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Less than 7% of the world's population live at an altitude above 1500 m. Yet, as many as 67% of medalists in the 2020 men's and women's Olympic marathon, and 100% of medalists in the 2020 men's and women's Olympic 5000 m track race may have been born or raised above this otherwise rare threshold. As a possible explanation, research spanning nearly a quarter of a century demonstrates that indigenous highlanders exhibit pulmonary adaptations distinct from their lowland counterparts. These adaptations may then promote endurance performance. Indeed, healthy indigenous highlanders often exhibit a larger aerobic exercise capacity compared to sea-level residents who travel to high altitude. However, questions remain on whether high-altitude birth is advantageous for sea-level competitions. In this review, we ask whether being born at a high altitude generates an ergogenic advantage for endurance performance in the Summer Olympics-a venue that is generally held at sea level. In so doing, we distinguish between three groups of high-altitude residents: (i) the indigenous highlander, (ii) the highland newcomer, and (iii) the highland sojourner. Concentrating specifically on altitude-induced alterations to pulmonary physiology beginning in the perinatal period, we propose that if altitude-related maladaptations are avoided, genomic and developmental alterations accompanying highland birth may present benefits for endurance competitions at sea level., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Eccentric muscle contractions can cause structural damage to muscle cells resulting in temporarily decreased muscle force production and soreness. Prior work indicates pasture-raised dairy products from grass-fed cows have greater anti-inflammatory and antioxidant properties compared to grain-fed counterparts. However, limited research has evaluated the utility of whey protein from pasture-raised, grass-fed cows to enhance recovery compared to whey protein from non-grass-fed cows. Therefore, using a randomized, placebo-controlled design, we compared the effect of whey protein from pasture-raised, grass-fed cows (PRWP) to conventional whey protein (CWP) supplementation on indirect markers of muscle damage in response to eccentric exercise-induced muscle damage (EIMD) in resistance-trained individuals. Thirty-nine subjects (PRWP, n  = 14; CWP, n  = 12) completed an eccentric squat protocol to induce EIMD with measurements performed at 24, 48, and 72 h of recovery. Dependent variables included: delayed onset muscle soreness (DOMS), urinary titin, maximal isometric voluntary contraction (MIVC), potentiated quadriceps twitch force, countermovement jump (CMJ), and barbell back squat velocity (BBSV). Between-condition comparisons did not reveal any significant differences ( p  ≤ 0.05) in markers of EIMD via DOMS, urinary titin, MIVC, potentiated quadriceps twitch force, CMJ, or BBSV. In conclusion, neither PRWP nor CWP attenuate indirect markers of muscle damage and soreness following eccentric exercise in resistance-trained individuals.

Increasing evidence indicates that dietary nitrate supplementation has the potential to increase muscular power output during skeletal muscle contractions. However, there is still a paucity of data characterizing the impact of different nitrate dosing regimens on nitric oxide bioavailability its potential ergogenic effects across various population groups. This narrative review discusses the potential influence of different dietary nitrate supplementation strategies on nitric oxide bioavailability and muscular power output in healthy adults, athletes, older adults and some clinical populations. Areas for further research are also recommended including a focus individualized nitrate dosing regimens to optimize nitric oxide bioavailability and to promote muscular power enhancements in different populations., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Wearable devices represent one of the most popular trends in health and fitness. Rapid advances in wearable technology present a dizzying display of possible functions: from thermometers and barometers, magnetometers and accelerometers, to oximeters and calorimeters. Consumers and practitioners utilize wearable devices to track outcomes, such as energy expenditure, training load, step count, and heart rate. While some rely on these devices in tandem with more established tools, others lean on wearable technology for health-related outcomes, such as heart rhythm analysis, peripheral oxygen saturation, sleep quality, and caloric expenditure. Given the increasing popularity of wearable devices for both recreation and health initiatives, understanding the strengths and limitations of these technologies is increasingly relevant. Need exists for continued evaluation of the efficacy of wearable devices to accurately and reliably measure purported outcomes. The purposes of this review are (1) to assess the current state of wearable devices using recent research on validity and reliability, (2) to describe existing gaps between physiology and technology, and (3) to offer expert interpretation for the lay and professional audience on how best to approach wearable technology and employ it in the pursuit of health and fitness. Current literature demonstrates inconsistent validity and reliability for various metrics, with algorithms not publicly available or lacking high-quality validation studies. Advancements in wearable technology should consider standardizing validation metrics, providing transparency in used algorithms, and improving how technology can be tailored to individuals. Until then, it is prudent to exercise caution when interpreting metrics reported from consumer-wearable devices., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Inspiratory muscle training (IMT) has been studied as a rehabilitation tool and ergogenic aid in clinical, athletic, and healthy populations. This technique aims to improve respiratory muscle strength and endurance, which has been seen to enhance respiratory pressure generation, respiratory muscle weakness, exercise capacity, and quality of life. However, the effects of IMT have been discrepant between populations, with some studies showing improvements with IMT and others not. This may be due to the use of standardized IMT protocols which are uniformly applied to all study participants without considering individual characteristics and training needs. As such, we suggest that research on IMT veer away from a standardized, one-size-fits-all intervention, and instead utilize specific IMT training protocols. In particular, a more personalized approach to an individual's training prescription based upon goals, needs, and desired outcomes of the patient or athlete. In order for the coach or practitioner to adjust and personalize a given IMT prescription for an individual, factors, such as frequency, duration, and modality will be influenced, thus inevitably affecting overall training load and adaptations for a projected outcome. Therefore, by integrating specific methods based on optimization, periodization, and personalization, further studies may overcome previous discrepancies within IMT research., Competing Interests: R-JS is an employee of Mallinckrodt Pharmaceuticals. The work described herein is solely reflective of the author’s personal views and is unrelated to his job duties with Mallinckrodt Pharmaceuticals. These views do not constitute an endorsement by Mallinckrodt Pharmaceuticals, do not represent the views of Mallinckrodt Pharmaceuticals, and Mallinckrodt Pharmaceuticals had no role in the conception, writing, revision, or final approval of the manuscript. The author may or may not hold stock in Mallinckrodt Pharmaceuticals, and does not have any other financial relationships or conflicts to disclose. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shei, Paris, Sogard and Mickleborough.)

