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A study published in Acta Physiologica examined the effects of postmenopausal hormone replacement therapy (HRT) on skeletal muscle mitochondrial function. The researchers found that postmenopausal women who received a combination of estradiol and progestin had higher mitochondrial respiratory capacity in their skeletal muscles compared to non-treated postmenopausal women. Menopause is associated with skeletal muscle dysfunction, and HRT may help prevent this impairment. While previous studies have shown the effects of estrogen on skeletal muscle mitochondria in animal models, this study is the first to demonstrate the association in humans. Further research is needed to fully understand the effects of HRT on skeletal muscle mitochondrial function. [Extracted from the article]

Oxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients. [ABSTRACT FROM AUTHOR]

Epicardial adipose tissue (EAT) is an active endocrine organ that is closely associated with occurrence of atrial fibrillation (AF). However, the role of EAT in the development of postoperative AF (POAF) remains unclear. We aimed to investigate the association between EAT profile and POAF occurrence in patients who underwent cardiovascular surgery. We obtained EAT samples from 53 patients to evaluate gene expression, histological changes, mitochondrial oxidative phosphorylation (OXPHOS) capacity in the EAT, and protein secretion in EAT‐conditioned medium. EAT volume was measured using computed tomography scan. Eighteen patients (34%) experienced POAF within 7 days after surgery. Although no significant difference was observed in EAT profile between patients with and without POAF, logistic regression analysis identified that the mRNA expression levels of tumor necrosis factor‐alpha (TNF‐α) were positively correlated and adipocyte size in the EAT was inversely correlated with onset of POAF, respectively. Mitochondrial OXPHOS capacity in the EAT was not associated with POAF occurrence; however, it showed an inverse correlation with adipocyte size and a positive correlation with adiponectin secretion. In conclusion, changes in the secretory profile and adipocyte morphology of the EAT, which represent qualitative aspects of the adipose tissue, were present before the onset of AF. [ABSTRACT FROM AUTHOR]

Aims/Introduction Low aerobic capacity is a strong and independent predictor of all-cause mortality in patients with metabolic syndrome (MetS). Here, we investigated the effects of pioglitazone treatment on whole-body aerobic capacity and skeletal muscle energy metabolism in MetS patients. Materials and Methods A total of 14 male patients with MetS received oral pioglitazone 15 mg/day for 4 months. To assess whole-body aerobic capacity, exercise testing with a bicycle ergometer was carried out before and after pioglitazone treatment. To assess skeletal muscle energy metabolism, intramyocellular lipid in the resting leg and high-energy phosphates in the calf muscle during plantar-flexion exercise were measured using 1proton- and 31phosphorus magnetic resonance spectroscopy, respectively. Results Pioglitazone significantly increased peak oxygen uptake (25.1 ± 4.9 mL/kg/min pretreatment vs 27.2 ± 3.9 mL/kg/min post- treatment, P < 0.05) and anaerobic threshold (12.7 ± 1.9 mL/kg/min pretreatment vs 13.6 ± 1.6 mL/kg/min post-treatment, P < 0.05), although daily physical activity was comparable before and after the treatment. Intramyocellular lipid content was significantly reduced after pioglitazone treatment by 26%, indicating improved skeletal muscle fatty acid metabolism. Pioglitazone also significantly decreased the muscle phosphocreatine loss during exercise by 13%, indicating improved skeletal muscle high-energy phosphate metabolism. Notably, the increase in anaerobic threshold; that is, submaximal aerobic capacity, closely correlated with the decrease in intramyocellular lipid content after pioglitazone treatment. Conclusions Pioglitazone significantly improved the MetS patients' whole-body aerobic capacity and skeletal muscle energy metabolism. The beneficial effect of pioglitazone on whole-body aerobic capacity might be at least in part through improved fatty acid metabolism in the skeletal muscle. [ABSTRACT FROM AUTHOR]

Key points Pre-ischaemic administration of aminooxiacetate (AOA), an inhibitor of the malate-aspartate shuttle (MAS), provides cardioprotection against ischaemia-reperfusion injury. The underlying mechanism remains unknown., We examined whether transient inhibition of the MAS during ischaemia and early reperfusion by AOA treatment could prevent mitochondrial damage at later reperfusion., The AOA treatment preserved mitochondrial respiratory capacity with reduced mitochondrial oxidative stress during late reperfusion to the same extent as ischaemic preconditioning (IPC)., However, AOA treatment, but not IPC, reduced the myocardial interstitial concentration of tricarboxylic acid cycle intermediates at the onset of reperfusion., The results obtained in the present study demonstrate that metabolic regulation by inhibition of the MAS at the onset of reperfusion may be beneficial for the preservation of mitochondrial function during late reperfusion in an IR-injured heart., Abstract Mitochondrial dysfunction plays a central role in ischaemia-reperfusion (IR) injury. Pre-ischaemic administration of aminooxyacetate (AOA), an inhibitor of the malate-aspartate shuttle (MAS), provides cardioprotection against IR injury, although the underlying mechanism remains unknown. We hypothesized that a transient inhibition of the MAS during ischaemia and early reperfusion could preserve mitochondrial function at later phase of reperfusion in the IR-injured heart to the same extent as ischaemic preconditioning (IPC), which is a well-validated cardioprotective strategy against IR injury. In the present study, we show that pre-ischaemic administration of AOA preserved mitochondrial complex I-linked state 3 respiration and fatty acid oxidation during late reperfusion in IR-injured isolated rat hearts. AOA treatment also attenuated the excessive emission of mitochondrial reactive oxygen species during state 3 with complex I-linked substrates during late reperfusion, which was consistent with reduced oxidative damage in the IR-injured heart. As a result, AOA treatment reduced infarct size after reperfusion. These protective effects of MAS inhibition on the mitochondria were similar to those of IPC. Intriguingly, the protection of mitochondrial function by AOA treatment appears to be different from that of IPC because AOA treatment, but not IPC, downregulated myocardial tricarboxilic acid (TCA)-cycle intermediates at the onset of reperfusion. MAS inhibition thus preserved mitochondrial respiratory capacity and decreased mitochondrial oxidative stress during late reperfusion in the IR-injured heart, at least in part, via metabolic regulation of TCA cycle intermediates in the mitochondria at the onset of reperfusion. [ABSTRACT FROM AUTHOR]

