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Elbow flexors (EFs) and knee extensors (KEs) have shown differences in performance fatigability and recovery of neuromuscular function after isometric and isotonic single-joint fatiguing contractions. However, dynamic multi-joint movements are more representative of real-world activities. The aim of the study was to assess central and peripheral mechanisms of fatigability after either arm-cranking or cycling. Ten physically active men performed maximal incremental arm-cranking and cycling until task failure. Maximal voluntary isometric contraction (MVIC) and electrically evoked forces of both EF and KE were assessed before (PRE) and 1 (POST) and 20 (POST20) min after exercise. At POST, MVIC decreased similarly to 76 ± 8% and 81 ± 7% (both P < 0.001) of PRE for EF and KE, respectively. MVIC force remained lower than PRE at POST20 for both EF and KE (85 ± 8% vs. 95 ± 3% of PRE, P ≤ 0.033), having recovered less in EF than in KE ( P = 0.003). Electrically evoked forces decreased similarly from PRE to POST in EF and KE (all P > 0.05). At POST20, the ratio of low-to-high frequency doublets was lower in EF than in KE (75 ± 13% vs. 85 ± 10% of PRE; P ≤ 0.034). Dynamic maximal incremental exercise acutely induced similar magnitudes of MVIC and evoked force loss in EF and KE. However, at POST20, impaired MVIC recovery and lower ratio of low-to-high frequency doublets in EF than in KE suggest the recovery of neuromuscular function after dynamic maximal exercises is specific to and dependent on changes within the muscles investigated.

Background Late onset Pompe disease (LOPD) is a lysosomal neuromuscular disorder which can progressively impair the patients’ exercise tolerance, motor and respiratory functions, and quality of life. The available enzyme replacement therapy (ERT) does not completely counteract disease progression. We investigated the effect of exercise training alone, or associated with a high-protein diet, on the exercise tolerance, muscle and pulmonary functions, and quality of life of LOPD patients on long term ERT. Methods The patients were asked to participate to a crossover randomized study comprehending a control period (free diet, no exercise) followed by 2 intervention periods: exercise or exercise + diet, each lasting 26 weeks and separated by 13 weeks washout periods. Exercise training included moderate-intensity aerobic exercise on a cycle ergometer, stretching and balance exercises, strength training. The diet was composed by 25–30% protein, 30–35% carbohydrate and 35–40% fat. Before and after each period patients were assessed for: exercise tolerance test on a cycle-ergometer, serum muscle enzymes, pulmonary function tests and SF36 questionnaire for quality of life. Compliance was evaluated by training and dietary diaries. Patients were contacted weekly by researchers to optimize adherence to treatments. Results Thirteen LOPD patients, median age 49 ± 11 years, under chronic ERT (median 6.0 ± 4.0 years) were recruited. Peak aerobic power (peak pulmonary O2 uptake) decreased after control, whereas it increased after exercise, and more markedlyafter exercise + diet. Serum levels of lactate dehydrogenase (LDH) significantly decreased after exercise + diet; both creatine kinase (CK) and LDH levels were significantly reduced after exercise + diet compared to exercise. Pulmonary function showed no changes after control and exercise, whereas a significant improvement of forced expiratory volume in 1 sec (FEV1) was observed after exercise + diet. SF36 showed a slight improvement in the “mental component” scale after exercise, and a significant improvement in “general health” and “vitality” after exercise + diet. The compliance to prescriptions was higher than 70% for both diet and exercise. Conclusions Exercise tolerance (as evaluated by peak aerobic power) showed a tendency to decrease in LOPD patients on long term ERT. Exercise training, particularly if combined with high-protein diet, could reverse this decrease and result in an improvement, which was accompanied by improved quality of life. The association of the two lifestyle interventions resulted also in a reduction of muscle enzyme levels and improved pulmonary function.