Hypoxia impairs aerobic performance by accelerating fatiguing processes. These processes may originate from sites either distal (peripheral) or proximal (central) to the neuromuscular junction, though these are not mutually exclusive. Peripheral mechanisms include decrements in muscle glycogen or fluctuations in intramuscular metabolites, whereas central responses commonly refer to reductions in central motor drive elicited by alterations in blood glucose and neurotransmitter concentrations as well as arterial hypoxemia. Hypoxia may accelerate both peripheral and central pathways of fatigue, with the level of hypoxia strongly dictating the degree and primary locus of impairment. As more people journey to hypoxic settings for work and recreation, developing strategies to improve work capacity in these environments becomes increasingly relevant. Given that sea level performance improves with nutritional interventions such as carbohydrate (CHO) ingestion, a similar strategy may prove effective in delaying fatigue in hypoxia, particularly considering how the metabolic pathways enhanced with CHO supplementation overlap the fatiguing pathways upregulated in hypoxia. Many questions regarding the relationship between CHO, hypoxia, and fatigue remain unanswered, including specifics on when to ingest, what to ingest, and how varying altitudes influence supplementation effectiveness. Therefore, the purpose of this narrative review is to examine the peripheral and central mechanisms contributing to fatigue during aerobic exercise at varying degrees of hypoxia and to assess the role of CHO ingestion in attenuating fatigue onset.

Baranauskas, Marissa N., Joseph Powell, Alyce D. Fly, Bruce J. Martin, Timothy D. Mickleborough, Hunter L. Paris, and Robert F. Chapman. Influence of zinc on the acute changes in erythropoietin and proinflammatory cytokines with hypoxia. High Alt Med Biol . 22: 148-156, 2021. Background: Considerable, unexplained, interindividual variability characterizes the erythropoietin (EPO) response to hypoxia, which can impact hematological acclimatization for individuals sojourning to altitude. Zinc supplementation has the potential to alter EPO by attenuating increases in inflammation and oxidative stress. Yet, the application of such an intervention has not been evaluated in humans. In this proof-of-concept study, we aimed to evaluate the EPO and inflammatory responses to acute hypoxia in human participants following chronic zinc supplementation. Methods: Nine physically active participants (men n  = 5, women n  = 4, age 28 ± 4 years, height 176 ± 11 cm, mass 77 ± 21 kg) were exposed to 12 hours of normobaric hypoxia simulating an altitude of 3,000 m (F i O 2  = 0.14) before and after 8 weeks of supplementation with 40 mg/day of elemental zinc from picolinate. Blood samples for subsequent analysis of serum zinc, EPO, superoxide dismutase (extracellular superoxide dismutase [EC-SOD]), C-reactive protein (CRP), and proinflammatory cytokines were obtained pre- and postsupplementation and exposure to hypoxia. Results: After zinc supplementation, EPO increased by 64.9 ± 36.0% (mean ± standard deviation) following 12 hours of hypoxia, but this response was not different from presupplementation (70.8 ± 46.1%). Considerable interindividual (range: -1% to +208%) variability was apparent in the acute EPO response. While most markers of inflammation did not change with hypoxia, interleukin-6 concentrations increased from 1.17 ± 0.05 to 1.97 ± 0.32 pg/ml during the final 6 hours. The acute EPO response at 12 hours was not related to changes in serum zinc, EC-SOD, CRP, or proinflammatory cytokines. Conclusions: Zinc supplementation does not influence the acute EPO or inflammatory response with short-term exposure to moderate levels of normobaric hypoxia (3,000 m) in apparently healthy young adults.

