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Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure.
Zhou, B, Wang, DD, Qiu, Y, Airhart, S, Liu, Y, Stempien-Otero, A, O'Brien, KD, Tian, R
The Journal of clinical investigation. 2020;(11):6054-6063
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Abstract
BACKGROUNDWhile mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level.METHODSWe compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage-associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor.RESULTSWe demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF.CONCLUSIONThese findings suggest that systemic inflammation in patients with HF is causally linked to mitochondrial function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF.TRIAL REGISTRATIONClinicalTrials.gov NCT03727646.FUNDINGThis study was funded by the NIH, the University of Washington, and the American Heart Association.
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Classical monocytes from older adults maintain capacity for metabolic compensation during glucose deprivation and lipopolysaccharide stimulation.
Yarbro, JR, Pence, BD
Mechanisms of ageing and development. 2019;:111146
Abstract
Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that classical monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism along with impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose deprivation as measured on a Seahorse XFp system. Additionally, aged classical monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged classical monocytes maintain effector and metabolic functions during glucose deprivation, at least in an ex vivo context.
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Effects of a Short-Term Recreational Team Handball-Based Programme on Physical Fitness and Cardiovascular and Metabolic Health of 33-55-Year-Old Men: A Pilot Study.
Póvoas, SCA, Castagna, C, Resende, C, Coelho, EF, Silva, P, Santos, R, Pereira, R, Krustrup, P
BioMed research international. 2018;:4109796
Abstract
Recreational team handball is an intermittent high-intensity exercise mode with physiological demands in the range of those found to enhance health and physical fitness of sedentary adults. We examined the effects of a short-term team handball-based training programme on physical fitness and metabolic and cardiovascular health of sedentary 33-55-year-old former male team handball players. Twenty-four participants were divided into team handball (THG; n=15) and control groups (CG; n=9) and evaluated at baseline and postintervention. During 12 weeks, THG performed 2-3 60-min recreational team handball matches weekly (average: 2.2 ± 0.7), and CG maintained an inactive lifestyle. Average heart rate (HR) during matches was 80 ± 7%HRmax, with peak values of 91 ± 6%HRmax. A time-by-group interaction was shown in aerobic performance (p=0.016), postural balance (p=0.019), maximum oxygen uptake (VO2max) (p=0.023), resting HR (p<0.001), high-density lipoprotein (HDL) cholesterol (p=0.048), and fasting blood glucose (p=0.052) in favor of THG. THG improved aerobic performance (80%, p<0.001), VO2max (14%, p<0.001), and postural balance (27%, p=0.018). Decreases in resting HR (16%, p<0.001) and fasting blood glucose (7%, p=0.015) and increases in HDL cholesterol (11%, p=0.002) were found in THG. Recreational team handball practice shows positive physical fitness and health-related adaptations, with high attendance, which may contribute to the reduction of the risk of developing lifestyle diseases.
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High dietary fat intake increases fat oxidation and reduces skeletal muscle mitochondrial respiration in trained humans.
Leckey, JJ, Hoffman, NJ, Parr, EB, Devlin, BL, Trewin, AJ, Stepto, NK, Morton, JP, Burke, LM, Hawley, JA
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2018;(6):2979-2991
Abstract
High-fat, low-carbohydrate (CHO) diets increase whole-body rates of fat oxidation and down-regulate CHO metabolism. We measured substrate utilization and skeletal muscle mitochondrial respiration to determine whether these adaptations are driven by high fat or low CHO availability. In a randomized crossover design, 8 male cyclists consumed 5 d of a high-CHO diet [>70% energy intake (EI)], followed by 5 d of either an isoenergetic high-fat (HFAT; >65% EI) or high-protein diet (HPRO; >65% EI) with CHO intake clamped at <20% EI. During the intervention, participants undertook daily exercise training. On d 6, participants consumed a high-CHO diet before performing 100 min of submaximal steady-state cycling plus an ∼30-min time trial. After 5 d of HFAT, skeletal muscle mitochondrial respiration supported by octanoylcarnitine and pyruvate, as well as uncoupled respiration, was decreased at rest, and rates of whole-body fat oxidation were higher during exercise compared with HPRO. After 1 d of high-CHO diet intake, mitochondrial respiration returned to baseline values in HFAT, whereas rates of substrate oxidation returned toward baseline in both conditions. These findings demonstrate that high dietary fat intake, rather than low-CHO intake, contributes to reductions in mitochondrial respiration and increases in whole-body rates of fat oxidation after a consuming a high-fat, low-CHO diet.-Leckey, J. J., Hoffman, N. J., Parr, E. B., Devlin, B. L., Trewin, A. J., Stepto, N. K., Morton, J. P., Burke, L. M., Hawley, J. A. High dietary fat intake increases fat oxidation and reduces skeletal muscle mitochondrial respiration in trained humans.