Concordia Station is the permanent, research station on the Antarctic Plateau at 3230 m. During the eleventh winter-over campaign (DC11-2015; February 2015 to November 2015) at Antarctic Concordia Station, 13 healthy team members were studied and blood samples were collected at six different time points: baseline measurements (T0), performed at sea level before the departure, and during the campaign at 3, 7, 20, 90, and 300 days after arrival at Concordia Station. Reducing the partial pressure of O2 as barometric pressure falls, hypobaric hypoxia (HH) triggers several physiological adaptations. Among the others, increased oxidative stress and enhanced generation of reactive oxygen/nitrogen species (ROS/RNS), resulting in severe oxidative damage, were observed, which can share potential physiopathological mechanisms associated with many diseases. This study characterized the extent and time-course changes after acute and chronic HH exposure, elucidating possible fundamental mechanisms of adaptation. ROS, oxidative stress biomarkers, nitric oxide, and proinflammatory cytokines significantly increased (range 24-135%) during acute and chronic hypoxia exposure (peak 20th day) with a decrease in antioxidant capacity (peak 90th day: -52%). Results suggest that the adaptive response of oxidative stress balance to HH requires a relatively long time, more than 300th days, as all the observed variables do not return to the preexposition level. These findings may also be relevant to patients in whom oxygen availability is limited through disease (i.e., chronic heart and lung and/or kidney disease) and/or during long-duration space missions.

During cancer treatments in childhood hematological malignancies, reduced exercise tolerance is one of the main hardships. Precision-based training programs help children, adolescents, and young adults and their families to resume regular physical activity, exercise, and sports once they return to their communities after the intensive phases spent in hospital. This study was aimed at verifying whether an intermittent recovery test, the Yo-Yo AD, could provide a simple and valid way to evaluate an individual’s capacity to perform repeated intense exercise and to follow up on the impact of tailored exercise in children, adolescents, and young adults with hematological malignancies. The Yo-Yo AD involved the repetition of several shuttles to muscle exhaustion, at pre-established speeds (walking and slow running). The heart rate (HR) and oxygen saturation (SaO2) were monitored during the test. The total distance and the walking/running ability, measured as the slope of the HR vs. distance correlation, were investigated before (T0) and after 11 weeks (T1) of precision exercise intervention. The Yo-Yo AD was also performed by healthy children (CTRL). Ninety-seven patients (10.58 ± 4.5 years, 46% female) were enrolled. The Yo-Yo AD showed the positive impact of the exercise intervention by increasing the distance covered by the individuals (T0 = 946.6 ± 438.2 vs. T1 = 1352.3 ± 600.6 m, p < 0.001) with a more efficient walking/running ability (T0 = 2.17 ± 0.84 vs. T1 = 1.73 ± 0.89 slope, p < 0.0164). CTRLs performed better (1754.0 ± 444.0 m, p = 0.010). They were equally skillful (1.71 ± 0.27 slope) when compared to the patients after they received the precision-based intervention. No adverse events occurred during the Yo-Yo AD and it proved to be an accurate way of correctly depicting the changes in performance in childhood hematological malignancies.

The relevance of translational medicine (bringing basic science methods "to the bed of patients") is universally recognized. Too often, however, the tools to be applied translationally are thought to derive only from the "-omics" (genomics, proteomics, transcriptomics, metabolomics, etc.) world. The failures of this "reductionist" approach are widely recognized. In the review, we discuss studies demonstrating that scientifically sound mechanistic insights into diseases, relevant both in terms of basic science and clinically, and very well suited to be utilized within a translational medicine approach, can be obtained from the established field of exercise physiology. Methods originally aimed toward basic physiological mechanisms, and applied for the functional evaluation of athletes and sport performance, can have a valuable translational application in patients with metabolic myopathies; such as myophosphorylase deficiency (McArdle disease) or mitochondrial myopathies, diseases which share the common denominator of an impaired skeletal muscle oxidative metabolism. Several variables can yield pathophysiological insights, can identify and quantify the metabolic impairment and the effects on exercise tolerance (one of the main determinants of the patients' clinical picture and quality of life), and can offer diagnostic clues: the impaired capacity of O2 extraction by skeletal muscle, evaluated by near-infrared spectroscopy; the "exaggerated" cardiovascular response to exercise; the slower speed of adjustment of oxidative metabolism during metabolic transitions; the "slow component" of pulmonary O2 uptake kinetics and the associated reduced efficiency and fatigue; the impaired intramuscular matching between O2 delivery and O2 utilization. The proposed methods are noninvasive, and therefore facilitate repeated or serial evaluations. They provide support for a simple message: physiology and physiological research remain the essential link between genes, molecules, and clinical care.