Environmental stressors, such as heat or altitude, elicit dissimilar physiological adaptations to endurance training programs. Whether these differences (i.e., increased hemoglobin mass vs plasma volume) differentially influence performance is debated. We review data in support of our novel hypothesis, which proposes altitude as the preferred environmental training stimulus for elite endurance athletes preparing to compete in temperate, sea-level climates (5°C-18°C).

Purpose: This study aimed to determine if preexisting respiratory muscle fatigue (RMF) alters motoneuronal output, locomotor muscle fatigue, and cycling performance., Methods: Eight trained male cyclists performed 5-km cycling time trials after a resistive breathing task that induced RMF and under control conditions (CON). Motoneuronal output was estimated using vastus lateralis surface electromyography, and locomotor muscle fatigue was quantified as the change in potentiated quadriceps twitch force from preexercise to postexercise., Results: Time to complete the time trial was 1.9% ± 0.9% longer in RMF compared with CON (P < 0.001). Estimated motoneuronal output was lower in RMF compared with CON during 1 km (45% ± 11% vs 53% ± 13%, P = 0.004) and 2 km (45% ± 14% vs 51% ± 14%, P = 0.008), but was not different thereafter. Ventilation was lower in RMF compared with CON during 1 km (114 ± 19 vs 135 ± 24 L·min, P = 0.003) and 2 km (136 ± 23 vs 152 ± 31 L·min, P = 0.009); however, ratings of dyspnea were similar. After the 5-km time trial, locomotor muscle fatigue was attenuated in RMF compared with CON (-22% ± 6%, vs -28% ± 7%, P = 0.02)., Conclusions: Alterations to dyspnea for a given ventilation seem to have constrained power output during cycling exercise, thereby limiting the development of locomotor muscle fatigue. These findings indicate that the respiratory system is an integral component in a global feedback loop that regulates exercise performance and the development of locomotor muscle fatigue.

Objective: The purpose of this study was to investigate the effects of "train-high sleep-low" (THSL) dietary periodization on ventilatory strategies during cycling exercise at submaximal and maximal intensities. Method: In a randomized crossover design, 8 trained men [age (mean ± SEM) = 28 ± 1 y; peak oxygen uptake = 56.8 ± 2.4 mL kg -1 min -1 ] completed two glycogen-depleting protocols on a cycle ergometer on separate days, with the cycling followed by a low carbohydrate (CHO) meal and beverages containing either no additional CHO (THSL) or beverages containing 1.2 g kg -1 CHO [traditional CHO replacement (TRAD)]. The following morning, participants completed 4 minutes of cycling below (Stage 1), at (Stage 2), and above (Stage 3) gas exchange threshold, followed by a 5-km time trial. Results: Timetrial performance was significantly faster in TRAD compared to THSL (8.7 ± 0.3 minutes and 9.0 ± 0.3 minutes, respectively; p  = 0.02). No differences in ventilation, tidal volume, or carbon dioxide production occurred between conditions at any exercise intensity ( p  > 0.05). During Stage 1, oxygen uptake was 37.9 ± 1.5 mL kg -1 min -1 in the TRAD condition and 39.6 ± 1.8 mL kg -1 min -1 in THSL ( p  = 0.05). During Stage 2, VO2 was 44.6 ± 1.7 mL kg -1 min -1 in the TRAD condition and 47.0 ± 1.9 mL kg -1 min -1 in THSL ( p  = 0.07). No change in operating lung volume was detected between dietary conditions ( p  > 0.05). Conclusions: THSL impairs performance following the dietary intervention, but this occurs with no alteration of ventilatory measures.

Long-term maintenance of weight loss requires sustained energy balance at the reduced body weight. This could be attained by coupling low total daily energy intake (TDEI) with low total daily energy expenditure (TDEE; low energy flux), or by pairing high TDEI with high TDEE (high energy flux). Within an environment characterized by high energy dense food and a lack of need for movement, it may be particularly difficult for weight-reduced individuals to maintain energy balance in a low flux state. Most of these individuals will increase body mass due to an inability to sustain the necessary level of food restriction. This increase in TDEI may lead to the re-establishment of high energy flux at or near the original body weight. We propose that following weight loss, increasing physical activity can effectively re-establish a state of high energy flux without significant weight regain. Although the effect of extremely high levels of physical activity on TDEE may be constrained by compensatory reductions in non-activity energy expenditure, moderate increases following weight loss may elevate energy flux and encourage physiological adaptations favorable to weight loss maintenance, including better appetite regulation. It may be time to recognize that few individuals are able to re-establish energy balance at a lower body weight without permanent increases in physical activity. Accordingly, there is an urgent need for more research to better understand the role of energy flux in long-term weight maintenance.

