Stimulating the sir2-pgc-1α axis rescues exercise capacity and mitochondrial respiration in Drosophila tafazzin mutants.

Cardiolipin (CL) is a phospholipid required for proper mitochondrial function. Tafazzin remodels CL to create highly unsaturated fatty acid chains. However, when tafazzin is mutated, CL remodeling is impeded, leading to mitochondrial dysfunction and the disease Barth syndrome. Patients with Barth syndrome often have severe exercise intolerance, which negatively impacts their overall quality of life. Boosting NAD+ levels can improve symptoms of other mitochondrial diseases, but its effect in the context of Barth syndrome has not been examined. We demonstrate for the first time that nicotinamide riboside (NR) can rescue exercise tolerance and mitochondrial respiration in a Drosophila tafazzin mutant and that the beneficial effects are dependent on sir2 and pgc-1α . Overexpressing pgc-1α increased the total abundance of cardiolipin in mutants. In addition, muscles and neurons were identified as key targets for future therapies because sir2 or pgc-1α overexpression in either of these tissues is sufficient to restore the exercise capacity of Drosophila tafazzin mutants.

The Impact of Elevated Body Core Temperature on Critical Power as Determined by a 3-min All-Out Test

Critical power (CP) delineates the heavy and severe exercise intensity domains, and sustained work rates above CP result in an inexorable progression of oxygen uptake to a maximal value and, subsequently, the limit of exercise tolerance. The finite work capacity above CP, W′, is defined by the curvature constant of the power-duration relationship. Heavy or severe exercise in a hot environment generates additional challenges related to the rise in body core temperature (Tc) that may impact CP and W′. The purpose of this study was to determine the effect of elevated Tc on CP and W′. CP and W′ were estimated by end-test power (EP; mean of final 30s) and work above end-test power (WEP), respectively, from 3-min "all-out" tests performed on a cycle ergometer. Volunteers (n = 8, 4 female) performed the 3-min tests during a familiarization visit and two experimental visits (Thermoneutral vs Hot, randomized crossover design). Before experimental 3-min tests, subjects were immersed in water (Thermoneutral: 36°C for 30 min; Hot: 40.5°C until Tc was ≥ 38.5°C). Mean Tc was significantly greater in Hot compared to Thermoneutral (38.5±0.0°C vs. 37.4±0.2°C; mean±SD, P<0.01). All 3-min tests were performed in an environmental chamber (Thermoneutral: 18°C, 45% RH; Hot: 38°C, 40% RH). EP was similar between Thermoneutral (239 ± 57W) and Hot (234 ± 66W; P = 0.55). WEP was similar between Thermoneutral (10.9 ± 3.0 kJ) and Hot (9.3 ± 3.6; P = 0.19). These results suggest that elevated Tc has no significant impact on EP or WEP.

Portable High-Flow Nasal Oxygen during Walking in Patients with Severe Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial

<b><i>Background:</i></b> High-flow nasal oxygen (HFNO) improves exercise capacity, oxygen saturation, and symptoms in patients with chronic obstructive pulmonary disease (COPD). Due to the need of electricity supply, HFNO has not been applied during free ambulation. <b><i>Objective:</i></b> We evaluated whether HFNO delivered during walking by a battery-supplied portable device was more effective than usual portable oxygen in improving exercise capacity in patients with COPD and severe exercise limitation. The effects on 6-min walking tests (6MWTs) were the primary outcome. <b><i>Methods:</i></b> After a baseline 6MWT, 20 stable patients requiring an oxygen inspiratory fraction (FiO₂) &#x3c;0.60 during exercise, randomly underwent 2 6MWT carrying a rollator, under either HFNO with a portable device (HFNO test) or oxygen supplementation by a Venturi mask (Control) at isoFiO₂. Walked distance, perceived dyspnea, pulse oximetry, and inspiratory capacity at end of the tests as well as patients’ comfort were compared between the tests. <b><i>Results:</i></b> As compared to baseline, walked distance improved significantly more in HFNO than in the control test (by 61.1 ± 37.8 and 39.7 ± 43.8 m, respectively, <i>p</i> = 0.01). There were no significant differences between the tests in dyspnea, peripheral oxygen saturation, or inspiratory capacity, but HFNO test was appreciated as more comfortable. <b><i>Conclusion:</i></b> In patients with COPD and severe exercise limitation, HFNO delivered by a battery-supplied portable device was more effective in improving walking distance than usual oxygen supplementation.

