Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

Astaxanthin promotes mitochondrial biogenesis and antioxidant capacity in chronic high-intensity interval training.

PURPOSE: Reactive oxygen and nitrogen species are required for exercise-induced molecular adaptations; however, excessive exercise may cause cellular oxidative distress. We postulate that astaxanthin (ASX) can neutralize oxidative distress and stimulate mitochondrial biogenesis in high-intensity exercise-trained mice. METHODS: Six-week-old mice (n = 8/group) were treated with ASX (10 mg/kg BW) or placebo. Training groups participated in 30 min/day high-intensity interval training (HIIT) for 6 weeks. Gastrocnemius muscle was collected and assayed following the exercise training period. RESULTS: Compared to the HIIT control mice, the ASX-treated HIIT mice reduced malonaldehyde levels and upregulated the expression of Nrf2 and FOXO3a. Meanwhile, the genes NQO1 and GCLC, modulated by Nrf2, and SOD2, regulated by FOXO3a, and GPx4, were transcriptionally upregulated in the ASX-treated HIIT group. Meanwhile, the expression of energy sensors, AMPK, SIRT1, and SIRT3, increased in the ASX-treated HIIT group compared to the HIIT control group. Additionally, PGC-1α, regulated by AMPK and SIRT1, was upregulated in the ASX-treated HIIT group. Further, the increased PGC-1α stimulated the transcript of NRF1 and Tfam and mitochondrial proteins IDH2 and ATP50. Finally, the ASX-treated HIIT mice had upregulations in the transcript level of mitochondrial fusion factors, including Mfn1, Mfn2, and OPA1. However, the protein level of AMPK, SIRT1, and FOXO3a, and the transcript level of Nrf2, NQO1, PGC-1α, NRF1, Mfn1, Mfn2, and OPA1 decreased in the HIIT control group compared to the sedentary control group. CONCLUSION: Supplementation with ASX can reduce oxidative stress and promote antioxidant capacity and mitochondrial biogenesis during strenuous HIIT exercise in mice.

Exercise and Cardioprotection in Coronary Artery Disease: A Pilot Quasi-Experimental Study.

Sirtuin-1 is a protein that may orchestrate the cardioprotective effect of exercise by controlling cellular processes. This pilot study assessed the feasibility of performing a quasi-experimental study in this area. Patients with postacute myocardial infarction were recruited across four hospital sites in the United Kingdom. The participants were offered one weekly exercise session at Phase-III and Phase-IV cardiac rehabilitation (CR). Measurements were obtained pre-Phase-III CR (Week 1), post-Phase-III CR (Week 8), and post-Phase-IV CR (Week 22). Twenty-eight patients were recruited (79% male, 100% White, 60.2 ± 10.5 years old). The recruitment rate was not fulfilled (<70% eligible patients recruited; 0.9 participants recruited per week over 30 weeks). The success criteria for dropout rate, adherence rate, and collection of sirtuin-1 measures were satisfied. A large increase in sirtuin-1 (0.14 ± 0.03, d ≥ 0.8) was seen after Phase-III and Phase-IV CR. Collectively, a quasi-experimental study is feasible with a revised recruitment strategy.

Effectiveness of Exercise on Fatigue and Sleep Quality in Fibromyalgia: A Systematic Review and Meta-analysis of Randomized Trials.