Fucoidan, a sulfated polysaccharide extracted from brown seaweeds, possesses many biological activities including anti-inflammatory and antioxidant activities. We aimed to investigate the protective effects of fucoidan on dyslipidemia and atherosclerosis in apolipoprotein E-deficient mice (ApoE(shl) mice) and to elucidate its molecular targets in the liver by using a transcriptomic approach. For 12weeks, ApoE(shl) mice were fed a high-fat diet (HFD) supplemented with either 1% or 5% fucoidan. Fucoidan supplementation significantly reduced tissue weight (liver and white adipose tissue), blood lipid, total cholesterol (TC), triglyceride (TG), non-high-density lipoprotein cholesterol (non-HDL-C) and glucose levels in HFD-fed ApoE(shl) mice but increased plasma lipoprotein lipase (LPL) activity and HDL-C levels. Fucoidan also reduced hepatic steatosis levels (liver size, TC and TG levels, and lipid peroxidation) and increased white adipose tissue LPL activity. DNA microarray analysis and quantitative reverse transcription-polymerase chain reaction demonstrated differential expression of genes encoding proteins involved in lipid metabolism, energy homeostasis and insulin sensitivity, by activating Ppara and inactivating Srebf1. Fucoidan supplementation markedly reduced the thickness of the lipid-rich plaque, lipid peroxidation and foaming macrophage accumulation in the aorta in HFD-fed ApoE(shl) mice. Thus, fucoidan supplementation appears to have anti-dyslipidemic and anti-atherosclerotic effects by inducing LPL activity and inhibiting the effects of inflammation and oxidative stress in HFD-fed ApoE(shl) mice. [ABSTRACT FROM AUTHOR]

The effects of starvation at the first feeding stage on the survival and growth of walleye pollock Gadus chalcogrammus larvae were examined in rearing experiments performed in the laboratory. Newly hatched larvae grown at 2 °C, 5 °C, and 8 °C that commenced feeding at 3, 2, and 1 days post-hatching (dph) exhibited yolk exhaustion at 8, 8, and 5 dph and reached the point-of-no-return (PNR) at 15, 14, and 10 dph, respectively. Larvae kept at 5 °C were starved for 2-16 dph and then reared to examine the effect of delayed initial feeding on growth and survival. The larvae that were fed earlier grew better and showed higher survival rates. The time thresholds after which delayed feeding would prevent the larvae from growing and surviving were 2-3 and 0-1 days, respectively, before the PNR. Walleye pollock larvae have a long mixed endogenous and exogenous feeding period and relatively high starvation tolerance, as is typically observed in cold water fishes. Delayed initial feeding affects their survival and growth, even during the mixed feeding period. The availability of prey at the first feeding stage would have a critical effect on the stock size of this species. [ABSTRACT FROM AUTHOR]

Background Oxidative and nitrative processes have an important role in the pathogenesis of glaucomatous neurodegeneration. Oxidative stress occurs when cellular production of reactive oxygen species outweighs the protective capacity of antioxidant defences. Reactive oxygen species are generated as by-products of cellular metabolism, primarily in the mitochondria. Herein, we present a novel investigation of the effects of molecular hydrogen ( H2) on retinal cells exposed to oxidative stress. Methods We cultured adult rat retinal tissues in an organotypic culture system with a nitric oxide donor, S-nitroso- N-acetylpenicillamine, in the presence or absence of H2. Loss of mitochondrial membrane potential and apoptosis of retinal cells were analysed using a MitoTMRE detection kit and TdT-mediated dUTP nick end labeling ( TUNEL) assay, respectively. Tyrosine nitration levels and oxidative stress damage in the retina were evaluated using immunohistochemical staining. Retinal damage was quantified by measuring the numbers of cells in the ganglion cell and inner nuclear layers and the thickness of the retina. Results H2 suppressed loss of mitochondrial membrane potential and apoptosis in retinal cells. Moreover, H2 decreased the tyrosine nitration level and suppressed oxidative stress damage in retinal cells. S-nitroso- N-acetylpenicillamine treatment decreased the cell numbers in the ganglion cell layer and inner nuclear layer, but the presence of H2 inhibited this reduction. These findings suggest that H2 has a neuroprotective effect against retinal cell oxidative damage, presumably by scavenging peroxynitrite. Conclusions H2 reduces cellular peroxynitrite, a highly toxic reactive nitrogen species. Thus, H2 may be an effective and novel clinical tool for treating glaucoma and other oxidative stress-related diseases. [ABSTRACT FROM AUTHOR]

Keywords: androgen receptor; BDNF; Kennedy's disease; muscles; spinal bulbar muscular atrophy EN androgen receptor BDNF Kennedy's disease muscles spinal bulbar muscular atrophy 2543 2544 2 07/03/20 20200701 NES 200701 Kennedy's disease (KD), also known as a spinal and bulbar muscular atrophy (SBMA), is a rare, X-linked neuromuscular disease characterized by slowly progressive weakness and atrophy of the bulbar and extremity muscles. The phenotype of this mouse model is similar to that of human KD, as male AR-97Q mice exhibit progressive muscle weakness and atrophy with neuropathological changes that are commonly observed in KD patients. Androgen receptor, BDNF, Kennedy's disease, muscles, spinal bulbar muscular atrophy. [Extracted from the article]

We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Although type 2 diabetes mellitus (T2DM) is one of the most frequent comorbidities in patients with chronic heart failure (CHF), the effects of T2DM on the exercise capacity of CHF patients are fully unknown. Here, we tested the hypothesis that the coexistence of T2DM lowers CHF patients' peak aerobic capacity. Methods: We retrospectively analyzed the cases of 275 Japanese CHF patients with non-reduced ejection fraction (left ventricular ejection fraction [LVEF] ≥ 40%) or reduced EF (LVEF < 40%) who underwent cardiopulmonary exercise testing. We divided them into diabetic and nondiabetic groups in each CHF cohort. Results: The mean peak oxygen uptake (VO2) value was 16.87 mL/kg/min in the non-reduced LVEF cohort and 15.52 mL/kg/min in the reduced LVEF cohort. The peak VO2 was lower in the diabetics versus the nondiabetics in the non-reduced LVEF cohort with the mean difference (95% confidence interval [95% CI]) of − 0.93 (− 1.82 to − 0.04) mL/kg/min and in the reduced LVEF cohort with the mean difference of − 1.05 (− 1.96 to − 0.15) mL/kg/min, after adjustment for age-squared, gender, anemia, renal function, LVEF, and log B-type natriuretic peptide (BNP). The adjusted VO2 at anaerobic threshold (AT), a submaximal aerobic capacity, was also decreased in the diabetic patients with both non-reduced and reduced LVEFs. Intriguingly, the diabetic patients had a lower adjusted peak O2 pulse than the nondiabetic patients in the reduced LVEF cohort, but not in the non-reduced LVEF cohort. A multivariate analysis showed that the presence of T2DM was an independent predictor of lowered peak VO2 in CHF patients with non-reduced LVEF and those with reduced LVEF. Conclusions: T2DM was associated with lowered peak VO2 in CHF patients with non-reduced or reduced LVEF. The presence of T2DM has a negative impact on CHF patients' exercise capacity, and the degree of impact is partly dependent on their LV systolic function. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Low aerobic capacity is a strong and independent predictor of all-cause mortality for both diabetic patients and chronic heart failure (CHF) patients. We tested the hypothesis that coexistence of type 2 diabetes lowers peak aerobic capacity in patients with CHF. Methods: We retrospectively studied 276 CHF patients with or without type 2 diabetes who underwent cardiopulmonary exercise testing (CPET). All CHF patients had a history of hospital admission due to worsening HF with either non-reduced left ventricular ejection fraction (LVEF; ≥40%) or reduced LVEF (<40%). Results: Peak oxygen uptake (VO2) was significantly decreased in diabetic group compared to nondiabetic group not only in total CHF population (median 13.8 [interquartile range 11.8-16.4] vs. 16.4 [13.2-20.2] mL/kg/min) but also in CHF patients with LVEF ≥40% (14.1 [12.4-16.6] vs. 17.4 [13.9-20.7] mL/kg/min) and in CHF patients with LVEF <40% (13.4 [10.3-16.3] vs. 16.0 [12.5-20.0] mL/kg/min). There was an inverse correlation between peak VO2 and glycosylated hemoglobin in total CHF population (r=-0.16, P=0.017). Multivariate analysis showed that the presence of type 2 diabetes was an independent predictor of the lowered peak VO2 in CHF patients with LVEF ≥40% and <40%, respectively, after adjustment for age, gender, anemia, renal function, LVEF, and B-type natriuretic peptide. Conclusions: Type 2 diabetes is an independent predictor of the lowered peak VO2 in CHF patients. The presence of type 2 diabetes has a negative impact on peak aerobic capacity in CHF patients with both reduced and non-reduced LVEF. Disclosure: T. Abe: None. T. Yokota: None. [ABSTRACT FROM AUTHOR]