Introduction: Ischemic preconditioning (IPC) before exercise has been shown to be a novel approach to improve performance in different exercise modes in normoxia (NORM). Few studies have been conducted examining potential mechanisms behind these improvements, and less has been done examining its influence during exercise in hypoxia (HYP). Oxygen uptake and extraction kinetics are factors that have been implicated as possible determinants of cycling performance. We hypothesized that IPC would lead to improvements in oxygen extraction and peripheral blood flow kinetics, and this would translate to improvements in cycling time trial (TT) performance in both NORM and HYP., Methods: Thirteen men (age, 24 ± 7 yr; V˙O2max, 63.1 ± 5.1 mL·kg·min) participated in the study. Subjects completed trials of each combination of normobaric HYP (FiO2 = 0.16, simulating ~8000 ft/2500 m) or NORM (FiO2 = 0.21) with preexercise IPC protocol (4 × 5 min at 220 mm Hg) or SHAM procedure. Trials included submaximal constant load cycle exercise bouts (power outputs of 15% below gas exchange threshold, and 85% of V˙O2max), and a 5-km cycling performance TT., Results: Ischemic preconditioning significantly improved 5-km TT time in NORM by 0.9% ± 1.8% compared with SHAM (IPC, 491.2 ± 35.2 s vs SHAM, 495.9 ± 36.0 s; P < 0.05). Ischemic preconditioning did not alter 5-km TT performance times in HYP (P = 0.231). Ischemic preconditioning did, however, improve tissue oxygen extraction in HYP (deoxygenated hemoglobin/myoglobin: IPC, 21.23 ± 10.95 μM; SHAM, 19.93 ± 9.91 μM; P < 0.05) during moderate-intensity exercise., Conclusions: Our data confirm that IPC is an effective ergogenic aid for athletes performing 5-km cycling TT bouts in NORM. Ischemic preconditioning did mitigate the declines in tissue oxygen during moderate-intensity exercise in HYP, but this did not translate to a significant effect on mean group performance. These data suggest that IPC may be of benefit for athletes training and competing in NORM.

To determine whether acute exposure to moderate hypoxia alters central and peripheral fatigue and to test whether carbohydrate ingestion impacts fatigue characteristics, 12 trained runners completed three running trials lasting 1 h each at 65% of normoxic maximum oxygen uptake. The first trial was performed in normoxia [inspired O 2 fraction ( F i O 2 ) = 0.21], and the last two trials were completed in hypoxia ( F i O 2  = 0.15). Participants ingested a placebo drink in normoxia (NORM-PLA), a placebo drink in hypoxia (HYP-PLA), or a carbohydrate solution in hypoxia (HYP-CHO). HYP conditions were randomized. Peripheral [change in potentiated quadriceps twitch force (ΔQ tw,pot )] and central [change in voluntary activation (ΔVA)] fatigue were assessed via preexercise-to-postexercise changes in magnetically evoked quadriceps twitch. In HYP, blood was drawn to determine the ratio of free-tryptophan (f-TRP) to branched-chain amino acids (BCAA). After exercise, peripheral fatigue was reduced to a similar degree in normoxia and hypoxia (ΔQ tw,pot  = -4.5 ± 1.3% and -4.0 ± 1.5% in NORM-PLA and HYP-PLA, respectively; P = 0.61). Central fatigue was present after normoxic and hypoxic exercise but to a greater degree in HYP-PLA compared with NORM-PLA (ΔVA: -4.7 ± 0.9% vs. -1.9 ± 0.7%; P < 0.01). Carbohydrate ingestion did not influence central fatigue (ΔVA in HYP-CHO: -5.7 ± 1.2%; P = 0.51 vs. HYP-PLA). After exercise, no differences were observed in the ratio of f-TRP to BCAA between HYP-PLA and HYP-CHO ( P = 0.67). Central fatigue increased during prolonged running exercise in moderate hypoxia although the ratio of f-TRP to BCAA remained unchanged. Ingesting carbohydrates while running in hypoxia did not influence fatigue development. NEW & NOTEWORTHY Hypoxic exposure influences the origin of exercise-induced fatigue and the rate of fatigue development depending on the severity of hypoxia. Our data suggest that moderate hypoxia increases central, but not peripheral, fatigue in trained runners exercising at 65% of normoxic maximum oxygen uptake. The increase in central fatigue was unaffected by carbohydrate intake and occurred although the ratio of free tryptophan to branched-chain amino acids remained unchanged.