OBJECTIVES: To determine the effects of exercise on fatigue and sleep quality in fibromyalgia (primary aim) and to identify which type of exercise is the most effective in achieving these outcomes (secondary aim). DATA SOURCES: PubMed and Web of Science were searched from inception until October 18, 2018. STUDY SELECTION: Eligible studies contained information on population (fibromyalgia), intervention (exercise), and outcomes (fatigue or sleep). Randomized controlled trials (RCT) testing the effectiveness of exercise compared with usual care and randomized trials (RT) comparing the effectiveness of 2 different exercise interventions were included for the primary and secondary aims of the present review, respectively. Two independent researchers performed the search, screening, and final eligibility of the articles. Of 696 studies identified, 17 RCTs (n=1003) were included for fatigue and 12 RCTs (n=731) for sleep. Furthermore, 21 RTs compared the effectiveness of different exercise interventions (n=1254). DATA EXTRACTION: Two independent researchers extracted the key information from each eligible study. DATA SYNTHESIS: Separate random-effect meta-analyses were performed to examine the effects from RCTs and from RTs (primary and secondary aims). Standardized mean differences (SMD) effect sizes were calculated using Hedges' adjusted g. Effect sizes of 0.2, 0.4, and 0.8 were considered small, moderate, and large. Compared with usual care, exercise had moderate effects on fatigue and a small effect on sleep quality (SMD, -0.47; 95% confidence interval [CI], -0.67 to -0.27; P<.001 and SMD, -0.17; 95% CI, -0.32 to -0.01; P=.04). RTs in which fatigue was the primary outcome were the most beneficial for lowering fatigue. Additionally, meditative exercise programs were the most effective for improving sleep quality. CONCLUSIONS: Exercise is moderately effective for lowering fatigue and has small effects on enhancing sleep quality in fibromyalgia. Meditative exercise programs may be considered for improving sleep quality in fibromyalgia.

Exercise and inflammation in coronary artery disease: A systematic review and meta-analysis of randomised trials.

Current evidence suggests that chronic inflammation contributes to the development of coronary artery disease (CAD). Interestingly, exercise may constitute a method of reducing inflammation in this patient population. As such, this systematic review and meta-analysis examined the evidence generated by randomised studies that investigated the effect of exercise on inflammatory biomarkers in CAD. Literature was sought from various sources. Outcomes were pooled in a random-effects model to calculate standardised mean differences (SMD) with 95% confidence intervals (CI). Twenty-five studies were reviewed; post-intervention C-reactive protein (SMD: -0.55 (95% CI: -0.93, -0.16), P = 0.005), fibrinogen (SMD: -0.52 (95% CI: -0.74, -0.29, P = <0.00001)), and von Willebrand factor (SMD: -1.57 (95% CI: -2.23, -0.92), P = <0.00001) values were significantly lower in exercise groups compared to controls. In addition, qualitative analyses identified evidence that supports a beneficial effect of exercise on these acute-phase reactants. However, the impact of exercise on anti-inflammatory cytokines, adhesion molecules, and chemokines is equivocal, which may be attributed to a paucity of research. Nevertheless, the findings of this review suggest that exercise induces an anti-inflammatory effect in CAD patients. Although, the quality of evidence needs to be improved by further randomised studies with high methodological qualities and large sample sizes.

Preceding exercise and postprandial hypertriglyceridemia: effects on lymphocyte cell DNA damage and vascular inflammation.

BACKGROUND: Exercise has proved effective in attenuating the unfavourable response normally associated with postprandial hypertriglyceridemia (PHTG) and accompanying oxidative stress. Yet, the acute effects of prior exercise and PHTG on DNA damage remains unknown. The purpose of this study was to examine if walking alters PHTG-induced oxidative damage and the interrelated inflammatory mechanisms. METHODS: Twelve apparently healthy, recreationally active, male participants (22.4 ± 4.1 years; 179.2 ± 6 cm; 84.2 ± 14.7 kg; 51.3 ± 8.6 ml·kg- 1·min- 1) completed a randomised, crossover study consisting of two trials: (1) a high-fat meal alone (resting control) or (2) a high-fat meal immediately following 1 h of moderate exercise (65% maximal heart rate). Venous blood samples were collected at baseline, immediately post-exercise or rest, as well as at 2, 4 and 6 h post-meal. Biomarkers of oxidative damage (DNA single-strand breaks, lipid peroxidation and free radical metabolism) and inflammation were determined using conventional biochemistry techniques. RESULTS: DNA damage, lipid peroxidation, free radical metabolism and triglycerides increased postprandially (main effect for time, p < 0.05), regardless of completing 1 h of preceding moderate intensity exercise. Plasma antioxidants (α-tocopherol and γ-tocopherol) also mobilised in response to the high-fat meal (main effect for time, p < 0.05), but no changes were detected for retinol-binding protein-4. CONCLUSION: The ingestion of a high fat meal induces postprandial oxidative stress, inflammation and a rise in DNA damage that remains unaltered by one hour of preceding exercise.

The acute effects of walking exercise intensity on systemic cytokines and oxidative stress.