In order to identify peripheral biomarkers of impaired oxidative metabolism during exercise following a 10-day bed rest, 10 males performed an incremental exercise (to determine peak pulmonary VO2 (VO2 p)) and moderate-intensity exercises, before (PRE) and after (POST) bed rest. Blood flow response was evaluated in the common femoral artery by Eco-Doppler during 1 min of passive leg movements (PLM). The intramuscular matching between O2 delivery and O2 utilization was evaluated by near-infrared spectroscopy (NIRS). Mitochondrial respiration was evaluated ex vivo by high-resolution respirometry in isolated muscle fibres, and in vivo by NIRS by the evaluation of skeletal muscle VO2 (VO2 m) recovery kinetics. Resting VO2 m was estimated by NIRS. Peak VO2 p was lower in POST vs. PRE. The area under the blood flow vs. time curve during PLM was smaller (P = 0.03) in POST (274 ± 233 mL) vs. PRE (427 ± 291). An increased (P = 0.03) overshoot of muscle deoxygenation during a metabolic transition was identified in POST. Skeletal muscle citrate synthase activity was not different (P = 0.11) in POST (131 ± 16 nmol min-1 mg-1 ) vs. PRE (138 ± 19). Maximal ADP-stimulated mitochondrial respiration (66 ± 18 pmol s-1 mg-1 (POST) vs. 72 ± 14 (PRE), P = 0.41) was not affected by bed rest. Apparent Km for ADP sensitivity of mitochondrial respiration was reduced in POST vs. PRE (P = 0.04). The VO2 m recovery time constant was not different (P = 0.79) in POST (22 ± 6 s) vs. PRE (22 ± 6). Resting VO2 m was reduced by 25% in POST vs. PRE (P = 0.006). Microvascular-endothelial function was impaired following a 10-day bed rest, whereas mitochondrial mass and function (both in vivo and ex vivo) were unaffected or slightly enhanced. KEY POINTS: Ten days of horizontal bed rest impaired in vivo oxidative function during exercise. Microvascular impairments were identified by different methods. Mitochondrial mass and mitochondrial function (evaluated both in vivo and ex vivo) were unchanged or even improved (i.e. enhanced mitochondrial sensitivity to submaximal [ADP]). Resting muscle oxygen uptake was significantly lower following bed rest, suggesting that muscle catabolic processes induced by bed rest/inactivity are less energy-consuming than anabolic ones.

Purpose High altitude results in lower barometric pressure and hence partial pressure of O2 decrease can lead to several molecular and cellular changes, such as generation of reactive oxygen species (ROS). Electron Paramagnetic Resonance technique was adopted in the field, to evaluate the effects of acute and sub-acute hypobaric hypoxia (HH) on ROS production by micro-invasive method. Biological biomarkers, indicators of oxidative stress, renal function and inflammation were investigated too. Methods Fourteen lowlander subjects (mean age 27.3 ± 5.9 years) were exposed to HH at 3269 m s.l. ROS production, related oxidative damage to cellular components, systemic inflammatory response and renal function were determined through blood and urine profile performed at 1st, 2nd, 4th, 7th, and 14th days during sojourn. Results Kinetics of changes during HH exposition showed out significant (range p < 0.05-0.0001) increases that at max corresponds to 38% for ROS production rate, 140% for protein carbonyl, 44% for lipid peroxidation, 42% for DNA damage, 200% for inflammatory cytokines and modifications in renal function (assessed by neopterin concentration: 48%). Conversely, antioxidant capacity significantly (p < 0.0001) decreased - 17% at max. Conclusion This 14 days in-field study describes changes of oxidative-stress biomarkers during HH exposure in lowlanders. The results show an overproduction of ROS and consequent oxidative damage to protein, lipids and DNA with a decrease in antioxidant capacity and the involvement of inflammatory status and a transient renal dysfunction. Exposure at high altitude induces a hypoxic condition during acute and sub-acute phases accompanied by molecular adaptation mechanism indicating acclimatization.

We propose a quantitative and systematic investigation of the differential pathlength factor (DPF) behavior for skeletal muscles and its dependence on different factors, such as the subcutaneous adipose tissue thickness (ATT), the variations of the tissue absorption (µa) and reduced scattering (µ′s) coefficients, and the source-detector distance. A time domain (TD) NIRS simulation study is performed in a two-layer geometry mimicking a human skeletal muscle with an overlying adipose tissue layer. The DPF decreases when µa increases, while it increases when µ′s increases. Moreover, a positive correlation between DPF and ATT is found. These results are supported by an in-vivo TD NIRS study on vastus lateralis and biceps brachii muscles of eleven subjects at rest, showing a high inter-subject and inter-muscle variability.