The Oxygen Uptake Plateau—A Critical Review of the Frequently Misunderstood Phenomenon

A flattening of the oxygen uptake–work rate relationship at severe exercise indicates the achievement of maximum oxygen uptake $$\left({\text{VO}}_{2\max } \right)$$ VO 2 max . Unfortunately, a distinct plateau $$\left( {{{\text{VO}}}_{2} {\text{pl}}} \right)$$ VO 2 pl at $${{\text{VO}}}_{2\max }$$ VO 2 max is not found in all participants. The aim of this investigation was to critically review the influence of research methods and physiological factors on the $${{\text{VO}}}_{2} {\text{pl}}$$ VO 2 pl incidence. It is shown that many studies used inappropriate definitions or methodical approaches to check for the occurrence of a $${{\text{VO}}}_{2} {\text{pl}}$$ VO 2 pl . In contrast to the widespread assumptions it is unclear whether there is higher $${{\text{VO}}}_{2} {\text{pl}}$$ VO 2 pl incidence in (uphill) running compared to cycling exercise or in discontinuous compared to continuous incremental exercise tests. Furthermore, most studies that evaluated the validity of supramaximal verification phases, reported verification bout durations, which are too short to ensure that $${{\text{VO}}}_{2\max }$$ VO 2 max have been achieved by all participants. As a result, there is little evidence for a higher $${{\text{VO}}}_{2} {\text{pl}}$$ VO 2 pl incidence and a corresponding advantage for the diagnoses of $${{\text{VO}}}_{2\max }$$ VO 2 max when incremental tests are supplemented by supramaximal verification bouts. Preliminary evidence suggests that the occurrence of a $${{\text{VO}}}_{2} {\text{pl}}$$ VO 2 pl in continuous incremental tests is determined by physiological factors like anaerobic capacity, $${{\text{VO}}}_{2}$$ VO 2 -kinetics and accumulation of metabolites in the submaximal intensity domain. Subsequent studies should take more attention to the use of valid $${{\text{VO}}}_{2} {\text{pl}}$$ VO 2 pl definitions, which require a cut-off at ~ 50% of the submaximal $${{\text{VO}}}_{2}$$ VO 2 increase and rather large sampling intervals. Furthermore, if verification bouts are used to verify the achievement of $${{\text{VO}}}_{{2{\text{peak}}}}$$ VO 2 peak /$${{\text{VO}}}_{2\max }$$ VO 2 max , it should be ensured that they can be sustained for sufficient durations.

The Balance of Muscle Oxygen Supply and Demand Reveals Critical Metabolic Rate and Predicts Time to Exhaustion

We tested the hypothesis that during whole body exercise, the balance between muscle O2supply and metabolic demand may elucidate intensity domains, reveal a critical metabolic rate, and predict time to exhaustion. Seventeen active, healthy volunteers (12 male, 5 female; 32±2 years) participated in two distinct protocols. Study 1 (N=7) consisted of constant work rate cycling in the moderate, heavy, and severe exercise intensity domains with concurrent measures of pulmonary VO2and local %SmO2(via NIRS) on quadriceps and forearm sites. Average %SmO2at both sites displayed a domain dependent response (P<0.05). A negative %SmO2slope was evident during severe domain exercise but was positive during exercise below critical power (CP) at both muscle sites. In study 2 (N=10), quadriceps and forearm site %SmO2was measured during 3 continuous running trials to exhaustion and 3 intermittent intensity (ratio = 60s severe: 30s lower intensity) trials to exhaustion. Intensity dependent negative %SmO2slopes were observed for all trials (P<0.05), and predicted zero slope at critical velocity. %SmO2accurately predicted depletion and repletion of %D´ balance on a second-by-second basis (R2= 0.99, P<0.05; both sites). Time to exhaustion predictions during continuous and intermittent exercise were either not different or better with %SmO2(SEE < 20.52sec for quad, < 44.03sec for forearm) vs running velocity (SEE < 65.76sec). Muscle O2balance provides a dynamic physiological delineation between sustainable and unsustainable exercise (consistent with a 'critical metabolic rate'), and predicts real time depletion and repletion of finite work capacity and time to exhaustion.

