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Limb muscle dysfunction in patients with COPD may be associated with local muscle and/or systemic inflammation, and therefore we investigated whether exercise training altered markers of inflammation and oxidative stress. We obtained vastus lateralis muscle biopsies and venous blood samples from patients with COPD (n = 30) before and after 8 weeks of resistance training (RT) (n = 15) or endurance training (ET) (n = 15). Healthy age‐matched subjects were included as baseline controls (n = 8). Inflammatory markers in muscle and systemically were determined by interleukins (IL), tumour necrosis factor alfa (TNF‐α), leukocyte concentration together with immunohistochemical staining for macrophages. Muscle oxidative stress and antioxidant capacity were determined by NADPH oxidase (NOX) and superoxide dismutase 2 (SOD2), respectively. Before exercise training, COPD patients had a higher muscular NOX protein content and circulating IL‐8, IL‐18, CRP, and leukocyte levels but a similar number of muscle‐infiltrating macrophages compared with controls. Eight weeks of ET or RT increased muscle SOD2 content with no difference between groups. Plasma TNF‐α, increased (P < .05) after ET and tended to (P = .06) increase after RT, but had no effect on muscular NOX protein content, number of muscle‐infiltrating macrophages, or systemic levels of other pro‐inflammatory cytokines or leukocytes. In patients with COPD, we found no evidence for muscular inflammation and no effect of exercise training. However, systemic inflammation was elevated in COPD and both training modalities induced an upregulation of muscle antioxidant capacity. [ABSTRACT FROM AUTHOR]

Live high-train low (LHTL) using hypobaric hypoxia was previously found to improve sea-level endurance performance in well-trained individuals; however, confirmatory controlled data in athletes are lacking. Here, we test the hypothesis that natural-altitude LHTL improves aerobic performance in cross-country skiers, in conjunction with expansion of total hemoglobin mass (Hbmass, carbon monoxide rebreathing technique) promoted by accelerated erythropoiesis. Following duplicate baseline measurements at sea level over the course of 2 weeks, nineteen Norwegian cross-country skiers (three women, sixteen men, age 20 ± 2 year, maximal oxygen uptake (VO2max) 69 ± 5 mL/min/kg) were assigned to 26 consecutive nights spent at either low (1035 m, control, n = 8) or moderate altitude (2207 m, daily exposure 16.7 ± 0.5 hours, LHTL, n = 11). All athletes trained together daily at a common location ranging from 550 to 1500 m (21.2% of training time at 550 m, 44.2% at 550-800 m, 16.6% at 800-1100 m, 18.0% at 1100-1500 m). Three test sessions at sea level were performed over the first 3 weeks after intervention. Despite the demonstration of nocturnal hypoxemia at moderate altitude (pulse oximetry), LHTL had no specific effect on serum erythropoietin, reticulocytes, Hbmass, VO2max, or 3000-m running performance. Also, LHTL had no specific effect on (a) running economy (VO2 assessed during steady-state submaximal exercise), (b) respiratory capacities or efficiency of the skeletal muscle (biopsy), and (c) diffusing capacity of the lung. This study, showing similar physiological responses and performance improvements in the two groups following intervention, suggests that in young cross-country skiers, improvements in sea-level aerobic performance associated with LHTL may not be due to moderate-altitude acclimatization. [ABSTRACT FROM AUTHOR]

Abstract: Aims: (i) To determine whether exercise‐induced increases in muscle mitochondrial volume density (MitoVD) are related to enlargement of existing mitochondria or de novo biogenesis and (ii) to establish whether measures of mitochondrial‐specific enzymatic activities are valid biomarkers for exercise‐induced increases in MitoVD. Method: Skeletal muscle samples were collected from 21 healthy males prior to and following 6 weeks of endurance training. Transmission electron microscopy was used for the estimation of mitochondrial densities and profiles. Biochemical assays, western blotting and high‐resolution respirometry were applied to detect changes in specific mitochondrial functions. Result: MitoVD increased with 55 ± 9% (P < 0.001), whereas the number of mitochondrial profiles per area of skeletal muscle remained unchanged following training. Citrate synthase activity (CS) increased (44 ± 12%, P < 0.001); however, there were no functional changes in oxidative phosphorylation capacity (OXPHOS, CI+IIP) or cytochrome c oxidase (COX) activity. Correlations were found between MitoVD and CS (P = 0.01; r = 0.58), OXPHOS, CI+CIIP (P = 0.01; R = 0.58) and COX (P = 0.02; R = 0.52) before training; after training, a correlation was found between MitoVD and CS activity only (P = 0.04; R = 0.49). Intrinsic respiratory capacities decreased (P < 0.05) with training when respiration was normalized to MitoVD. This was not the case when normalized to CS activity although the percentage change was comparable. Conclusions: MitoVD was increased by inducing mitochondrial enlargement rather than de novo biogenesis. CS activity may be appropriate to track training‐induced changes in MitoVD. [ABSTRACT FROM AUTHOR]