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. [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]

Nintedanib is a unique tyrosine kinase inhibitor used to suppress fibrosis in patients with idiopathic pulmonary fibrosis (IPF). Nintedanib has been shown to suppress multiple processes of fibrosis, thereby reducing the rate of lung function decline in patients with IPF. Since vascular endothelial growth factor is one of this agent's targets, nephrotoxicity, including renal thrombotic microangiopathy (TMA), is a possible major adverse effect. However, only 2 previous cases of nintedanib-induced renal TMA have been published. Our patient was an 83-year-old man with IPF. As adverse effects including liver enzyme level elevation, diarrhoea, anorexia, and nephrotoxicity developed, the nintedanib dosage was reduced after 9 months. The digestive symptoms resolved promptly, but the proteinuria and reduced kidney function remained. Although the kidney injury had improved to some extent, we performed a percutaneous renal biopsy. The biopsy revealed typical TMA findings such as microaneurysms filled with pale material, segmental double contours of glomerular basement membranes, and intracapillary foam cells. After discontinuation of nintedanib, the patient's nephrotoxicity improved. Nintedanib-induced renal TMA is reversible and is possibly dose-dependent. Here, we report the clinical course of our case and review the characteristics of nintedanib-induced renal TMA. [ABSTRACT FROM AUTHOR]

Aim: We compared muscular metabolic stress during exercise performed at multiple intensities, from very low to moderate, with blood flow restriction (BFR) adjusted by the same work volume. Methods: Twenty‐five healthy young adults performed unilateral plantar flexion at 1 repetition/2 s in a magnetic resonance system. The BFR exercise protocols were as follows: (A) exercise with 10% of one repetition maximum (1‐RM) for 360 s, (B) 15% 1‐RM for 240 s, (C) 20% 1‐RM for 180 s, (D) 30% 1‐RM for 120 s, and (E) 40% 1‐RM for 90 s. All protocols had the same total work volume (load × repetitions = 1800). A high‐intensity protocol at 65% 1‐RM without BFR (60 s) was also performed for comparison. We used 31P‐magnetic resonance spectroscopy to evaluate the muscular metabolic stress in the subjects' calf muscle, defined as decreases in phosphocreatine and intramuscular pH. Results: The phosphocreatine depletion (A: 15.6 ± 0.7, B: 14.8 ± 0.8, C: 15.2 ± 0.6, D: 14.3 ± 0.6, E: 10.9 ± 0.5 mM; no significant difference [ns]) and the intramuscular pH decrease (A: 6.82 ± 0.02, B: 6.84 ± 0.01, C: 6.83 ± 0.02, D: 6.83 ± 0.02, E: 6.77 ± 0.02; ns) at the end of each exercise were similar and greater than those produced by the 65% 1‐RM without BFR. Conclusion: If the total work volumes are equal, the metabolic stress in exercising muscle may reach similar levels at the end of exercise with BFR and could provide similar successful training effects. [ABSTRACT FROM AUTHOR]

The effects of water temperature during the non-spawning season (yolkless to early yolk formation stage of the ovary) on the growth and reproductive characteristics of 4-year-old hatchery-reared walleye pollock Gadus chalcogrammus (repeat spawners) were examined. Fish were kept in tanks under two temperature regimes (non-controlled: 6.4–17.2 °C; cooled: 5.1–15.7 °C) from 42 to 46 months post-hatching (non-spawning period) and showed differences in growth (in terms of weight and condition factor) shortly before the spawning period (mostly at the early yolk formation stage of the ovary). The fish spawned spontaneously from 47 to 51 months post-hatching at 5 °C. Growth differences were related to egg diameter but not to the timing of spawning. Larger eggs were spawned from fish that had greater increases in weight and condition during the non-spawning season. In contrast, the main spawning period did not vary according to the non-spawning season treatment. These results were compared with the spawning records of 2- and 3-year-old walleye pollock from two previous years, showing that the timing of spawning advances as fish size increases with age. In addition, spawning experience and the amount of energy acquired before the spawning period likely influence egg size. [ABSTRACT FROM AUTHOR]

Atrial metabolic disturbance contributes to the onset and development of atrial fibrillation (AF). Autophagy plays a role in maintaining the cellular energy balance. We examined whether atrial gene expressions related to fatty acid metabolism and autophagy are altered in chronic AF and whether they are related to each other. Right atrial tissue was obtained during heart surgery from 51 patients with sinus rhythm (SR, n = 38) or chronic AF (n = 13). Preoperative fasting serum free-fatty-acid levels were significantly higher in the AF patients. The atrial gene expression of fatty acid binding protein 3 (FABP3), which is involved in the cells' fatty acid uptake and intracellular fatty acid transport, was significantly increased in AF patients compared to SR patients; in the SR patients it was positively correlated with the right atrial diameter and intra-atrial electromechanical delay (EMD), parameters of structural and electrical atrial remodeling that were evaluated by an echocardiography. In contrast, the two groups' atrial contents of diacylglycerol (DAG), a toxic fatty acid metabolite, were comparable. Importantly, the atrial gene expression of microtubule-associated protein light chain 3 (LC3) was significantly increased in AF patients, and autophagy-related genes including LC3 were positively correlated with the atrial expression of FABP3. In conclusion, in chronic AF patients, the atrial expression of FABP3 was upregulated in association with autophagy-related genes without altered atrial DAG content. Our findings may support the hypothesis that dysregulated cardiac fatty acid metabolism contributes to the progression of AF and induction of autophagy has a cardioprotective effect against cardiac lipotoxicity in chronic AF. [ABSTRACT FROM AUTHOR]