NEW FINDINGS What is the central question of this study? The role of the cerebral haemodynamic response to either normobaric or hypobaric hypoxia in people susceptible to acute mountain sickness (AMS) is still under debate. Prefrontal cortex near-infrared spectroscopy-derived parameters were monitored in normobaric hypoxia at rest and during moderate-intensity exercise in AMS-prone and non-AMS individuals. What is the main finding and its importance? The AMS-prone individuals did not increase microvascular blood volume and showed lower prefrontal cerebral oxygenation in normobaric hypoxia both at rest and during exercise compared with non-AMS subjects, suggesting that these changes might underpin later development of AMS at altitude. ABSTRACT The aim of this study was to evaluate changes in prefrontal cerebral oxygenation and microvascular blood volume during exercise in normobaric hypoxia and to investigate possible associations with the occurrence of acute mountain sickness (AMS) at altitude. Twenty-two healthy individuals (age, 26 ± 4 years; peak oxygen uptake, 42 ± 4 ml kg-1 min-1 ) were tested in two different conditions: normoxia (NORM) and normobaric hypoxia (fraction of inspired O2 = 0.13; HYPO). Data were collected at rest and during submaximal constant-speed exercise. The peripheral oxyhaemoglobin saturation was measured by finger pulse oximeter. Changes in prefrontal cerebral oxygenation (ΔHbO2 ), deoxygenation (ΔHHb) and microvascular blood volume (ΔHbtot ) were obtained by near-infrared spectroscopy. Within 2 weeks after laboratory testing, subjects rapidly ascended to 3647 m a.s.l., and AMS was evaluated using the Lake Louise scale. Eight subjects were AMS+ , whereas 14 were AMS- . During NORM, near-infrared spectroscopy variables did not change from baseline values both at rest and during exercise, with similar results in AMS+ and AMS- subjects. During HYPO, ΔHHb increased to a similar extent in both groups, both at rest and during exercise. The ΔHbO2 was significantly less in AMS+ compared with AMS- subjects, both at rest [-3.23 ± 5.90 versus 1.44 ± 2.14 μm, P = 0.04, effect size (ES) = 1.1, respectively] and during exercise (-6.56 ± 5.51 versus 0.37 ± 4.36 μm, P

Background: The burden of musculoskeletal trauma is increasing in low- and middle-income countries. Due to the low clinical follow-up rates in these regions, the Squat-and-Smile test (S&S) has previously been proposed as a proxy to assess bone healing (BH) capacity after surgery involving bone fractures. This study deals with various aspects of using S&S and bone radiography examination to obtain information about an individual's ability to recover after a trauma. In summary, we performed the S&S test to assess the possibility of recovering biomechanical function in lower limbs in a remote area of Kenya (Samburu County). Methods: Eighty-nine patients (17.9% F; 31.7 ± 18.9 yrs) who underwent intramedullary nail treatment for femur or tibia fractures were enrolled in this study. Both S&S [evaluated by a goal attainment scale (GAS)] and x-ray (evaluated by REBORNE, Bone Healing Score) were performed at 6 and 24 weeks, postoperatively. An acceptable margin for satisfactory S&S GAS scores was determined by assessing its validity, reliability, and sensitivity. Results: S&S GAS scores increased over time: 80.2% of patients performed a satisfactory S&S at the 24-weeks follow-up with a complete BH. A high correlation between S&S GAS and REBORNE at the 6- and 24- weeks’ timepoint was found. Facial expression correlated partially with BH. The S&S proved to be accurate at correctly depicting the BH process (75% area fell under the Receiver Operator Curve). Conclusion: The S&S provides a possible substitution for bone x-ray during BH assessment. The potential to remotely follow up the BH is certainly appealing in low- and middle-income countries, but also in high-income countries; as was recently observed with the Covid-19 pandemic when access to a hospital is not conceivable.

Functional near infrared spectroscopy (NIRS) is a widespread non-invasive technique to monitor skeletal muscle metabolism. However, only variation of oxygenated (HHb), deoxygenated (O2Hb), total (tHb) hemoglobin and saturation (SO2) are usually reported. In this study, Time Domain (TD) NIRS approach was exploited to perform a preliminary quantitative characterization of vastus lateralis muscle during incremental exercise. A population of 11 healthy young male subjects performed on a mechanical cycle ergometer an incremental exercise (initial work rate range = 60-96 W, increment = 12-18 W/min) until exhaustion. TD NIRS, heart rate, pulmonary ventilation (VE), O2 uptake (VO2), CO2 output (VCO2), blood lactate concentration ([La]b) and Borg scale were measured during the exercise. From TD NIRS, muscles absolute values of absorption and scattering coefficients were obtained with a homogeneous approach and hemoglobin concentrations and saturation levels were calculated. The time courses of HHb, O2Hb, tHb and SO2 were consistent with previous literature results. A high inter-subject variability was found for both optical properties and hemodynamic concentrations. Further statistical group analysis will be required in order to highlight significant behavior within the population and correlation with physiological parameters.