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Dietary nitrate does not reduce oxygen cost of exercise or improve muscle mitochondrial function in patients with mitochondrial myopathy.
Nabben, M, Schmitz, JPJ, Ciapaite, J, le Clercq, CMP, van Riel, NA, Haak, HR, Nicolay, K, de Coo, IFM, Smeets, H, Praet, SF, et al
American journal of physiology. Regulatory, integrative and comparative physiology. 2017;(5):R689-R701
Abstract
Muscle weakness and exercise intolerance negatively affect the quality of life of patients with mitochondrial myopathy. Short-term dietary nitrate supplementation has been shown to improve exercise performance and reduce oxygen cost of exercise in healthy humans and trained athletes. We investigated whether 1 wk of dietary inorganic nitrate supplementation decreases the oxygen cost of exercise and improves mitochondrial function in patients with mitochondrial myopathy. Ten patients with mitochondrial myopathy (40 ± 5 yr, maximal whole body oxygen uptake = 21.2 ± 3.2 ml·min-1·kg body wt-1, maximal work load = 122 ± 26 W) received 8.5 mg·kg body wt-1·day-1 inorganic nitrate (~7 mmol) for 8 days. Whole body oxygen consumption at 50% of the maximal work load, in vivo skeletal muscle oxidative capacity (evaluated from postexercise phosphocreatine recovery using 31P-magnetic resonance spectroscopy), and ex vivo mitochondrial oxidative capacity in permeabilized skinned muscle fibers (measured with high-resolution respirometry) were determined before and after nitrate supplementation. Despite a sixfold increase in plasma nitrate levels, nitrate supplementation did not affect whole body oxygen cost during submaximal exercise. Additionally, no beneficial effects of nitrate were found on in vivo or ex vivo muscle mitochondrial oxidative capacity. This is the first time that the therapeutic potential of dietary nitrate for patients with mitochondrial myopathy was evaluated. We conclude that 1 wk of dietary nitrate supplementation does not reduce oxygen cost of exercise or improve mitochondrial function in the group of patients tested.
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Assessing the effects of a short-term green tea intervention in skin microvascular function and oxygen tension in older and younger adults.
Wasilewski, R, Ubara, EO, Klonizakis, M
Microvascular research. 2016;:65-71
Abstract
Green tea consumption has been associated with a reduction in cardiovascular disease risk factors. However, there is little evidence examining its potential differing effect between younger and older populations, whilst little is known on its effect on the circulatory system when oxygen demand is higher. Therefore the aim of this study was to evaluate the short-term effects of green tea consumption on microvascular functioning in both an older and younger population. Fifteen young [24 (4.0)] and fifteen older [61 (4.0)] participants, consumed two cups of green tea daily for 14days. We used Laser Doppler Flowmetry (LDF) to assess cutaneous microvascular function and Transcutaneous Oxygen monitoring (TcPO2) to assess skin oxygen tension. Systolic and diastolic blood pressure were also assessed on both visits. We observed significant improvements in axon-mediated microvascular vasodilation for the younger group [1.6 (0.59) vs 2.05 (0.72), p<0.05] and the older group [1.25 (0.58) vs 1.65 (0.5) p<0.05]. Improvements in skin oxygen tension were also noted for both groups in both noted TcPO2 measures (i.e. 1.25 (0.58) vs 1.65 (0.5) (p<0.05), for ΔTcPO2max for the older group, between visits) respectively. Improvements were also observed for systolic blood pressure in both the younger [120 (10) vs 112 (10), p<0.05] and older group [129 (12) v 124 (11), p<0.001]. In conclusion, we observed statistically-significant improvements in microvascular function and skin oxygen tension. Our results suggest that green tea may prove beneficial as a dietary element in lifestyle interventions aiming to lower cardiovascular disease risk, in both older and younger populations.