Reproductive characteristics under different water temperature regimes were examined in hatchery-reared walleye pollock Gadus chalcogrammus. The fish had been cultured for 33 months post-hatching before the experiment, and the first spawning was observed from 24 to 27 months post-hatching. From 33 months post-hatching, fish were cultured at three temperature regimes (2, 5, and 8 °C), and spawning was observed from 36 to 39 months post-hatching. The peak of the spawning period was earliest at 8 °C and latest at 2 °C, and a 3 °C difference resulted in the 2–5 weeks difference in the peak spawning period. Thus, high temperature would have accelerated gonadal maturation. In contrast, the effect of temperature on the egg quality was unclear. Egg diameter was largest at 5 °C, followed by 2 °C and 8 °C, but the starvation tolerance of larvae was not significantly explained by spawning temperature. These results elucidate the mechanisms that underlie variability of the spawning period and the larval survival of wild walleye pollock. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults." The original article contained errors in Figure 1 and its accompanying legend, specifically regarding complex II and its surroundings. The corrected version of the article is available online. The article discusses the evaluation of mitochondrial respiratory capacity in obese and healthy control subjects using a specific protocol. The correction notice provides a summarized explanation of the respiratory states and substrates used in the study. [Extracted from the article]

Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg−1 min−1) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Oxidative stress is involved in the progression of diabetes and its associated complications. However, it is unclear whether increased oxidative stress plays a primary role in the onset of diabetes or is a secondary indicator caused by tissue damage. Previous methods of analyzing oxidative stress have involved measuring the changes in oxidative stress biomarkers. Our aim is to identify a novel approach to clarify whether oxidative stress plays a primary role in the onset of diabetes. We constructed transgenic type 2 diabetes mouse models expressing redox-sensitive green fluorescent proteins (roGFPs) that distinguished between mitochondria and whole cells. Pancreas, liver, skeletal muscle, and kidney redox states were measured in vivo. Hepatic mitochondrial oxidation increased when the mice were 4 weeks old and continued to increase in an age-dependent manner. The increase in hepatic mitochondrial oxidation occurred simultaneously with weight gain and increased blood insulin levels before the blood glucose levels increased. Administering the oxidative stress inducer acetaminophen increased the vulnerability of the liver mitochondria to oxidative stress. This study demonstrates that oxidative stress in liver mitochondria in mice begins at the onset of diabetes rather than after the disease has progressed. RoGFP-expressing transgenic type 2 diabetes mouse models are effective and convenient tools for measuring hepatic mitochondrial redox statuses in vivo. These models may be used to assess mitochondria-targeting antioxidants and establish the role of oxidative stress in type 2 diabetes. • Type 2 diabetes mouse models with redox biosensors were generated. • Oxidative stress was observed in liver mitochondria in early-stage diabetes. • Liver mitochondria in diabetic mice are vulnerable to oxidative stress. [ABSTRACT FROM AUTHOR]

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]

Unprecedented large-scale algal blooms were observed during autumn 2021 around the Katsurakoi fishing port, Kushiro, eastern Hokkaido, Japan. Monitoring of shoreline water showed that chlorophyll a (Chl a) concentrations and the cell density of Karenia spp., dominated by Karenia selliformis, repeatedly increased synchronously between September and November 2021. These increases were associated with a southerly wind-driven current, which transported offshore water on the shelf towards the shoreline at the sea surface. The blooms were prolonged as a result of algal accumulation in the semi-closed fishing port. The maximum Chl a concentration and cell density exceeded 50 µg Chl a/L and 104 cells/mL, respectively. During the autumn bloom of Karenia spp., the nitrate + nitrite and phosphate concentrations in the water were lower than those in 2019 and 2020, and the silicate concentration was comparable. The ammonium concentration during the bloom was notably higher than before the bloom period, reaching 15 µM. Mass mortality of several fish species and echinoderms that were cultured using rearing water intake from the same shoreline occurred synchronously with the increase in Karenia spp. [ABSTRACT FROM AUTHOR]

Key points Currently, it is not known whether impaired mitochondrial function contributes to human ageing or whether potential impairments in mitochondrial function with age are secondary to physical inactivity., The present study investigated mitochondrial respiratory function and reactive oxygen species emission at a predefined membrane potential in young and older men subjected to 2 weeks of one-leg immobilization followed by 6 weeks of aerobic cycle training., Immobilization increased reactive oxygen species emission and decreased ATP generating respiration. Subsequent aerobic training reversed these effects., By contrast, age had no effect on the measured variables., The results of the present study support the notion that increased mitochondrial reactive oxygen species production mediates the detrimental effects seen after physical inactivity and that ageing per se does not cause mitochondrial dysfunction., Abstract Mitochondrial dysfunction, defined as increased oxidative stress and lower capacity for energy production, may be seen with ageing and may cause frailty, or it could be that it is secondary to physical inactivity. We studied the effect of 2 weeks of one-leg immobilization followed by 6 weeks of supervised cycle training on mitochondrial function in 17 young (mean ± SEM: 23 ± 1 years) and 15 older (68 ± 1 years) healthy men. Submaximal H2O2 emission and respiration were measured simultaneously at a predefined membrane potential in isolated mitochondria from skeletal muscle using two protocols: pyruvate + malate (PM) and succinate + rotenone (SR). This allowed measurement of leak and ATP generating respiration from which the coupling efficiency can be calculated. The protein content of the anti-oxidants manganese superoxide dismuthase (MnSOD), CuZn superoxide dismuthase, catalase and gluthathione peroxidase 1 was measured by western blotting. Immobilization decreased ATP generating respiration using PM and increased H2O2 emission using both PM and SR similarly in young and older men. Both were restored to baseline after the training period. Furthermore, MnSOD and catalase content increased with endurance training. The young men had a higher leak respiration at inclusion using PM and a higher membrane potential in State 3 using both substrate combinations. Collectively, the findings of the present study support the notion that increased mitochondrial reactive oxygen species mediates the detrimental effects seen after physical inactivity. Age, on the other hand, was not associated with impairments in anti-oxidant protein levels, mitochondrial respiration or H2O2 emission using either protocol. [ABSTRACT FROM AUTHOR]

Oxidative stress is known to play a prominent role in the onset and early stage progression of Alzheimer’s disease (AD). For example, protein oxidation and lipid peroxidation levels are increased in patients with mild cognitive impairment. Here, we created a double-transgenic mouse model of AD to explore the pathological and behavioral effects of oxidative stress. Double transgenic (APP/DAL) mice were constructed by crossing Tg2576 (APP) mice, which express a mutant form of human amyloid precursor protein (APP), with DAL mice expressing a dominant-negative mutant of mitochondrial aldehyde dehydrogenase 2 (ALDH2), in which oxidative stress is enhanced. Y-maze and object recognition tests were performed at 3 and 6 months of age to evaluate learning and memory. The accumulation of amyloid plaques, deposition of phosphorylated-tau protein, and number of astrocytes in the brain were assessed histopathologically at 3, 6, 9, and 12–15 months of age. The life span of APP/DAL mice was significantly shorter than that of APP or DAL mice. In addition, they showed accelerated amyloid deposition, tau phosphorylation, and gliosis. Furthermore, these mice showed impaired performance on Y-maze and object recognition tests at 3 months of age. These data suggest that oxidative stress accelerates cognitive dysfunction and pathological insults in the brain. APP/DAL mice could be a useful model for exploring new approaches to AD treatment. [ABSTRACT FROM AUTHOR]

