeletal muscle strength, and skeletal muscle weight. Mitochondrial oxidative phosphorylation capacity with fatty acid substrates was reduced in the skeletal muscle of HF mice, and this decrease was ameliorated in the HF+Empa mice. Our results demonstrate that SGLT2 inhibitors may be novel therapeutics against reduced exercise endurance capacity in HF, by improving mitochondrial fatty acid oxidation in skeletal muscle. [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]