PURPOSE: Oxidative stress is associated with tissue cytokine secretion although the precise mechanism(s) underpinning this relationship during high intensity intermittent exercise remains unclear. This study investigates the acute response to a bout of high intensity intermittent walking (HIIW), compared to continuous moderate intensity walking (CMW), on various cytokines and biomarkers of oxidative stress. METHODS: Seventeen (n = 17) apparently healthy male participants (aged 22.6 ± 4.6 years; [Formula: see text]: 53.7 ± 7.1 ml kg-1 min-1) undertook a randomised crossover study consisting of two exercise trials: (1) HIIW requiring 3 × 5 min bursts at 80% [Formula: see text] (each separated by 5 min of walking at 30% [Formula: see text]) and (2) CMW (60% [Formula: see text] for 30 min). Each trial was separated by 7 days. Venous blood samples were obtained pre-exercise, post-exercise and at 2, 4, 24 and 48 h post-exercise for determination of systemic inflammation (IL-6 and TNF-α), lipid soluble antioxidants and oxidative stress (LOOH, H2O2 and the ascorbyl free radical). RESULTS: Both IL-6 and TNF-α increased immediately post exercise, regardless of intensity and remained elevated until at least 4 h (main effect for time; p < 0.05). While there was no change in either lipid peroxidation or free radical metabolism (Asc· and H2O2), α-tocopherol increased (pooled HIIW and CMW, p < 0.05), whereas lycopene decreased at 2 h post HIIW (p < 0.05). CONCLUSION: Bouts of both HIIW and CMW promote cytokine secretion post exercise, and this seems to be independent of oxidative stress. Further investigation is required to assess how such changes may underpin some of the transient health benefits of exercise.

Extremely short duration interval exercise improves 24-h glycaemia in men with type 2 diabetes.

PURPOSE: Reduced-exertion high-intensity interval training (REHIT) is a genuinely time-efficient exercise intervention that improves aerobic capacity and blood pressure in men with type 2 diabetes. However, the acute effects of REHIT on 24-h glycaemia have not been examined. METHODS: 11 men with type 2 diabetes (mean ± SD: age, 52 ± 6 years; BMI, 29.7 ± 3.1 kg/m2; HbA1c, 7.0 ± 0.8%) participated in a randomised, four-trial crossover study, with continual interstitial glucose measurements captured during a 24-h dietary-standardised period following either (1) no exercise (CON); (2) 30 min of continuous exercise (MICT); (3) 10 × 1 min at ~ 90 HRmax (HIIT; time commitment, ~ 25 min); and (4) 2 × 20 s 'all-out' sprints (REHIT; time commitment, 10 min). RESULTS: Compared to CON, mean 24-h glucose was lower following REHIT (mean ± 95%CI: - 0.58 ± 0.41 mmol/L, p = 0.008, d = 0.55) and tended to be lower with MICT (- 0.37 ± 0.41 mmol/L, p = 0.08, d = 0.35), but was not significantly altered following HIIT (- 0.37 ± 0.59 mmol/L, p = 0.31, d = 0.35). This seemed to be largely driven by a lower glycaemic response (area under the curve) to dinner following both REHIT and MICT (- 11%, p < 0.05 and d > 0.9 for both) but not HIIT (- 4%, p = 0.22, d = 0.38). Time in hyperglycaemia appeared to be reduced with all three exercise conditions compared with CON (REHIT: - 112 ± 63 min, p = 0.002, d = 0.50; MICT: -115 ± 127 min, p = 0.08, d = 0.50; HIIT - 125 ± 122 min, p = 0.04, d = 0.54), whilst indices of glycaemic variability were not significantly altered. CONCLUSION: REHIT may offer a genuinely time-efficient exercise option for improving 24-h glycaemia in men with type 2 diabetes and warrants further study.

The effect of a classroom activity break on physical activity levels and adiposity in primary school children.