Physical inactivity affects human skeletal muscle mitochondrial oxidative capacity but the influence of aging combined with physical inactivity is not known. This study investigates the effect of two weeks of immobilization followed by six weeks of supervised cycle training on muscle oxidative capacity in 17 young (23 ± 1 years) and 15 elderly (68 ± 1 years) healthy men. We applied high-resolution respirometry in permeabilized fibers from muscle biopsies at inclusion after immobilization and training. Furthermore, protein content of mitochondrial complexes I–V, mitochondrial heat shock protein 70 (mtHSP70) and voltage dependent anion channel (VDAC) were measured in skeletal muscle by Western blotting. The elderly men had lower content of complexes I–V and mtHSP70 but similar respiratory capacity and content of VDAC compared to the young. In both groups the respiratory capacity and protein content of VDAC, mtHSP70 and complexes I, II, IV and V decreased with immobilization and increased with retraining. Moreover, there was no overall difference in the response between the groups. When the intrinsic mitochondrial capacity was evaluated by normalizing respiration to citrate synthase activity, the respiratory differences with immobilization and training disappeared. In conclusion, aging is not associated with a decrease in muscle respiratory capacity in spite of lower complexes I–V and mtHSP70 protein content. Furthermore, immobilization decreased and aerobic training increased the respiratory capacity and protein contents of complexes I–V, mtHSP70 and VDAC similarly in the two groups. This suggests that inactivity and training alter mitochondrial biogenesis equally in young and elderly men. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?We questioned whether an angiotensin‐converting enzyme (ACE) inhibitor prevents skeletal muscle fibrosis in diabetic mice.What is the main finding and its importance?Administration of ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after induction of diabetes by streptozotocin. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. Fibrosis is characterized by the excessive production and accumulation of extracellular matrix components, including collagen. Although the extracellular matrix is an essential component of skeletal muscle, fibrosis can have negative effects on muscle function. Skeletal muscle fibrosis was shown to be increased in spontaneously hypertensive rats and to be prevented by an angiotensin‐converting enzyme (ACE) inhibitor, an antihypertensive drug, in dystrophic mice or a mouse model of myocardial infarction. In this study, we therefore analysed whether (1) there is increased skeletal muscle fibrosis in streptozotocin (STZ)‐induced diabetic mice, and (2) a preventive effect on skeletal muscle fibrosis by administration of an ACE inhibitor. Skeletal muscle fibrosis was significantly increased in STZ‐induced diabetic mice compared with control mice from 2 to 14 days post‐STZ. The ACE inhibitor prevented both skeletal muscle fibrosis and the reduction in muscle function in STZ‐treated mice. Our study demonstrated that administration of an ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after onset of diabetes. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. Future studies are required to clarify whether skeletal muscle fibrosis is also linked directly to physical activity. [ABSTRACT FROM AUTHOR]

We previously showed a sodium glucose co-transporter 2 (SGLT2) inhibitor, luseogliflozin, increased beta cell mass and improved beta cell function in db/db mice, but the mechanism has remained unclear. The aim of this study is to investigate the mechanism of favorable effects of luseogliflozin on beta cells. Six-week-old db/db mice were fed to standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group) for 4 weeks. DNA microarray analysis, real-time PCR analysis, measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation, and metabolome analysis were performed using isolated islets. Immunohistochemistry and electron microscopy were performed using pancreatic tissues. DNA microarray and real-time PCR analysis showed gene expressions of solute carrier family 2 member 2 (Slc2a2) related to glucose uptake, pyruvate carboxylase (Pcx) and enzymes related to the tricarboxylic acid (TCA) cycle, and cytochrome c oxidase subunit 6A2 (Cox6a2) related to electron transport chain were upregulated in the luseo group. The luseo group had a higher mitochondrial complex II-linked oxidative phosphorylation capacity, and had a lower mitochondrial ROS generation compared with the control group. Electron microscopy showed mitochondrial swelling in the control group, while the mitochondrial size was normally maintained in the luseo group. Immunohistochemistry showed the proportion of Nkx6.1 positive cells/beta cells was significantly higher in the luseo group compared with the control group (89.8 ± 1.8% vs. 75.3 ± 3.5%, P < 0.01). In metabolome analysis, the metabolites in the TCA cycle were greater in the luseo group compared with the control group. Relief of glucotoxicity by luseogliflozin may reduce mitochondrial ROS generation and elevate Nkx6.1 expression related to beta cell proliferation. The elevated expression of Nkx6.1 could improve glucose metabolism in the TCA cycle, resulting in protection of beta cells. Disclosure: Y. Yamauchi: None. K. Cho: None. T. Anzai: None. S. Tanaka: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Novo Nordisk, Sanofi, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Speaker's Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Miyoshi: Research Support; Self; Abbott Japan Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K. K., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd. T. Atsumi: Research Support; Self; Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly Japan K. K., Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., UCB Japan Co. Ltd., Speaker's Bureau; Self; AbbVie Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Takeda Pharmaceutical Co., UCB Japan Co. Ltd. A. Nakamura: Research Support; Self; Boehringer Ingelheim International GmbH, Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Taisho Pharmaceutical Co., Ltd. T. Yokota: None. K. Takahashi: None. S. Kawata: None. K. Tsuchida: None. K. Omori: None. H. Nomoto: None. H. Kameda: None. [ABSTRACT FROM AUTHOR]

Aims Exercise intolerance in patients with heart failure (HF) is partly attributed to skeletal muscle abnormalities. We have shown that reactive oxygen species (ROS) play a crucial role in skeletal muscle abnormalities, but the pathogenic mechanism remains unclear. Xanthine oxidase (XO) is reported to be an important mediator of ROS overproduction in ischaemic tissue. Here, we tested the hypothesis that skeletal muscle abnormalities in HF are initially caused by XO-derived ROS and are prevented by the inhibition of their production. Methods and results Myocardial infarction (MI) was induced in male C57BL/6J mice, which eventually led to HF, and a sham operation was performed in control mice. The time course of XO-derived ROS production in mouse skeletal muscle post-MI was first analysed. XO-derived ROS production was significantly increased in MI mice from Days 1 to 3 post-surgery (acute phase), whereas it did not differ between the MI and sham groups from 7 to 28 days (chronic phase). Second, mice were divided into three groups: sham + vehicle (Sham + Veh), MI + vehicle (MI + Veh), and MI + febuxostat (an XO inhibitor, 5 mg/kg body weight/day; MI + Feb). Febuxostat or vehicle was administered at 1 and 24 h before surgery, and once-daily on Days 1–7 post-surgery. On Day 28 post-surgery, exercise capacity and mitochondrial respiration in skeletal muscle fibres were significantly decreased in MI + Veh compared with Sham + Veh mice. An increase in damaged mitochondria in MI + Veh compared with Sham + Veh mice was also observed. The wet weight and cross-sectional area of slow muscle fibres (higher XO-derived ROS) was reduced via the down-regulation of protein synthesis-associated mTOR-p70S6K signalling in MI + Veh compared with Sham + Veh mice. These impairments were ameliorated in MI + Feb mice, in association with a reduction of XO-derived ROS production, without affecting cardiac function. Conclusion XO inhibition during the acute phase post-MI can prevent skeletal muscle abnormalities and exercise intolerance in mice with HF. [ABSTRACT FROM AUTHOR]