Red blood cell volume ( RBCV) is a main determinant of cardiorespiratory fitness in healthy individuals. However, it remains controversial to what extent exercise training (ExT) enhances RBCV. Therefore, we sought to systematically review and determine the effect of ExT on RBCV in healthy individuals across all ages. We conducted a systematic search of MEDLINE, Scopus, and Web of Science, since their inceptions until February 2016 for articles assessing the effect of ExT interventions (not including hypoxic training) on blood volumes in healthy individuals. A meta-analysis was performed to determine the mean difference ( MD) in RBCV between post- and pre-ExT measurements. Thirty studies were included after systematic review, comprising a total of 299 healthy individuals (mean age = 19-71 years, 271 males). Exercise training programs primarily consisted in lower limb endurance training interventions (mean duration = 15.2 weeks). After data pooling, RBCV was not increased following ExT ( MD = 49 mL, 95% CI = −11, 108; P = 0.11). In subgroup analyses, RBCV was increased after ExT in young and middle-aged individuals (mean age <60 year) ( n = 106, MD = 81 mL, 95% CI = 0, 162; P < 0.05) but not in older study participants (mean age ≥60 year) ( n = 110, MD = 13 mL, 95% CI = −76, 102; P = 0.77). Heterogeneity was not detected among studies in young and middle-aged ( I2 = 0%) and older individuals ( I2 = 0%). In conclusion, RBCV is moderately, yet consistently, enhanced by ExT in young and middle-aged but not in older healthy individuals. Therefore, RBCV adaptations to ExT appear to be age dependent. [ABSTRACT FROM AUTHOR]

In this review, we argue that several key features of maximal oxygen uptake (VO2max) should underpin discussions about the biological and reductionist determinants of its interindividual variability: (i) training-induced increases in VO2max are largely facilitated by expansion of red blood cell volume and an associated improvement in stroke volume, which also adapts independent of changes in red blood cell volume. These general concepts are also informed by cross-sectional studies in athletes that have very high values for VO2max. Therefore, (ii) variations in VO2max improvements with exercise training are also likely related to variations in these physiological determinants. (iii) All previously untrained individuals will respond to endurance exercise training in terms of improvements in VO2max provided the stimulus exceeds a certain volume and/or intensity. Thus, genetic analysis and/or reductionist studies performed to understand or predict such variations might focus specifically on DNA variants or other molecular phenomena of relevance to these physiological pathways. [ABSTRACT FROM AUTHOR]

We sought to test the hypothesis that brain blood flow and cerebral vascular responsiveness to carbon dioxide (CVRCO2) are greater in aerobically trained young and old individuals compared to their untrained counterparts. In 11 young trained {[23 (20-26) years] [mean (95% confidence interval)]}, 10 young untrained [25 (22-28) years], 8 older trained [65 (61-69) years], and 9 older untrained [67 (64-71) years] healthy individuals, Doppler ultrasound of the internal carotid ( ICA) and vertebral ( VA) artery blood flow were determined, along with middle cerebral artery mean flow velocity ( MCA Vmean). Bilateral ICA blood flow was higher in trained individuals when compared to untrained (≈31%, P < 0.05), but was not influenced by age. VA blood flow was not affected by age or cardiorespiratory fitness. MCA Vmean was reduced with age [59.5 (55.0-64.1) cm/s young vs 43.6 (38.4-48.9) cm/s old, P < 0.05] with no significant effect of training observed. MCA CVRCO2 were not significantly affected by either age or training status, while ICA CVRCO2 tended to be elevated in the old trained group. These findings indicate that endurance training enhances bilateral ICA but not VA blood flow in both young and older individuals. [ABSTRACT FROM AUTHOR]