Shei, R-J, Paris, HL, Beck, CP, Chapman, RF, and Mickleborough, TD. Repeated high-intensity cycling performance is unaffected by timing of carbohydrate ingestion. J Strength Cond Res 32(8): 2243-2249, 2018-To determine whether carbohydrate (CHO) feeding taken immediately before, early, or late in a series of high-intensity cycling exercises affected cycling performance. A total of 16 trained, male cyclists (>6 hours postprandial) performed 3-, 4-km cycling time trials (TT1, TT2, and TT3) separated by 15 minutes of active recovery on 4 separate occasions. Carbohydrate feeding (80 g) was given either before TT1 (PRE1), before TT2 (PRE2), before TT3 (PRE3), or not at all (control, CTL). Treatment order was randomized. Sweet placebo was given before the other TTs. Blood glucose (BG) concentration was measured before each trial. Mean power output (Pmean) and time to completion (TTC) were recorded. Pmean was higher in TT1 compared with TT2 (p = 0.001) and TT3 (p = 0.004) in all conditions, but no differences were observed between treatments. Time to completion was lower in TT1 compared with TT2 (p = 0.01), but no other differences in TTC (within or between treatments) were observed. Within CTL and PRE1, BG did not differ between TT1, TT2, and TT3. In PRE2, BG was significantly higher in TT2 compared with TT1 (p = 0.006), in TT3 compared with TT1 (p = 0.001), and in TT3 compared with TT2 (p = 0.01). In PRE3, BG was significantly higher in TT3 compared with TT1 and TT2 (p = 0.001 for both). Given that performance was not influenced by the timing of CHO ingestion, athletes engaging in repeated, high-intensity cycling exercise do not need to ingest CHO before- or between-exercise bouts; furthermore, athletes should refrain from ingesting CHO between bouts if they wish to avoid a rise in BG.

To determine whether acute exposure to simulated moderate altitude alters locomotor-respiratory coupling (LRC) patterns in runners, 13 trained male distance runners performed a running economy and maximal oxygen uptake (V̇o 2max ) test in normoxia (NORM) and hypoxia (HYP) ([Formula: see text]= 15.8%; ~2,400 m/8,000 ft) on separate days. Running economy (RE), the degree of LRC, stride frequency-to-breathing frequency quotients (SF/f b ), ratings of perceived exertion (RPE), and dyspnea were assessed at three common submaximal speeds and V̇o 2max . SF/f b were significantly lower at each submaximal speed in HYP (12.9 km/h: 2.91 ± 0.20 vs. 2.45 ± 0.17, 14.3 km/h: 2.53 ± 0.17 vs. 2.21 ± 0.14, 16.1 km/h: 2.22 ± 0.14 vs. 1.95 ± 0.09; P < 0.05). The degree of LRC (range: 36-99%) in HYP was not significantly different than NORM at any of the three common submaximal speeds. However, the degree of LRC was significantly higher at V̇o 2max in HYP than NORM (43.8 ± 3.4% vs. 57.1 ± 3.8%; P < 0.05). RE and RPE were similar at all running speeds. Dyspnea was significantly greater in HYP compared with NORM at 16.1 km/h ( P < 0.05). Trained distance runners are able to maintain LRC in HYP, despite increases in breathing frequency. Within this unique population, years of training may enhance and optimize the ability to maintain LRC to minimize metabolic costs and dyspnea. NEW & NOTEWORTHY Exposure to acute altitude causes increases in ventilation at rest and any submaximal exercising workload, which may alter locomotor-respiratory coupling (LRC). Our data suggest that trained distance runners can maintain LRC during acute exposure to simulated moderate altitude, even when breathing frequency is increased at any submaximal pace.

Rinsing the mouth with a carbohydrate solution has been shown to improve exercise performance in a manner similar to carbohydrate ingestion. However, the underlying mechanisms behind these ergogenic benefits remain unclear. This study evaluated whether rinsing the mouth with a carbohydrate solution alters plasma insulin and glucose concentration during the initial stages of a 40 km cycling time-trial. Eight trained, competitive cyclists [age (mean ± SEM) = 24 ± 2 y; V̇O 2 max = 64.5 ± 2.2 ml·kg -1 ·min -1 ] completed three simulated 40 km time-trials comprised of a familiarization trial, a carbohydrate condition (CHO) and a placebo mouth rinse condition (PLA). In the two mouth rinse conditions, rinsing was administered prior to onset of exercise and every 5 km throughout exercise. Plasma insulin was collected at 5 km intervals throughout the first 25 km, and glucose samples were collected at 5 km intervals throughout the exercise bout. No change in plasma insulin was detected between conditions (p = 0.638, ES < 0.03) for the first 25 km of the time-trial. Likewise, plasma glucose concentration did not differ between CHO and PLA (p = 0.801, ES < 0.01) and remained relatively stable throughout exercise. Time to complete the 40 km time-trial was significantly faster for CHO (67.1 ± 1.1 min) compared to PLA [67.9 ± 1.0 min; (P = 0.028, ES 0.27)]. Performance time was faster by an average of 1.1% (95% confidence interval range 0.2-2.0%) in the CHO condition. Exercise intensity (% V̇O 2 max) throughout the trial was similar between conditions (p = 0.846). Respiratory exchange ratio was not significantly different between conditions (0.88 ± 0.01 for PLA, and 0.91 ± 0.01 for GLC; p = 0.081). Performance gains elicited by a carbohydrate mouth rinse occurred independently of changes in plasma insulin concentration.