AIM: Despite recognition that regular physical activity is essential for good health, many children do not accumulate sufficient daily physical activity. The aim of this study was to examine the effect of a classroom-based activity break on accelerometer-determined moderate-to-vigorous intensity physical activity (MVPA) and adiposity in primary school children. METHODS: One hundred twenty children from seven primary schools in Northern Ireland participated in the study. In each school, one class of children was randomly assigned to an intervention group and another class to a control group. Teachers of the intervention classes led a 5-min activity break three times per day for 12 weeks. Accelerometer-determined MVPA, height, weight and four skinfolds were measured at baseline and post-intervention. RESULTS: Compared with the control group, the intervention group significantly increased weekday MVPA (+9.5 min) from baseline to post-intervention. There were no significant changes in BMI; however, an increase in sum-of-skinfolds of the intervention group was observed. CONCLUSIONS: Classroom-based activity breaks led by the teacher are successful in increasing children's physical activity levels. The programme shows a positive step in improving overall physical activity levels and contributing to the goal of 60 min daily MVPA.

The effects of aerobic exercise training at two different intensities in obesity and type 2 diabetes: implications for oxidative stress, low-grade inflammation and nitric oxide production.

AIMS: To investigate the effect of 16 weeks of aerobic training performed at two different intensities on nitric oxide (tNOx) availability and iNOS/nNOS expression, oxidative stress (OS) and inflammation in obese humans with or without type 2 diabetes mellitus (T2DM). METHODS: Twenty-five sedentary, obese (BMI > 30 kg/m2) males (52.8 ± 7.2 years); 12 controls versus 13 T2DM were randomly allocated to four groups that exercised for 30 min, three times per week either at low (Fat-Max; 30-40% VO(2max)) or moderate (T(vent); 55-65 % VO(2max)) intensity. Before and after training, blood and muscle samples (v. lateralis) were collected. RESULTS: Baseline erythrocyte glutathione was lower (21.8 ± 2.8 vs. 32.7 ± 4.4 nmol/ml) and plasma protein oxidative damage and IL-6 were higher in T2DM (141.7 ± 52.1 vs. 75.5 ± 41.6 nmol/ml). Plasma catalase increased in T2DM after T(vent) training (from 0.98 ± 0.22 to 1.96 ± 0.3 nmol/min/ml). T2DM groups demonstrated evidence of oxidative damage in response to training (elevated protein carbonyls). Baseline serum tNOx were higher in controls than T2DM (18.68 ± 2.78 vs. 12.34 ± 3.56 µmol/l). Training at T(vent) increased muscle nNOS and tNOx in the control group only. Pre-training muscle nNOS was higher in controls than in T2DMs, while the opposite was found for iNOS. No differences were found after training for plasma inflammatory markers. CONCLUSION: Exercise training did not change body composition or aerobic fitness, but improved OS markers, especially when performed at T(vent). Non-diabetics responded to T(vent) training by increasing muscle nNOS expression and tNOx levels in skeletal muscle while these parameters did not change in T2DM, perhaps due to higher insulin resistance (unchanged after intervention).

Redox signaling and skeletal muscle adaptation during aerobic exercise.

Redox regulation is a fundamental physiological phenomenon related to oxygen-dependent metabolism, and skeletal muscle is mainly regarded as a primary site for oxidative phosphorylation. Several studies have revealed the importance of reactive oxygen and nitrogen species (RONS) in the signaling process relating to muscle adaptation during exercise. To date, improving knowledge of redox signaling in modulating exercise adaptation has been the subject of comprehensive work and scientific inquiry. The primary aim of this review is to elucidate the molecular and biochemical pathways aligned to RONS as activators of skeletal muscle adaptation and to further identify the interconnecting mechanisms controlling redox balance. We also discuss the RONS-mediated pathways during the muscle adaptive process, including mitochondrial biogenesis, muscle remodeling, vascular angiogenesis, neuron regeneration, and the role of exogenous antioxidants.

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle.

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

Acute and chronic watercress supplementation attenuates exercise-induced peripheral mononuclear cell DNA damage and lipid peroxidation.