Bed rest leads to rapid impairments in glucose tolerance. Plasma volume and thus dilution space for glucose are also reduced with bed rest, but the potential influence on glucose tolerance has not been investigated. Accordingly, the aim was to investigate whether bed rest-induced impairments in glucose tolerance are related to a concomitant reduction in plasma volume. This hypothesis was tested mechanistically by restoring plasma volume with albumin infusion after bed rest and parallel determination of glucose tolerance. Fifteen healthy volunteers (age 24 ± 3 yr, body mass index 23 ± 2 kg/m², maximal oxygen uptake 44 ± 8 ml⋅min-1⋅kg-1; means ± SD) completed 4 days of strict bed rest. Glucose tolerance [oral glucose tolerance test (OGTT)] and plasma and blood volumes (carbon monoxide rebreathing) were assessed before and after 3 days of bed rest. On the fourth day of bed rest, plasma volume was restored by means of an albumin infusion prior to an OGTT. Plasma volume was reduced by 9.9 ± 3.0% on bed rest day 3 and area under the curve for OGTT was augmented by 55 ± 67%. However, no association (R² = 0.09, P = 0.33) between these simultaneously occurring responses was found. While normalization of plasma volume by matched albumin administration (408 ± 104 ml) transiently decreased (P ± 0.05) resting plasma glucose concentration (5.0 ± 0.4 to 4.8 ± 0.3 mmol/l), this did not restore glucose tolerance. Bed rest-induced alterations in dilution space may influence resting glucose values but do not affect area under the curve for OGTT. [ABSTRACT FROM AUTHOR]

Aims Erythropoiesis is a tightly controlled biological event, but its regulation under non-hypoxic conditions, however, remains unresolved. We examined whether acute changes in central venous blood pressure ( CVP) elicited by whole-body tilting affect erythropoietin ( EPO) concentration according to volume-regulating hormones. Methods Plasma EPO, angiotensin II ( ANGII), aldosterone, pro-atrial natriuretic peptide (pro ANP) and copeptin concentrations were measured at supine rest and up to 3 h during 30° head-up ( HUT) and head-down tilt ( HDT) in ten healthy male volunteers. Plasma albumin concentration was used to correct for changes in plasma volume and CVP was estimated through the internal jugular vein ( IJV) aspect ratio with ultrasonography. Results From supine rest, the IJV aspect ratio was decreased and increased throughout HUT and HDT respectively. Plasma EPO concentration increased during HUT (13%; P = 0.001, P for linear component = 0.017), independent of changes in albumin concentration. Moreover, ANGII and copeptin concentrations increased during HUT, while pro ANP decreased. The increase in EPO concentration during HUT disappeared when adjusted for changes in copeptin. During HDT, EPO, ANGII and copeptin concentrations remained unaffected while pro ANP increased. In regression analyses, EPO was positively associated with copeptin ( β = 0.55; 95% CI = 0.18, 0.93; P = 0.004) irrespective of changes in other hormones and albumin concentration. Conclusion Reduction in CVP prompts an increase in plasma EPO concentration independent of hemoconcentration and hence suggests CVP per se as an acute regulator of EPO synthesis. This effect may be explained by changes in volume-regulating hormones. [ABSTRACT FROM AUTHOR]