Heart failure (HF) occurs frequently among older individuals, and dysfunction of cardiac mitochondria is often observed. We here show the cardiac-specific downregulation of a certain mitochondrial component during the chronological aging of mice, which is detrimental to the heart. MitoNEET is a mitochondrial outer membrane protein, encoded by CDGSH iron sulfur domain 1 (CISD1). Expression of mitoNEET was specifically downregulated in the heart and kidney of chronologically aged mice. Mice with a constitutive cardiac-specific deletion of CISD1 on the C57BL/6J background showed cardiac dysfunction only after 12 months of age and developed HF after 16 months; whereas irregular morphology and higher levels of reactive oxygen species in their cardiac mitochondria were observed at earlier time points. Our results suggest a possible mechanism by which cardiac mitochondria may gradually lose their integrity during natural aging, and shed light on an uncharted molecular basis closely related to age-associated HF. Takaaki Furihata et al. report a new mouse model with heart-specific deletion of the mitochondrial protein, mitoNEET. Their results suggest that loss of mitoNEET expression may contribute to age-associated heart failure in older adults. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor beta (TGF-β)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-β-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis. Methods: Male C57BL/6 J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20 mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14 days postsurgery. Results: Skeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14 days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14 days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-β and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1–7 postsurgery) and blood angiotensin II at 14 days postsurgery was increased in MI mice compared with sham mice. These impairments were improved in MI + Lis mice, without any effects on spontaneous physical activity, muscle strength, muscle weight, and blood pressure. Conclusions: ACE inhibitor administration prevents increased skeletal muscle fibrosis during the early phase after MI. Our findings indicate a new therapeutic target for ameliorating skeletal muscle abnormalities in heart diseases. [ABSTRACT FROM AUTHOR]

Patients with acute myocardial infarction (AMI) with low body mass index (BMI) have worse outcomes than obese patients, and this phenomenon is recognized as "obesity paradox." Coronary calcification is associated with cardiac events. However, the association between BMI and calcification and their involvement in the mortality of AMI patients remain unknown. This study consecutively enrolled 517 patients with AMI who underwent emergent coronary intervention within 24 h after onset. Patients were divided into four groups according to the baseline BMI interquartile ranges: Q1 (BMI < 21.9 kg/m2), Q2 (21.9 ≤ BMI < 24.0 kg/m2), Q3 (24.0 ≤ BMI < 26.0 kg/m2), and Q4 (BMI ≥ 26.0 kg/m2). Calcification in the culprit lesion was also evaluated. The Q1 group was older and had a lower frequency of coronary risk factors. Moderate/severe calcification was most frequently observed in Q1, followed by Q2, Q3, and Q4. The Q1 group had the highest all-cause mortality, and patients with moderate/severe calcification had a higher all-cause mortality than that in patients without calcification. The highest all-cause mortality was observed in Q1with calcification, and the lowest was in Q4 without calcification. Q1 and the presence of moderate/severe calcification were independently associated with all-cause mortality. Although low-BMI patients with AMI had a lower frequency of coronary risk factors, they had a worse all-cause mortality than that in high-BMI patients. Our findings suggest that lesion calcification and its possible association with low BMI are involved in the higher mortality rate in these patients. [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]

CCAAT/enhancer binding protein epsilon (C/EBPε), a myeloid-specific transcription factor, plays an important role in granulopoiesis. A loss-of-function mutation in this protein can result in an abnormal development of neutrophils and eosinophils, known as neutrophil-specific granule deficiency (SGD). The transcriptional activity of C/EBPε is regulated by interactions with other transcription factors and/or post-translational modification, including acetylation. Previously, we reported a novel SGD patient who had a homozygous mutation for two amino acids, arginine (R247) and serine (S248), which were deleted in the basic leucine zipper domain of C/EBPε (ΔRS) and exhibited loss of transcriptional activity with aberrant protein–protein interactions. In the present study, we found that a single amino acid deletion of either R247 (ΔR) or S248 (ΔS) was sufficient for the loss of C/EBPε transcriptional activity, while an amino acid substitution at S248 to alanine in C/EBPε (SA) had comparable transcriptional activity with the wild-type C/EBPε (WT). Although acetylation at lysine residues (K121 and K198) is indispensable for C/EBPε transcriptional activity, an acetylation mimic form of ΔRS (ΔRS-K121/198Q) did not exhibit the transcriptional activity. Interestingly, we discovered that ΔRS, ΔR, ΔS, and ΔRS-K121/198Q interacted with histone deacetylase 1 (HDAC1), whereas WT and SA did not. Furthermore, the proteoglycan 2/eosinophil major basic protein induction activity of ΔRS, ΔR, and ΔS could be restored by the HDAC inhibitor, trichostatin A (TSA), and protein–protein interactions between ΔRS and Gata1 could also be recovered by TSA treatment. Taken together, our results show that TSA has the potential to restore the transcriptional activity of ΔRS, indicating that the inhibition of HDAC1 could be a molecularly targeted treatment for SGD with ΔRS. • A deletion of either R247 or S248 is sufficient for the dysfunction of C/EBPε. • An acetylation mimic form of C/EBPε ΔRS does not have transcriptional activity. • C/EBPε ΔRS interacts with HDAC1. • TSA restores Prg2/MaBP induction activity and Gata1 interaction of C/EBPε ΔRS. [ABSTRACT FROM AUTHOR]