Metformin augments glucose/glycogen regulation and may acutely promote fatigue resistance during high-intensity exercise. In hypobaric environments, such as high altitude, the important contribution of carbohydrates to physiological function is accentuated as glucose/glycogen dependence is increased. Because hypoxia/hypobaria decreases insulin sensitivity, replenishing skeletal muscle glycogen in high altitude becomes challenging and subsequent physical performance may be compromised. We hypothesized that in conditions where glycogen repletion was critical to physical outcomes, metformin would attenuate hypoxia-mediated decrements in exercise performance. On three separate randomly ordered occasions, 13 healthy men performed glycogen-depleting exercise and ingested a low-carbohydrate dinner (1200 kcals, <10% carbohydrate). The next morning, in either normoxia or hypoxia (FiO 2 =0.15), they ingested a high-carbohydrate breakfast (1225 kcals, 70% carbohydrate). Placebo (719 mg maltodextrin) or metformin (500 mg BID) was consumed 3 days prior to each hypoxia visit. Subjects completed a 12.5 km cycle ergometer time trial 3.5 hours following breakfast. Hypoxia decreased resting and exercise oxyhemoglobin saturation (P<.001). Neither hypoxia nor metformin affected the glucose response to breakfast (P=.977), however, compared with placebo, metformin lowered insulin concentration in hypoxia 45 minutes after breakfast (64.1±6.6 μU/mL vs 48.5±7.8 μU/mL; mean±SE; P<.001). Post-breakfast, pre-exercise vastus lateralis glycogen content increased in normoxia (+33%: P=.025) and in hypoxia with metformin (+81%; P=.006), but not in hypoxia with placebo (+27%; P=.167). Hypoxia decreased time trial performance compared with normoxia (P<.01). This decrement was similar with placebo (+2.6±0.8 minutes) and metformin (+1.6±0.3 minutes). These results indicate that metformin promotes glycogen synthesis but not endurance exercise performance in healthy men exposed to simulated high altitude., (© 2017 John Wiley & Sons Australia, Ltd.)

Metabolic adaptations occur with weight loss that result in increased hunger with discordant simultaneous reductions in energy requirements-producing the so-called energy gap in which more energy is desired than is required. The increased hunger is associated with elevation of the orexigenic hormone ghrelin and decrements in anorexigenic hormones. The lower total daily energy expenditure with diet-induced weight loss results from (1) a disproportionately greater decrease in circulating leptin and resting metabolic rate (RMR) than would be predicted based on the decline in body mass, (2) decreased thermic effect of food (TEF), and (3) increased energy efficiency at work intensities characteristic of activities of daily living. These metabolic adaptations can readily promote weight regain. While more experimental research is needed to identify effective strategies to narrow the energy gap and attenuate weight regain, some factors contributing to long-term weight loss maintenance have been identified. Less hunger and greater satiation have been associated with higher intakes of protein and dietary fiber, and lower glycemic load diets. High levels of physical activity are characteristic of most successful weight maintainers. A high energy flux state characterized by high daily energy expenditure and matching energy intake may attenuate the declines in RMR and TEF, and may also result in more accurate regulation of energy intake to match daily energy expenditure.