Pharmacological antioxidant vitamins have previously been investigated for a prophylactic effect against exercise-induced oxidative stress. However, large doses are often required and may lead to a state of pro-oxidation and oxidative damage. Watercress contains an array of nutritional compounds such as ß-carotene and α-tocopherol which may increase protection against exercise-induced oxidative stress. The present randomised controlled investigation was designed to test the hypothesis that acute (consumption 2 h before exercise) and chronic (8 weeks consumption) watercress supplementation can attenuate exercise-induced oxidative stress. A total of ten apparently healthy male subjects (age 23 (SD 4) years, stature 179 (SD 10) cm and body mass 74 (SD 15) kg) were recruited to complete the 8-week chronic watercress intervention period (and then 8 weeks of control, with no ingestion) of the experiment before crossing over in order to compete the single-dose acute phase (with control, no ingestion). Blood samples were taken at baseline (pre-supplementation), at rest (pre-exercise) and following exercise. Each subject completed an incremental exercise test to volitional exhaustion following chronic and acute watercress supplementation or control. The main findings show an exercise-induced increase in DNA damage and lipid peroxidation over both acute and chronic control supplementation phases (P< 0.05 v. supplementation), while acute and chronic watercress attenuated DNA damage and lipid peroxidation and decreased H2O2 accumulation following exhaustive exercise (P< 0.05 v. control). A marked increase in the main lipid-soluble antioxidants (α-tocopherol, γ-tocopherol and xanthophyll) was observed following watercress supplementation (P< 0.05 v. control) in both experimental phases. These findings suggest that short- and long-term watercress ingestion has potential antioxidant effects against exercise-induced DNA damage and lipid peroxidation.

A systematic review and meta-analysis of the SIRT1 response to exercise.

Sirtuin 1 (SIRT1) is a key physiological regulator of metabolism and a target of therapeutic interventions for cardiometabolic and ageing-related disorders. Determining the factors and possible mechanisms of acute and adaptive SIRT1 response to exercise is essential for optimising exercise interventions aligned to the prevention and onset of disease. Exercise-induced SIRT1 upregulation has been reported in animals, but, to date, data in humans have been inconsistent. This exploratory systematic review and meta-analysis aims to assess various exercise interventions measuring SIRT1 in healthy participants. A total of 34 studies were included in the meta-analysis (13 single bout exercise, 21 training interventions). Studies were grouped according to tissue sample type (blood, muscle), biomarkers (gene expression, protein content, enzyme level, enzyme activity), and exercise protocols. A single bout of high-intensity or fasted exercise per se increases skeletal muscle SIRT1 gene expression as measured by qPCR or RT-PCR, while repeated resistance training alone increases blood SIRT1 levels measured by ELISA. A limited number of studies also show a propensity for an increase in muscle SIRT1 activity as measured by fluorometric or sirtuin activity assay. In conclusion, exercise acutely upregulates muscle SIRT1 gene expression and chronically increases SIRT1 blood enzyme levels.

Proof of concept of prehabilitation: a combination of education and behavioural change, to promote physical activity in people with fibromyalgia.

OBJECTIVES: To establish proof of concept of a prehabilitation intervention, a combination of education and behavioural change, preceding a physical activity programme in people with fibromyalgia (FM). SETTINGS: Open-label, feasibility clinical trial. PARTICIPANTS: Eleven people with FM (10 women). INTERVENTIONS: The prehabilitation intervention consisted of 4 weeks, 1 weekly session (~1 to 1.5 hours), aimed to increase self-efficacy and understand why and how to engage in a gentle and self-paced physical activity programme (6 weeks of walking with telephone support). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was the acceptability and credibility of the intervention by means of the Credibility/Expectancy Questionnaire. Secondary outcomes comprised scales to measure FM severity, specific symptoms and sedentary behaviour. An exit interview was conducted to identify the strengths and weaknesses and barriers to the intervention. RESULTS: One participant dropped out due to finding the walking programme excessively stressful. Participants expected the intervention would improve their symptoms by 22%-38% but resulted in 5%-26% improvements. Participants would be confident in recommending this intervention to a friend who experiences similar problems. The interviews suggested that the fluctuation of symptoms should be considered as an outcome and that the prehabilitation intervention should accomodate these fluctuation. Additional suggestions were to incorporate initial interviews (patient-centred approach), to tailor the programmes to individuals' priorities and to offer a variety of physical activity programmes to improve motivation. CONCLUSIONS: This feasibility study demonstrated that our novel approach is acceptable to people with FM. Future interventions should pay attention to flexibility, symptoms fluctuation and patients support. TRIAL REGISTRATION NUMBER: NCT03764397.