Increases in muscle size and strength similar to those obtained with high resistance load can be achieved by combining lower loads with continuous blood flow restriction (BFR). However, high ratings for distress have been reported for continuous BFR. Therefore, we investigated the efficacy (metabolic stress) of BFR applied only during intervals in resistance exercise. Seven healthy men performed three 1-min sets of plantar flexion (30 reps/min) with 1-min rest intervals under 4 conditions: low-load resistance exercise (L, 20% 1-repetition maximum (1RM)) without BFR (L-noBFR), L with BFR during exercise sets (L-exBFR), L with BFR during rest intervals (L-intBFR), and L with continuous BFR during both exercise and rest intervals (L-conBFR). Based on the results of the first experiment, we performed additional protocols using a moderate load (M, 40% 1RM) with intermittent (exercise or rest intervals) BFR (M-exBFR and M-intBFR). Intramuscular metabolic stress, defined as decreases in phosphocreatine and intramuscular pH, was evaluated by 31P magnetic resonance spectroscopy. Rated perceived exertion (RPE) was also assessed. At the end of exercise, total decreases in phosphocreatine and intramuscular pH were similar among L-noBFR, L-intBFR, and L-exBFR and significantly less than those in L-conBFR (p < 0.05). In contrast, changes in these variables in M-intBFR but not in M-exBFR were similar to those in L-conBFR. Nevertheless, RPE was lower in M-intBFR than in both M-exBFR and L-conBFR (p < 0.05). The effect of intermittent BFR during exercise might be insufficient to induce metabolic stress when using a low load. However, effective metabolic stress for muscle adaptation could be obtained by moderate-load resistance exercise with BFR during intervals with less ischemic duration and discomfort. [ABSTRACT FROM AUTHOR]

Liver stiffness (LS) has been reported to be a marker of liver congestion caused by elevated central venous pressure in heart failure (HF) patients. Recent studies demonstrated that LS could be non-invasively measured by virtual touch quantification (VTQ). However, its prognostic implication in patients with acute decompensated heart failure (ADHF) is unclear. This study sought to determine whether LS measured by VTQ could be a determinant of subsequent adverse events in ADHF patients. We prospectively recruited 70 ADHF patients who underwent LS measurement by VTQ on admission in our university hospital between June 2016 and April 2018. The primary outcome of interest was the composite of all-cause mortality and worsening HF. During a median follow-up period of 272 (interquartile range 122–578) days, there were 26 (37%) events, including 5 (7%) deaths and 21 (30%) cases of worsening HF. The c-index of LS for predicting the composite of adverse events was 0.77 (95% CI 0.66–0.88), and the optimal cut-off value of LS was 1.50 m/s. Adverse events were more frequently observed in patients with high LS (≥ 1.50 m/s) compared to those with low LS (< 1.50 m/s). Multivariable Cox regression analyzes revealed that higher LS was independently associated with increased subsequent risk of adverse events after adjustment for confounders. In conclusion, high admission LS was an independent determinant of worse clinical outcomes in patients with ADHF. This finding suggests that LS on admission is useful for risk stratification of patients with ADHF. [ABSTRACT FROM AUTHOR]

Brain aging is accompanied by declining mitochondrial respiration. We hypothesized that mitochondrial morphology and dynamics would reflect this decline. Using hippocampus and frontal cortex of a segmental progeroid mouse model lacking Cockayne syndrome protein B (CSB m/m ) and C57Bl/6 (WT) controls and comparing young (2–5 months) to middle-aged mice (13–14 months), we found that complex I-linked state 3 respiration (CI) was reduced at middle age in CSB m/m hippocampus, but not in CSB m/m cortex or WT brain. In hippocampus of both genotypes, mitochondrial size heterogeneity increased with age. Notably, an inverse correlation between heterogeneity and CI was found in both genotypes, indicating that heterogeneity reflects mitochondrial dysfunction. The ratio between fission and fusion gene expression reflected age-related alterations in mitochondrial morphology but not heterogeneity. Mitochondrial DNA content was lower, and hypoxia-induced factor 1α mRNA was greater at both ages in CSB m/m compared to WT brain. Our findings show that decreased CI and increased mitochondrial size heterogeneity are highly associated and point to declining mitochondrial quality control as an initial event in brain aging. [ABSTRACT FROM AUTHOR]

A failing heart shows severe energy insufficiency, and it is presumed that this energy shortage plays a critical role in the development of cardiac dysfunction. However, little is known about the mechanisms that cause energy metabolic alterations in the failing heart. Here, we show that the novel RING-finger protein 207 (RNF207), which is specifically expressed in the heart, plays a role in cardiac energy metabolism. Depletion of RNF207 in neonatal rat cardiomyocytes (NRCs) leads to a reduced cellular concentration of adenosine triphosphate (ATP) and mitochondrial dysfunction. Consistent with this result, we observed here that the expression of RNF207 was significantly reduced in mice with common cardiac diseases including heart failure. Intriguingly, proteomic approaches revealed that RNF207 interacts with the voltage-dependent anion channel (VDAC), which is considered to be a key regulator of mitochondria function, as an RNF207-interacting protein. Our findings indicate that RNF207 is involved in ATP production by cardiomyocytes, suggesting that RNF207 plays an important role in the development of heart failure. [ABSTRACT FROM AUTHOR]

Background It has been reported that skeletal muscle mass and strength are decreased in patients with heart failure (HF), and HF is associated with both reduced exercise capacity and adverse clinical outcomes. Myostatin has been known as a negative regulator of muscle growth, follistatin as the myostatin antagonist, maintaining tissue homeostasis. We thus determined serum myostatin levels in HF patients and whether they are associated with skeletal muscle wasting. Methods and results Forty one consecutive HF patients (58 ± 15 years old, New York Heart Association class I–III) and 30 age-matched healthy subjects as controls (53 ± 8 years old) were studied. Serum myostatin levels were significantly lower in HF patients than controls (18.7 ± 7.4 vs. 23.6 ± 5.2 ng/mL, P < 0.001). Circumference of the thickest part of the right thigh was significantly small (468 ± 72 vs. 559 ± 37 mm, P = 0.001) and lower extremity muscular strength was lower in patients with HF (129 ± 55 vs. 219 ± 52 N × m, P < 0.001). Fourteen HF patients (34%) had muscle wasting. By univariate analysis, higher age, higher serum follistatin, and lower serum myostatin were significantly associated with the presence of muscle wasting. By multivariate analysis, serum myostatin levels were independently associated with muscle wasting (OR = 0.77, 95% CI [0.58, 0.93], P = 0.02). Conclusion Serum myostatin levels were significantly decreased in HF patients and associated with lower extremity muscle wasting, suggesting that myostatin may be an important factor for maintaining skeletal muscle mass and strength in HF. [ABSTRACT FROM AUTHOR]

Estrogen-related receptor beta (Esrrb) is expressed in embryonic stem (ES) cells and is involved in self-renewal ability and pluripotency. Previously, we found that Dax1 is associated with Esrrb and represses its transcriptional activity. Further, the disruption of the Dax1–Esrrb interaction increases the expression of the extra-embryonic endoderm marker Gata6 in ES cells. Here, we investigated the influences of Esrrb and Dax1 on Gata6 expression. Esrrb overexpression in ES cells induced endogenous Gata6 mRNA and Gata6 promoter activity. In addition, the Gata6 promoter was found to contain the Esrrb recognition motifs ERRE1 and ERRE2, and the latter was the responsive element of Esrrb. Associations between ERRE2 and Esrrb were then confirmed by biotin DNA pulldown and chromatin immunoprecipitation assays. Subsequently, we showed that Esrrb activity at the Gata6 promoter was repressed by Dax1, and although Dax1 did not bind to ERRE2, it was associated with Esrrb, which directly binds to ERRE2. In addition, the transcriptional activity of Esrrb was enhanced by nuclear receptor co-activator 3 (Ncoa3), which has recently been shown to be a binding partner of Esrrb. Finally, we showed that Dax1 was associated with Ncoa3 and repressed its transcriptional activity. Taken together, the present study indicates that the Gata6 promoter is activated by Esrrb in association with Ncoa3, and Dax1 inhibited activities of Esrrb and Ncoa3, resulting maintenance of the undifferentiated status of ES cells. [ABSTRACT FROM AUTHOR]