Insulin resistance and obesity are characterized by low nitric oxide (NO) bioavailability. Insulin sensitivity is improved with stimulation of NO generating pathways. Consumption of dietary nitrate (NO 3 - ) increases NO formation, via NO 3 - reduction to nitrite (NO 2 - ) by oral bacteria. We hypothesized that acute dietary nitrate (beet juice) ingestion improves insulin sensitivity in obese but not in nonobese adults. 12 nonobese (body mass index: 26.3 ± 0.8 kg/m 2 (mean ± SE)) and 10 obese adults (34.0 ± 0.8 kg/m 2 ) ingested beet juice, supplemented with 25 g of glucose (carbohydrate load: 75 g), with and without prior use of antibacterial mouthwash to inhibit NO 3 - reduction to NO 2 - . Blood glucose concentrations after beet juice and glucose ingestion were greater in obese compared with nonobese adults at 60 and 90 minutes ( P = 0.004). Insulin sensitivity, as represented by the Matsuda Index (where higher values reflect greater insulin sensitivity), was lower in obese compared with nonobese adults ( P = 0.009). Antibacterial mouthwash rinsing decreased insulin sensitivity in obese (5.7 ± 0.7 versus 4.9 ± 0.6) but not in nonobese (8.1 ± 1.0 versus 8.9 ± 0.9) adults ( P = 0.048). In conclusion, insulin sensitivity was improved in obese but not in nonobese adults following coingestion of beet juice and glucose when oral bacteria nitrate reduction was not inhibited. Obese adults may benefit from ingestion of healthy nitrate-rich foods during meals., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Asthma is a pathological condition comprising of a variety of symptoms which affect the ability to function in daily life. Due to the high prevalence of asthma and associated healthcare costs, it is important to identify low-cost alternatives to traditional pharmacotherapy. One of these low cost alternatives is the use of inspiratory muscle training (IMT), which is a technique aimed at increasing the strength and endurance of the diaphragm and accessory muscles of respiration. IMT typically consists of taking voluntary inspirations against a resistive load across the entire range of vital capacity while at rest. In healthy individuals, the most notable benefits of IMT are an increase in diaphragm thickness and strength, a decrease in exertional dyspnea, and a decrease in the oxygen cost of breathing. Due to the presence of expiratory flow limitation in asthma and exercise-induced bronchoconstriction, dynamic lung hyperinflation is common. As a result of varying operational lung volumes, due in part to hyperinflation, the respiratory muscles may operate far from the optimal portion of the length-tension curve, and thus may be forced to operate against a low pulmonary compliance. Therefore, the ability of these muscles to generate tension is reduced, and for any given level of ventilation, the work of breathing is increased as compared to non-asthmatics. Evidence that IMT is an effective treatment for asthma is inconclusive, due to limited data and a wide variation in study methodologies. However, IMT has been shown to decrease dyspnea, increase inspiratory muscle strength, and improve exercise capacity in asthmatic individuals. In order to develop more concrete recommendations regarding IMT as an effective low-cost adjunct in addition to traditional asthma treatments, we recommend that a standard treatment protocol be developed and tested in a placebo-controlled clinical trial with a large representative sample.

Intravenous administration of vitamin C has been shown to decrease oxidative stress and, in some instances, improve physiological function in adult humans. Oral vitamin C administration is typically less effective than intravenous, due in part to inferior vitamin C bioavailability. The purpose of this study was to determine the efficacy of oral delivery of vitamin C encapsulated in liposomes. On 4 separate randomly ordered occasions, 11 men and women were administered an oral placebo, or 4 g of vitamin C via oral, oral liposomal, or intravenous delivery. The data indicate that oral delivery of 4 g of vitamin C encapsulated in liposomes (1) produces circulating concentrations of vitamin C that are greater than unencapsulated oral but less than intravenous administration and (2) provides protection from ischemia-reperfusion-mediated oxidative stress that is similar to the protection provided by unencapsulated oral and intravenous administrations.

Objective: Weight loss induces compensatory biological adjustments that increase hunger and decrease resting metabolic rate (RMR), which increase propensity for weight regain. In non-obese adults high levels of physical activity coupled with high energy intake (high energy flux) are associated with higher RMR and reduced hunger. We tested the possibility that a high flux state attenuates the increase in hunger and the decrease in RMR characteristic of diet-induced weight loss., Methods: Six obese adults [age (mean ± SE) = 42 ± 12 y; body mass index (BMI) = 35.7 ± 3.7 kg/m 2 ] underwent measures of RMR, the thermic effect of a meal (TEM), and fasting and postprandial measures of hunger and fullness as well as plasma glucose and insulin. Following weight loss, subjects completed two 5-day conditions of energy balance in random order-Low Flux (LF): sedentary with energy intake (EI) = RMR (kcal/d) × 1.35; and High Flux (HF): net exercise energy cost of ∼500 kcal/d and EI = RMR (kcal/d) × 1.7. RMR was measured daily for each flux condition. The morning following each of the respective experimentally controlled HF and LF conditions (flux day 5), they underwent the same pre-weight loss tests and also reported their perceptions of hunger and fullness during the previous four days of HF and LF, respectively., Results: Average daily RMR was higher during HF (1926 ± 138 kcal/day) compared to LF (1847 ± 126 kcal/day; P < 0.05). Perceived hunger at the end of day was lower (p < 0.03) and fullness throughout the day was higher (p < 0.02) in HF compared to LF conditions. On day 5 of each flux condition, the thermic effect of a meal and circulating glucose and insulin after the meal did not differ between HF and LF., Conclusion: Following weight loss, compared to a sedentary LF state of energy balance, a short-term HF energy balance state is associated with higher RMR, lower perceived hunger, and greater perceived fullness, all of which could help attenuate the biologic drive to regain weight. Given the pilot nature of this study and the relatively short period of time spent in the high and low flux states, future research is needed to address this research question in a larger sample over a longer time period., (Copyright © 2015 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