The effectiveness of supplemental oxygen during exercise training in patients with chronic obstructive pulmonary disease who show severe exercise-induced desaturation: a protocol for a meta-regression analysis and systematic review

Background Supplemental oxygen during exercise training is used to increase the training effect of an exercise program in patients with chronic obstructive pulmonary disease (COPD) who show exercise-induced desaturation. Exercise-induced desaturation is not clearly defined in the guidelines; however, it is generally defined in clinical studies as a decrease in SpO2 of more than 4% from rest or a decrease to less than 88% during exercise. Although some meta-analyses examined the effectiveness of supplemental oxygen during exercise training, these studies concluded that it does not further improve exercise tolerance compared to exercise training alone. However, supplemental oxygen during exercise training may be effective in improving exercise tolerance in COPD patients with severe exercise-induced desaturation. Therefore, this study will be performed to elucidate the effectiveness of supplemental oxygen during exercise training and the relationship between its effectiveness and severity of exercise-induced desaturation at baseline. Methods We will first assess the effectiveness of supplemental oxygen during exercise training in COPD. The main outcome is the change in exercise tolerance before and after the intervention, indicated by the 6-min walking distance, the walking distance, or the walking time in incremental shuttle walking test, and analyzed as the standardized mean difference (SMD). The quality and risk of bias in individual studies will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system and risk-of-bias tool (RoB ver.2). If statistical heterogeneity in terms of the effectiveness of exercise tolerance is shown, we will conduct meta-regression analyses to examine the association between the effectiveness of exercise training with supplemental oxygen and severity of exercise-induced desaturation at baseline. Discussion One strength of this study is that it is a systematic review with meta-regression analysis to elucidate the effectiveness of supplemental oxygen during exercise training in patients with COPD who show severe exercise-induced desaturation. Furthermore, we will assess the severity of exercise-induced desaturation for which exercise training with supplemental oxygen is effective, the influence of acute effects at baseline, and the effect of supplemental oxygen on adverse events. Systematic review registration Registration number, UMIN000039960.

Effects of Normobaric Hypoxia on Matched-severe Exercise and Power-duration Relationship

We investigated the effects of hypoxia on matched-severe intensity exercise and on the parameters of the power-duration relationship. Fifteen trained subjects performed in both normoxia and normobaric hypoxia (FiO2=0.13, ~3000 m) a maximal incremental test, a 3 min all-out test (3AOT) and a transition from rest to an exercise performed to exhaustion (Tlim) at the same relative intensity (80%∆). Respiratory and pulmonary gas-exchange variables were continuously measured (K5, Cosmed, Italy). Tlim test’s V̇O2 kinetics was calculated using a two-component exponential model. V̇O2max (44.1±5.1 vs. 58.7±6.4 ml.kg-1.min-1, p<0.001) was decreased in hypoxia. In Tlim, time-to-exhaustion sustained was similar (454±130 vs. 484±169 s) despite that V̇O2 kinetics was slower (τ1: 31.1±5.8 vs. 21.6±4.7 s, p<0.001) and the amplitude of the V̇O2 slow component lower (12.4±5.4 vs. 20.2±5.7 ml.kg-1.min-1, p<0.05) in hypoxia. CP was reduced (225±35 vs. 270±49 W, p<0.001) but W’ was unchanged (11.3±2.9 vs. 11.4±2.7 kJ) in hypoxia. The changes in CP/V̇O2max were positively correlated with changes in W’ (r = 0.58, p<0.05). The lower oxygen availability had an impact on aerobic related physiological parameters, but exercise tolerance is similar between hypoxia and normoxia when the relative intensity is matched despite a slower V̇O2 kinetics in hypoxia.