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Previous studies showed a higher O2 cost of exercise, and therefore, a reduced exercise tolerance in patients with obesity during constant work rate (CWR) exercise compared with healthy subjects. Among the ergogenic effects of dietary nitrate ([Formula: see text]) supplementation in sedentary healthy subjects, a reduced O2 cost and enhanced exercise tolerance have often been demonstrated. The aim of this study was to evaluate the effects of beetroot juice (BR) supplementation, rich in [Formula: see text], on physiological variables associated with exercise tolerance in adolescents with obesity. In a double-blind, randomized crossover study, 10 adolescents with obesity (8 girls, 2 boys; age = 16 ± 1 yr; body mass index = 35.2 ± 5.0 kg/m2) were tested after 6 days of supplementation with BR (5 mmol [Formula: see text] per day) or placebo (PLA). Following each supplementation period, patients carried out two repetitions of 6-min moderate-intensity CWR exercise and one severe-intensity CWR exercise until exhaustion. Plasma [Formula: see text] concentration was significantly higher in BR versus PLA (108 ± 37 vs. 15 ± 5 μM, P < 0.0001). The O2 cost of moderate-intensity exercise was not different in BR versus PLA (13.3 ± 1.7 vs. 12.9 ± 1.1 ml·min−1·W−1, P = 0.517). During severe-intensity exercise, signs of a reduced amplitude of the O2 uptake slow component were observed in BR, in association with a significantly longer time to exhaustion (561 ± 198 s in BR vs. 457 ± 101 s in PLA, P = 0.0143). In obese adolescents, short-term dietary [Formula: see text] supplementation is effective in improving exercise tolerance during severe-intensity exercise. This may prove to be useful in counteracting early fatigue and reduced physical activity in this at-risk population.

The study was carried out at Concordia Station (Antarctic Plateau). The aim was to investigate the respiratory and haematological responses to hypoxia in healthy subjects living at constant altitude. Thirteen men and women (34.1 ± 3.1 years) were exposed for 10 months to hypobaric hypoxia (oxygen level equivalent to 3800 m asl). These unique conditions enable a greater accuracy of monitoring human responses to chronic hypoxia than can be achieved elsewhere. Blood haemoglobin and erythropoietin concentrations were determined at sea level (Pre), and after 3, 7, 20, 90 and 300 days at altitude. Blood gas analysis, base excess and arterial oxygen saturation were measured at Pre, and after 150 and 300 days at altitude. Erythropoietin returned quickly to baseline level after a transient increase in the first days. Blood haemoglobin concentration started increasing at day 7 and remained markedly higher for the entire duration of the mission. At day 150 the blood carbon dioxide partial pressure was markedly reduced, and consequently blood pH remained higher at negative base excess until day 300. The arterial oxygen saturation remained lower than Pre throughout. In conclusion, humans display little capacity of hypoxia acclimatization even after ten months of constant exposure to low oxygen partial pressure.

Aerobic training can be effective in patients with mitochondrial myopathies (MM) and McArdle's disease (McA). The aim of the study was to use noninvasive functional evaluation methods, specifically aimed at skeletal muscle oxidative metabolism, to evaluate the effects of an aerobic exercise training (cycle ergometer, 12 wk, 4 days/wk, ∼65-70% of maximal heart rate) in 6 MM and 7 McA. Oxygen uptake and skeletal muscle vastus lateralis fractional O2 extraction by near-infrared spectroscopy were assessed during incremental and low-intensity constant work rate (CWR) exercises before (BEFORE) and at the end (AFTER) of training. Peak O2 uptake increased significantly with training both in MM [14.7 ± 1.2 vs. 17.6 ± 1.4 ml·kg−1·min−1 (mean ± SD)] and in McA (18.5 ± 1.8 ml·kg−1·min−1 vs. 21.6 ± 1.9). Peak skeletal muscle fractional O2 extraction increased with training both in MM (22.0 ± 6.7 vs. 32.6 ± 5.9%) and in McA (18.5 ± 6.2 vs. 37.2 ± 7.2%). During low-intensity CWR in both MM and McA: V̇o2 kinetics became faster in AFTER, but only in the patients with slow V̇o2 kinetics in BEFORE; the transient overshoot in fractional O2 extraction kinetics disappeared. The level of habitual physical activity was not higher 3 mo after training (FOLLOW-UP vs. PRE). In MM and McA patients a home-based aerobic training program significantly attenuated the impairment of skeletal muscle oxidative metabolism and improved variables associated with exercise tolerance. Our findings indicate that in MM and McA patients near-infrared spectroscopy and V̇o2 kinetics can effectively detect the functional improvements obtained by training.