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/6 J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10 mg/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. [ABSTRACT FROM AUTHOR]

Background: We previously showed that phospholipase C (PLC)-δ1 activity was enhanced by 3-fold in patients with coronary spastic angina (CSA). We also reported that p122Rho GTPase-activating protein/deleted in liver cancer-1 (p122RhoGAP/DLC-1) protein, which was discovered as a PLC-δ1 stimulator, was upregulated in CSA patients. We tested the hypothesis that p122RhoGAP/DLC-1 overexpression causes coronary spasm. Methods and Results: We generated transgenic (TG) mice with vascular smooth muscle (VSM)-specific overexpression of p122RhoGAP/DLC-1. The gene and protein expressions of p122RhoGAP/DLC-1 were markedly increased in the aorta of homozygous TG mice. Stronger staining with anti-p122RhoGAP/DLC-1 in the coronary artery was found in TG than in WT mice. PLC activities in the plasma membrane fraction and the whole cell were enhanced by 1.43 and 2.38 times, respectively, in cultured aortic vascular smooth muscle cells from homozygous TG compared with those from WT mice. Immediately after ergometrine injection, ST-segment elevation was observed in 1 of 7 WT (14%), 6 of 7 heterozygous TG (84%), and 7 of 7 homozygous TG mice (100%) (p<0.05, WT versus TGs). In the isolated Langendorff hearts, coronary perfusion pressure was increased after ergometrine in TG, but not in WT mice, despite of the similar response to prostaglandin F2α between TG and WT mice (n = 5). Focal narrowing of the coronary artery after ergometrine was documented only in TG mice. Conclusions: VSM-specific overexpression of p122RhoGAP/DLC-1 enhanced coronary vasomotility after ergometrine injection in mice, which is relevant to human CSA. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? Our aim was to examine whether sesamin can prevent a decline in exercise capacity in high-fat diet-induced diabetic mice. Our hypothesis was that maintenance of mitochondrial function and attenuation of oxidative stress in the skeletal muscle would contribute to this result., What is the main finding and its importance? The new findings are that sesamin prevents the diabetes-induced decrease in exercise capacity and impairment of mitochondrial function through the inhibition of NAD(P)H oxidase-dependent oxidative stress in the skeletal muscle. Sesamin may be useful as a novel agent for the treatment of diabetes mellitus., Abstract We previously reported that exercise capacity and skeletal muscle mitochondrial function in diabetic mice were impaired, in association with the activation of NAD(P)H oxidase. It has been reported that sesamin inhibits NAD(P)H oxidase-induced superoxide production. Therefore, we examined whether the antioxidant sesamin could prevent a decline in exercise capacity in mice with high-fat diet (HFD)-induced diabetes. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated or not with sesamin (0.2%) to yield the following four groups: ND, ND+Sesamin, HFD and HFD+Sesamin ( n = 10 each). After 8 weeks, body weight, fat weight, blood glucose, insulin, triglyceride, total cholesterol and fatty acid were significantly increased in HFD compared with ND mice. Sesamin prevented the increases in blood insulin and lipid levels in HFD-fed mice, but did not affect the plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in HFD mice, but almost completely recovered in HFD+Sesamin mice. Citrate synthase activity was significantly decreased in the skeletal muscle of HFD mice, and these decreases were also inhibited by sesamin. Superoxide anion and NAD(P)H oxidase activity were significantly increased in HFD mice compared with the ND mice and were ameliorated by sesamin. Sesamin prevented the decline in exercise capacity in HFD-induced diabetic mice via maintenance of mitochondrial function, fat oxidation and attenuation of oxidative stress in the skeletal muscle. Our data suggest that sesamin may be useful as a novel agent for the treatment of diabetes mellitus. [ABSTRACT FROM AUTHOR]

The article presents the study which examines how brain-derived neurotrophic factor (rhBDNF) improved limited exercise capacity in mice with heart failure. It offers details of the study which involved induction of a myocardial infarction (MI) in 10- to 12-week-old male mice by ligating the coronary artery.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to have beneficial effects on HF in large clinical trials; however, the mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms by which empagliflozin, one of SGLT2 inhibitors, affects heart failure. Eight-week-old male mice deficient for heart and skeletal muscle-specific manganese superoxide dismutase (MnSOD-cKO mice), a murine model of dilated cardiomyopathy, were given food mixed with or without 10 mg/kg empagliflozin for 7 weeks and evaluated. Both the survival rate and cardiac fibrosis were significantly improved in the empagliflozin group. The capacity for oxidative phosphorylation in cardiac mitochondria was significantly upregulated as measured with Oxygraph-2k respirometer, and blood lactate levels produced by anaerobic metabolism were significantly lower in the empagliflozin group. Energy expenditure was significantly improved in the empagliflozin group, measured by respiratory gas analysis, with a concomitant reduction in serum leptin concentration and increase in food intake. A moderate amount of glucose was excreted in urine in the empagliflozin group; however, the available energy substrate in the body nonetheless expanded because of the much higher caloric intake. We conclude that empagliflozin improved cardiac mitochondrial function and upregulated energy metabolism even in HF in mice. These findings provide novel mechanisms for the beneficial effects of SGLT2 inhibitors on HF. [Display omitted] • SGLT2 inhibitors improved HF hospitalization in large clinical trials, however, the mechanisms remain unclear. • Empagliflozin prolonged lifespan in HFrEF model mice. • In HFrEF mice, empagliflozin treatment maintained mitochondrial function and increased energy expenditure. • Empagliflozin reduced serum leptin, increased food intake, and subsequently improved nutritional status in HFrEF mice. [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]

Embryonic stem (ES) cells, derived from the inner cell mass of blastocysts, have a characteristic cell cycle with truncated G1 and G2 phases. Recent findings that suppression of Oct3/4 expression results in a reduced proliferation rate of ES cells suggest the involvement of Oct3/4 in the regulation of ES cell growth, although the underlying molecular mechanism remains unclear. In the present study, we identified E2F3a as a direct target gene of Oct3/4 in ES cells. Oct3/4 directly bound to the promoter region of the E2F3a gene and positively regulated expression of E2F3a in mouse ES cells. Suppression of E2F3a activity by E2F6 overexpression led to the reduced proliferation in ES cells, which was relieved by co-expression of E2F3a. Furthermore, cell growth retardation caused by loss of Oct3/4 was rescued by E2F3a expression. These results suggest that Oct3/4 upregulates E2F3a expression to promote ES cell growth. [ABSTRACT FROM AUTHOR]