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Acute ascorbic acid ingestion increases skeletal muscle blood flow and oxygen consumption via local vasodilation during graded handgrip exercise in older adults.
Richards, JC, Crecelius, AR, Larson, DG, Dinenno, FA
American journal of physiology. Heart and circulatory physiology. 2015;(2):H360-8
Abstract
Human aging is associated with reduced skeletal muscle perfusion during exercise, which may be a result of impaired endothelium-dependent dilation and/or attenuated ability to blunt sympathetically mediated vasoconstriction. Intra-arterial infusion of ascorbic acid (AA) increases nitric oxide-mediated vasodilation and forearm blood flow (FBF) during handgrip exercise in older adults, yet it remains unknown whether an acute oral dose can similarly improve FBF or enhance the ability to blunt sympathetic vasoconstriction during exercise. We hypothesized that 1) acute oral AA would improve FBF (Doppler ultrasound) and oxygen consumption (V̇o2) via local vasodilation during graded rhythmic handgrip exercise in older adults (protocol 1), and 2) AA ingestion would not enhance sympatholysis in older adults during handgrip exercise (protocol 2). In protocol 1 (n = 8; 65 ± 3 yr), AA did not influence FBF or V̇o2 during rest or 5% maximal voluntary contraction (MVC) exercise, but increased FBF (199 ± 13 vs. 248 ± 16 ml/min and 343 ± 24 vs. 403 ± 33 ml/min; P < 0.05) and V̇o2 (26 ± 2 vs. 34 ± 3 ml/min and 43 ± 4 vs. 50 ± 5 ml/min; P < 0.05) at both 15 and 25% MVC, respectively. The increased FBF was due to elevations in forearm vascular conductance (FVC). In protocol 2 (n = 10; 63 ± 2 yr), following AA, FBF was similarly elevated during 15% MVC (∼ 20%); however, vasoconstriction to reflex increases in sympathetic activity during -40 mmHg lower-body negative pressure at rest (ΔFVC: -16 ± 3 vs. -16 ± 2%) or during 15% MVC (ΔFVC: -12 ± 2 vs. -11 ± 4%) was unchanged. Our collective results indicate that acute oral ingestion of AA improves muscle blood flow and V̇o2 during exercise in older adults via local vasodilation.
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Use of the Wasserman equation in optimization of the duration of the power ramp in a cardiopulmonary exercise test: a study of Brazilian men.
Costa, DC, Santi, GL, Crescêncio, JC, Seabra, LP, Carvalho, EE, Papa, V, Marques, F, Gallo Junior, L, Schmidt, A
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2015;(12):1136-44
Abstract
This study aimed to analyze the agreement between measurements of unloaded oxygen uptake and peak oxygen uptake based on equations proposed by Wasserman and on real measurements directly obtained with the ergospirometry system. We performed an incremental cardiopulmonary exercise test (CPET), which was applied to two groups of sedentary male subjects: one apparently healthy group (HG, n=12) and the other had stable coronary artery disease (n=16). The mean age in the HG was 47±4 years and that in the coronary artery disease group (CG) was 57±8 years. Both groups performed CPET on a cycle ergometer with a ramp-type protocol at an intensity that was calculated according to the Wasserman equation. In the HG, there was no significant difference between measurements predicted by the formula and real measurements obtained in CPET in the unloaded condition. However, at peak effort, a significant difference was observed between oxygen uptake (V˙O2)peak(predicted)and V˙O2peak(real)(nonparametric Wilcoxon test). In the CG, there was a significant difference of 116.26 mL/min between the predicted values by the formula and the real values obtained in the unloaded condition. A significant difference in peak effort was found, where V˙O2peak(real)was 40% lower than V˙O2peak(predicted)(nonparametric Wilcoxon test). There was no agreement between the real and predicted measurements as analyzed by Lin's coefficient or the Bland and Altman model. The Wasserman formula does not appear to be appropriate for prediction of functional capacity of volunteers. Therefore, this formula cannot precisely predict the increase in power in incremental CPET on a cycle ergometer.