PURPOSE: Enzyme replacement therapy (ERT) has recently became available for Pompe's disease. Data on the effects of ERT on physiological variables related to exercise tolerance have never been published. METHODS: Pulmonary gas exchange, cardiac output (by impedance cardiography), vastus lateralis muscle O2 extraction (by near-infrared spectroscopy) were determined during cycle ergometer exercise in a 50-year-old patient BEFORE and after 1, 12 and 24 months of ERT. RESULTS: At the same constant-workload submaximal exercise, rates of self-perceived exertion and values of respiratory exchange ratio, pulmonary ventilation and heart rate were lower during ERT vs.. BEFORE, suggesting an increased exercise tolerance. Peak oxygen uptake (VÙO2peak) increased by ~35% from BEFORE (0.64 L/min, or 11.4 ml/kg/min) to 1 month (0.88 L/min, or 15.7 ml/kg/min) of treatment, and did not significantly change thereafter. Also peak cardiac output significantly increased during ERT, whereas peak skeletal muscle fractional O2 extraction was unchanged compared to BEFORE. CONCLUSIONS: Improvements of peak exercise capacity and exercise tolerance at submaximal workloads were observed in a patient with Pompe's disease after 1 month of ERT, with no further changes during the ensuing treatment period (up to 24 months).

Non-technical summary The endothelium is a thin layer of cells lining the interior surface of the entire circulatory system. Endothelial progenitor cells (EPCs) have a crucial role in maintaining the integrity of the endothelium, as they are recruited from the bone marrow to sites of endothelial injury where they contribute to blood vessel formation and repair. The factors regulating EPC mobilization and trafficking remain incompletely understood. We evaluated the time-course effects of a single 4 h bout of severe hypoxic breathing (simulating 4100 m altitude) followed by 4 h restoration in room air. We show that hypoxia alone induces a rapid disappearance of EPCs from blood, probably sustained by a prompt cell marginalization followed by a late increase in EPC apoptosis. These observations may broaden our understanding of the mechanisms operated by EPCs to maintain endothelial homeostasis and may help to elucidate the potential role of EPCs in regenerative medicine.

High-altitude Tibetans undergo a pattern of adaptations to chronic hypoxia characterized, among others, by a more efficient aerobic performance compared with acclimatized lowlanders. To test whether such changes may persist upon descent to moderate altitude, oxygen uptake of 17 male Tibetan natives lifelong residents at 3500–4500 m was assessed within 1 month upon migration to 1300 m. Exercise protocols were: 5 min treadmill walking at 6 km h−1 on increasing inclines from +5 to +15% and 5 min running at 10 km h−1 on a +5% grade. The data (mean ±s.e.m.) were compared with those obtained on Nepali lowlanders. When walking on +10, +12.5 and +15% inclines, net of Tibetans was 25.2 ± 0.7, 29.1 ± 1.1 and 31.3 ± 0.9 ml kg−1 min−1, respectively, i.e. 8, 10 and 13% less (P < 0.05) than that of Nepali. At the end of the heaviest load, blood lactate concentration was lower in Tibetans than in Nepali (6.0 ± 0.9 versus 8.9 ± 0.6 mm; P < 0.05). During running, of Tibetans was 35.1 ± 0.8 versus 39.3 ± 0.7 ml kg−1 min−1 (i.e. 11% less; P < 0.01). In conclusion, during submaximal walking and running at 1300 m, Tibetans are still characterized by lower aerobic energy expenditure than control subjects that is not accounted for by differences in mechanical power output and/or compensated for by anaerobic glycolysis. These findings indicate that chronic hypoxia induces metabolic adaptations whose underlying mechanisms still need to be elucidated, that persist for at least 1 month upon descent to moderate altitude.