In hypoxia, endurance exercise performance is diminished; pharmacotherapy may abrogate this performance deficit. Based on positive outcomes in preclinical trials, we hypothesized that oral administration of methazolamide, a carbonic anhydrase inhibitor, aminophylline, a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor, and/or methazolamide combined with aminophylline would attenuate hypoxia-mediated decrements in endurance exercise performance in humans. Fifteen healthy males (26 ± 5 years, body-mass index: 24.9 ± 1.6 kg/m(2); mean ± SD) were randomly assigned to one of four treatments: placebo (n = 9), methazolamide (250 mg; n = 10), aminophylline (400 mg; n = 9), or methazolamide (250 mg) with aminophylline (400 mg; n = 8). On two separate occasions, the first in normoxia (FIO2 = 0.21) and the second in hypoxia (FIO2 = 0.15), participants sat for 4.5 hours before completing a standardized exercise bout (30 minutes, stationary cycling, 100 W), followed by a 12.5-km time trial. The magnitude of time trial performance decrement in hypoxia versus normoxia did not differ between placebo (+3.0 ± 2.7 minutes), methazolamide (+1.4 ± 1.7 minutes), and aminophylline (+1.8 ± 1.2 minutes), all with p > 0.09; however, the performance decrement in hypoxia versus normoxia with methazolamide combined with aminophylline was less than placebo (+0.6 ± 1.5 minutes; p = 0.01). This improvement may have been partially mediated by increased SpO2 in hypoxia with methazolamide combined with aminophylline compared with placebo (73% ± 3% vs. 79% ± 6%; p < 0.02). In conclusion, coadministration of methazolamide and aminophylline may promote endurance exercise performance during a sojourn at high altitude.

Improved endurance exercise performance in adult humans after sprint interval training (SIT) has been attributed to mitochondrial biogenesis. However, muscle protein synthesis (MPS) and mitochondrial biogenesis during SIT have not been measured, nor have sex-specific differences. We hypothesized that males and females would have similar rates of MPS, mitochondrial biogenesis, and synthesis of individual proteins during SIT. Deuterium oxide (D2O) was orally administered to 21 adults [11 male, 10 female; mean age, 23±1 yr; body mass index (BMI), 22.8±0.6 kg/m(2); mean± SE] for 4 wk, to measure protein synthesis rates while completing 9 sessions of 4-8 bouts of 30 s duration on a cycle ergometer separated by 4 min of active recovery. Samples of the vastus lateralis were taken before and 48 h after SIT. SIT increased maximum oxygen uptake (VO(2max), males 43.4±2.1-44.0±2.3; females 39.5±0.9-42.5±1.3 ml/kg/min; P=0.002). MPS was greater in the males than in the females in the mixed (~150%; P < 0.001), cytosolic (~135%; P=0.038), and mitochondrial (~135%; P=0.056) fractions. The corresponding ontological clusters of individual proteins were significantly greater in the males than in the females (all P<0.00001). For the first time, we document greater MPS and mitochondrial biogenesis during SIT in males than in females and describe the synthetic response of individual proteins in humans during exercise training., (© FASEB.)

The conversion of white adipose to the highly thermogenic beige adipose tissue has been proposed as a potential strategy to counter the unfavorable consequences of obesity. Three regulators of this conversion have recently emerged but information regarding their control is limited, and contradictory. We present two studies examining the control of these regulators. Study 1: In 10 young men, the plasma concentrations of irisin and fibroblast growth factor 21 (FGF21) were determined prior to and during activation of the sympathetic nervous system via hypoxic gas breathing (FIO2 = 0.11). The measurements were performed twice, once with and once without prior/concurrent sympathetic inhibition via transdermal clonidine administration. FGF21 was unaffected by basal sympathetic inhibition (338±113 vs. 295±80 pg/mL; P = 0.43; mean±SE), but was increased during hypoxia mediated sympathetic activation (368±135); this response was abrogated (P = 0.035) with clonidine (269±93). Irisin was unaffected by sympathetic inhibition and/or hypoxia (P>0.21). Study 2: The plasma concentration of irisin and FGF21, and the skeletal muscle protein content of fibronectin type III domain containing 5 (FNDC5) was determined in 19 young adults prior to and following three weeks of sprint interval training (SIT). SIT decreased FGF21 (338±78 vs. 251±36; P = 0.046) but did not affect FNDC5 (P = 0.79). Irisin was decreased in males (127±18 vs. 90±23 ng/mL; P = 0.045) and increased in females (139±14 vs. 170±18). Collectively, these data suggest a potential regulatory role of acute sympathetic activation pertaining to the browning of white adipose; further, there appears to be a sexual dimorphic response of irisin to SIT.