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Health-Related Physical Fitness in Healthy Untrained Men: Effects on VO2max, Jump Performance and Flexibility of Soccer and Moderate-Intensity Continuous Running.
Milanović, Z, Pantelić, S, Sporiš, G, Mohr, M, Krustrup, P
PloS one. 2015;(8):e0135319
Abstract
The purpose of this study was to determine the effects of recreational soccer (SOC) compared to moderate-intensity continuous running (RUN) on all health-related physical fitness components in healthy untrained men. Sixty-nine participants were recruited and randomly assigned to one of three groups, of which sixty-four completed the study: a soccer training group (SOC; n = 20, 34±4 (means±SD) years, 78.1±8.3 kg, 179±4 cm); a running group (RUN; n = 21, 32±4 years, 78.0±5.5 kg, 179±7 cm); or a passive control group (CON; n = 23, 30±3 years, 76.6±12.0 kg, 178±8 cm). The training intervention lasted 12 weeks and consisted of three 60-min sessions per week. All participants were tested for each of the following physical fitness components: maximal aerobic power, minute ventilation, maximal heart rate, squat jump (SJ), countermovement jump with arm swing (CMJ), sit-and-reach flexibility, and body composition. Over the 12 weeks, VO2max relative to body weight increased more (p<0.05) in SOC (24.2%, ES = 1.20) and RUN (21.5%, ES = 1.17) than in CON (-5.0%, ES = -0.24), partly due to large changes in body mass (-5.9, -5.7 and +2.6 kg, p<0.05 for SOC, RUN and CON, respectively). Over the 12 weeks, SJ and CMJ performance increased more (p<0.05) in SOC (14.8 and 12.1%, ES = 1.08 and 0.81) than in RUN (3.3 and 3.0%, ES = 0.23 and 0.19) and CON (0.3 and 0.2%), while flexibility also increased more (p<0.05) in SOC (94%, ES = 0.97) than in RUN and CON (0-2%). In conclusion, untrained men displayed marked improvements in maximal aerobic power after 12 weeks of soccer training and moderate-intensity running, partly due to large decreases in body mass. Additionally soccer training induced pronounced positive effects on jump performance and flexibility, making soccer an effective broad-spectrum fitness training intervention.
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Endurance training decreases the non-linearity in the oxygen uptake-power output relationship in humans.
Majerczak, J, Korostynski, M, Nieckarz, Z, Szkutnik, Z, Duda, K, Zoladz, JA
Experimental physiology. 2012;(3):386-99
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Abstract
In this study, we hypothesized that 5 weeks of cycling endurance training can decrease the magnitude of the non-proportional increase in oxygen uptake (V(O(2))) to power output relationship (V(O(2)) 'excess') at exercise intensities exceeding the lactate threshold (LT). Ten untrained, physically active men performed a bout of incremental cycling exercise until exhaustion before and after training. The mitochondrial DNA copy number, myosin heavy chain composition and content of uncoupling protein 3 and sarcoplasmic reticulum Ca(2+)-ATPases (SERCAs) were analysed in muscle biopsies taken from vastus lateralis before and after training. The training resulted in an enhancement of the power-generating capabilities at maximal oxygen uptake (V(O(2)max)) by ∼7% (P = 0.002) despite there being no changes in V(O(2)max) (P = 0.49). This effect was due to a considerable reduction in the magnitude of the V(O(2)) 'excess' (P < 0.05) above the LT. A decrease in plasma ammonia concentration was found during exercise after training (P < 0.05). A downregulation of SERCA2 in vastus lateralis (P = 0.006) was observed after training. No changes in myosin heavy chain composition, selected electron transport chain proteins, uncoupling protein 3 or the mitochondrial DNA copy number (P > 0.05) were found after training. We conclude that the training-induced increase in power-generating capabilities at V(O(2)max) was due to attenuation of the V(O(2)) 'excess' above the LT. This adaptive response seems to be related to the improvement of muscle metabolic stability, as judged by a lowering of plasma ammonia concentration. The enhancement of muscle metabolic stability after training could be caused by a decrease in ATP usage at a given power output owing to downregulation of SERCA2 pumps.