It is investigated if recombinant human erythropoietin ( rHuEPO) treatment for 15 weeks ( n = 8) reduces extracellular accumulation of metabolic stress markers such as lactate, H+, and K+ during incremental exhaustive exercise. After rHuEPO treatment, normalization of blood volume and composition by hemodilution preceded an additional incremental test. Group averages were calculated for an exercise intensity ∼80% of pre- rHuEPO peak power output. After rHuEPO treatment, leg lactate release to the plasma compartment was similar to before (4.3 ± 1.6 vs 3.9 ± 2.5 mmol/min) and remained similar after hemodilution. Venous lactate concentration was higher ( P < 0.05) after rHuEPO treatment (7.1 ± 1.6 vs 5.2 ± 2.1 mM). Leg H+ release to the plasma compartment after rHuEPO was similar to before (19.6 ± 5.4 vs 17.6 ± 6.0 mmol/min) and remained similar after hemodilution. Nevertheless, venous pH was lower ( P < 0.05) after rHuEPO treatment (7.18 ± 0.04 vs 7.22 ± 0.05). Leg K+ release to the plasma compartment after rHuEPO treatment was similar to before (0.8 ± 0.5 vs 0.7 ± 0.7 mmol/min) and remained similar after hemodilution. Additionally, venous K+ concentrations were similar after vs before rHuEPO (5.3 ± 0.3 vs 5.1 ± 0.4 mM). In conclusion, rHuEPO does not reduce plasma accumulation of lactate, H+, and K+ at work rates corresponding to ∼80% of peak power output. [ABSTRACT FROM AUTHOR]

High altitude (HA) exposure facilitates a rapid contraction of plasma volume (PV) and a slower occurring expansion of hemoglobin mass (Hbmass). The kinetics of the Hbmass expansion has never been examined by multiple repeated measurements, and this was our primary study aim. The second aim was to investigate the mechanisms mediating the PV contraction. Nine healthy, normally trained sea-level (SL) residents (8 males, 1 female) sojourned for 28 days at 3,454 m. Hbmass was measured and PV was estimated by carbon monoxide rebreathing at SL, on every 4th day at HA, and 1 and 2 wk upon return to SL. Four weeks at HA increased Hbmass by 5.26% (range 2.5-11.1%; P < 0.001). The individual Hbmass increases commenced with up to 12 days of delay and reached a maximal rate of 4.04 ± 1.02 g/day after 14.9 ± 5.2 days. The probability for Hbmass to plateau increased steeply after 20-24 days. Upon return to SL Hbmass decayed by-2.46± 2.3 g/day, reaching values similar to baseline after 2 wk. PV, aldosterone concentration, and renin activity were reduced at HA (P < 0.001) while the total circulating protein mass remained unaffected. In summary, the Hbmass response to HA exposure followed a sigmoidal pattern with a delayed onset and a plateau after ~3 wk. The decay rate of Hbmass upon descent to SL did not indicate major changes in the rate of erythrolysis. Moreover, our data support that PV contraction at HA is regulated by the renin-angiotensin-aldosterone axis and not by changes in oncotic pressure. [ABSTRACT FROM AUTHOR]

Our objective is to highlight some key physiological determinants of endurance exercise performance and to discuss how these can be further improved. VO2max remains remarkably stable throughout an athletic career. By contrast, exercise economy, lactate threshold, and critical power may be improved in world-class athletes by specific exercise training regimes and/or with more years of training [ABSTRACT FROM AUTHOR]

Hypoxia increases the heart rate response to exercise, but the mechanism(s) remains unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate, but not combined, inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exercise to exhaustion in normoxia and hypoxia (fraction of inspired O² = 12%) after intravenous administration of 1) no drugs (Cont), 2) propranolol (Prop), 3) glycopyrrolate (Glyc), or 4) Prop + Glyc. HR increased with exercise in all drug conditions (P < 0.001) but was always higher at a given workload in hypoxia than normoxia (P < 0.001). Averaged over all workloads, the difference between hypoxia and normoxia was 19.8 ± 13.8 beats/min during Cont and similar (17.2 ± 7.7 beats/min, P = 0.95) during Prop but smaller (P < 0.001) during Glyc and Prop + Glyc (9.8 ± 9.6 and 8.1 ± 7.6 beats/min, respectively). Cardiac output was enhanced by hypoxia (P < 0.002) to an extent that was similar between Cont, Glyc, and Prop + Glyc (2.3 ± 1.9, 1.7 ± 1.8, and 2.3 ± 1.2 l/min, respectively, P > 0.4) but larger during Prop (3.4 ± 1.6 l/min, P = 0.004). Our results demonstrate that the tachycardic effect of hypoxia during exercise partially relies on vagal withdrawal. Conversely, sympathoexcitation either does not contribute or increases heart rate through mechanisms other than β-adrenergic transmission. A potential candidate is α-adrenergic transmission, which could also explain why a tachycardic effect of hypoxia persists during combined β-adrenergic and muscarinic receptor inhibition. [ABSTRACT FROM AUTHOR]