As is well known, with increasing altitude, peak aerobic power (VO2peak) of acclimatized lowlanders undergoes a progressive decrease as a consequence of the decline of barometric pressure and of oxygen partial pressure in inspired air. At any given altitude, however, the percentage reduction of VO2peak compared to sea level control values (ΔVO2peak,%) varies widely among individuals (Cerretelli & Hoppeler, 1996). Such variability appears to be mainly related to the extent of acclimatization and to the degree of fitness. A prolonged sojourn at very high altitude (>5500 m) may affect VO2peak of lowlanders both positively, by the increase of blood O2 carrying capacity (Grassi et al. 1996) and negatively, as a consequence of a progressive reduction of muscle mass (Cerretelli, 1976) and, possibly, of muscle deterioration (Martinelli et al. 1990). If the duration of the exposure is long enough (years) and altitude does not exceed ∼4000 m, developmental adaptation may occur (Moore, 2001) allowing a progressive recovery of the VO2peak towards levels only slightly lower than those found at sea level in age-, fitness- or training-matched individuals (Frisancho et al. 1973; Greska et al. 1985; Sun et al. 1990; Niu et al. 1995; Chen et al. 1997). With regard to fitness, in acute hypoxia, the peak aerobic power reduction was found to be greater in physically active than in inactive Caucasians (Lawler et al. 1988; Shephard et al. 1988; Martin & O'Kroy, 1993; Koistinen et al. 1995) as a consequence, among others, of a greater lung diffusion limitation (Dempsey et al. 1984; Dempsey & Wagner, 1999). Also in subchronic (Young et al. 1985) and chronic (Marzorati et al. 1995) hypoxia, there are hints that trained individuals may be more penalized in terms of ΔVO2peak than untrained subjects. Compared to acclimatized lowlanders and even Andean populations, altitude Tibetans exhibit at peak exercise peculiar adaptive features, such as higher arterial O2 saturation (Zhuang et al. 1996) and heart rate values (Niu et al. 1995), and absolute VO2peak levels (Sun et al. 1990; Niu et al. 1995; Chen et al. 1997) close to those found in Caucasians at sea level. These findings, along with a less pronounced polycythemic response (Beall et al. 1998), a reduced hypoxic pulmonary vasoconstriction (Groves et al. 1993), and a lower prevalence of chronic mountain sickness (Moore et al. 1998), suggest that in altitude Tibetans the pattern of adaptation to chronic hypoxia is different compared to that of any other population. The present study was designed primarily to establish whether resistance to hypoxia and, particularly the greater aerobic working capacity found in altitude Tibetans has a genetic basis. Should this be the case, Tibetan lowlanders born with the genetic adaptations of their ancestors, i.e. long-term processes occurring over generations (Moore, 2001), could be expected to acclimatize to high altitude more quickly than Caucasians. As an additional aim, we investigated the role of aerobic fitness, independent of ethnicity, on the preservation of peak aerobic performance at altitude. To achieve these aims, the respiratory and cardiovascular responses to peak exercise, particularly the altitude-induced decrease of VO2peak (ΔVO2peak) were assessed in Tibetans with different altitude exposure history and in Caucasian lowlanders with different levels of aerobic fitness, following an identical (26–28 days) altitude (5050 m) exposure protocol.

Patients with McArdle's disease (McA) typically show the “second-wind” phenomenon, a sudden decrease in heart rate (HR) and an improved exercise tolerance occurring after a few minutes of exercise. In the present study, we investigated whether in McA a first bout of exercise determines a second wind during a second bout, separated by the first by a few minutes of recovery. Eight McA (44 ± 4 yr) and a control group of six mitochondrial myopathy patients (51 ± 6 yr) performed two repetitions (CWR1 and CWR2) of 6-min constant work rate exercise (∼50% of peak work rate) separated by 6-min (SHORT) or 18-min (LONG) recovery. Pulmonary O2uptake (V̇o2), HR, cardiac output, rates of perceived exertion, vastus lateralis oxygenation {changes in deoxygenated Hb and myoglobin Mb concentrations, Δ[deoxy(Hb+Mb)], by near-infrared spectroscopy} were determined. In McA, V̇o2(0.86 ± 0.2 vs. 0.95 ± 0.1 l/min), HR (113 ± 10 vs. 150 ± 13 beats/min), cardiac output (11.6 ± 0.6 vs. 15.0 ± 0.8 l/min), and rates of perceived exertion (11 ± 2 vs. 14 ± 3) were lower, whereas Δ[deoxy(Hb+Mb)] was higher (14.7 ± 2.3 vs. −0.1 ± 4.6%) in CWR2-SHORT vs. CWR1; the “overshoot” of Δ[deoxy(Hb+Mb)] and the “slow component” of V̇o2kinetics disappeared in CWR2-SHORT. No differences (vs. CWR1) were observed in McA during CWR2-LONG, or in mitochondrial myopathy patients during both CWR2-SHORT and -LONG. A second-wind phenomenon was observed in McA during the second of two consecutive 6-min constant-work rate submaximal exercises. The second wind was associated with changes of physiological variables, suggesting an enhanced skeletal muscle oxidative metabolism. The second wind was not described after a longer (18-min) recovery period.

The following letters are in response to the Point:Counterpoint: Cardiac denervation does/does not play a major role in exercise limitation after heart transplantation. To the Editor : Denervation affects greatly cardiac function in HTx recipients. However, it is not the main determinant of their

The following letters are in response to the Point:Counterpoint “The lactate paradox does/does not occur during exercise at high altitude” that appears in this issue. To the Editor : I found the argument put forth by Van Hall ([5][1]) to contain a number of inaccurate and misleading statements

Enzyme replacement therapy (ERT) has recently became available for patients with glycogen storage disease type II. Previous studies have demonstrated clinical efficacy of enzyme replacement therapy, however, data on physiological variables related to exercise tolerance are scarce. Four glycogen storage disease type II late-onset patients (45 ± 6 years) performed an incremental exercise on a cycle ergometer, up to voluntary exhaustion, before (BEFORE) and after 12 months of ERT (AFTER). Peak workload, oxygen uptake, heart rate, cardiac output (by impedance cardiography) and vastus lateralis oxygenation indices (by continuous-wave near-infrared spectroscopy, NIRS) were determined. Peak workload and oxygen uptake values significantly increased during ERT (54 ± 30 vs. 63 ± 31 watt, and 17.2 ± 4.4 vs. 19.7 ± 3.5 ml/kg/min, respectively, in BEFORE vs. AFTER). On the other hand, for both peak cardiac output (12.3 ± 5.3 vs. 14.8 ± 4.5L/min) and the NIRS-determined peak skeletal muscle fractional O(2) extraction, expressed as a percentage of the maximal values during a transient limb ischemia (30 ± 39% vs. 38 ± 28%), the observed increases were not statistically significant. Our findings suggest that in glycogen storage disease type II patients enzyme replacement therapy is associated with a mild improvement of exercise tolerance. The findings need to be validated during a longer follow-up on a larger group of patients.

There are hints that hypoxia exposure may affect the number of circulating endothelial progenitor cells (EPCs) in humans. To test this hypothesis, the concentration of EPCs was determined by flow cytometry in the peripheral blood of 10 young healthy adults before (0 h), at different times (0.5 h, 1 h, 2 h and 4 h) during a 4 h normobaric hypoxic breathing simulating 4100 m altitude, and in the following recovery breathing room air. Results were interpreted mainly on the basis of the changes in surface expression of CXC chemokine receptor-4 (CXCR-4, a chemokine receptor essential for EPC migration and homing) and the percentage of apoptotic cells, the plasmatic levels of markers of oxidative stress induced by hypoxic breathing. Compared to 0 h, the concentration of EPCs, identified as either CD45(dim)/CD34(+)/KDR(+) or CD45(dim)/CD34(+)/KDR(+)/CD133(+) cells, decreased from 337 ± 83 ml(-1) (mean ± SEM) to 223 ± 52 ml(-1) (0.5 h; P0.005) and 100 ± 37 ml(-1) (4 h; P0.005), and from 216 ± 91 to 161 ± 50 ml(-1) (0.5 h; P0.05) and 45 ± 23 ml(-1) (4 h; P0.005), respectively. Upon return to normoxia, their concentration increased slowly, and after 4 h was still lower than at 0 h (P0.05). During hypoxia, CXCR-4 expression and plasmatic stromal derived cell factor-1 (SDF-1) increased abruptly (0.5 h: +126% and +13%, respectively; P0.05), suggesting cell marginalization as a possible cause of the rapid hypoxia-induced EPC reduction. Moreover, hypoxia exposure induced an increase in EPC apoptosis and markers of oxidative stress, which was significantly evident only starting from 2 h and 4 h after hypoxia offset, respectively, suggesting that EPC apoptosis may contribute to the later phase of hypoxia-induced EPC reduction. Overall, these observations may provide new insights into the understanding of the mechanisms operated by EPCs to maintain endothelial homeostasis.