To elucidate the molecular mechanisms behind physical inactivity-induced insulin resistance in skeletal muscle, 12 young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies obtained before and after. In six of the subjects, muscle biopsies were taken from both legs before and after a 3-h hyperinsulinemic euglycemic clamp performed 3 h after a 45-min, one-legged exercise. Blood samples were obtained from one femoral artery and both femoral veins before and during the clamp. Glucose infusion rate and leg glucose extraction during the clamp were lower after than before bed rest. This bed rest-induced insulin resistance occurred together with reduced muscle GLUT4, hexokinase II, protein kinase B/Akt1, and Akt2 protein level, and a tendency for reduced 3-hydroxyacyl-CoA dehydrogenase activity. The ability of insulin to phosphorylate Akt and activate glycogen synthase (GS) was reduced with normal GS site 3 but abnormal GS site 2+2a phosphorylation after bed rest. Exercise enhanced insulin-stimulated leg glucose extraction both before and after bed rest, which was accompanied by higher GS activity in the prior-exercised leg than the rested leg. The present findings demonstrate that physical inactivity-induced insulin resistance in muscle is associated with lower content/activity of key proteins in glucose transport/phosphorylation and storage. [ABSTRACT FROM AUTHOR]

Blood doping practices in sports have been around for at least half a century and will likely remain for several years to come. The main reason for the various forms of blood doping to be common is that they are easy to perform, and the effects on exercise performance are gigantic. Yet another reason for blood doping to be a popular illicit practice is that detection is difficult. For autologous blood transfusions, for example, no direct test exists, and the direct testing of misuse with recombinant human erythropoietin (rhEpo) has proven very difficult despite a test exists. Future blood doping practice will likely include the stabilization of the transcription factor hypoxia-inducible factor which leads to an increased endogenous erythropoietin synthesis. It seems unrealistic to develop specific test against such drugs (and the copies hereof originating from illegal laboratories). In an attempt to detect and limit blood doping, the World Anti-Doping Agency (WADA) has launched the Athlete Biological Passport where indirect markers for all types of blood doping are evaluated on an individual level. The approach seemed promising, but a recent publication demonstrates the system to be incapable of detecting even a single subject as 'suspicious' while treated with rhEpo for 10-12 weeks. Sad to say, the hope that the 2012 London Olympics should be cleaner in regard to blood doping seems faint. We propose that WADA strengthens the quality and capacities of the National Anti-Doping Agencies and that they work more efficiently with the international sports federations in an attempt to limit blood doping. [ABSTRACT FROM AUTHOR]

Human endurance, performance can be predicted from maximal oxygen consumption (Vo2max), lactate threshold, and exercise efficiency. These physiological parameters, however, are not wholly exclusive from one another, and their interplay is complex. Accordingly, we sought to identify more specific measurements explaining the range of performance among athletes. Out of 150 separate variables we identified 10 principal factors responsible for hematological, cardiovascular, respiratory, musculo-skeletal, and neurological variation in 16 highly trained cyclists. These principal factors were then correlated with a 26-km time trial and test of maximal incremental power output. Average power output during the 26-km time trial was attributed to, in order of importance, oxidative phosphorylation capacity of the vastus lateralis muscle (P = 0.0005), steady-state submaximal blood lactate concentrations (P = 0.0017), and maximal leg oxygenation (SO2LEG) (P = 0.0295), accounting for 78% of the variation in time trial performance. Variability in maximal power output, on the other hand, was attributed to total body hemoglobin mass (Hbmass; P = 0.0038), V̇O2max (P = 0.0213), and SO2LEG (P = 0.0463). In conclusion, 1) skeletal muscle oxidative capacity is the primary predictor of time trial performance in highly trained cyclists; 2) the strongest predictor for maximal incremental power output is Hbmass; and 3) overall exercise performance (time trial performance + maximal incremental power output) correlates most strongly to measures regarding the capability for oxygen transport, high V̇Oo2max and Hbmass, in addition to measures of oxygen utilization, maximal oxidative phosphorylation, and electron transport system capacities in the skeletal muscle. [ABSTRACT FROM AUTHOR]

INTRODUCTION:: The hypothesis that brief intermittent exercise-induced increases in human skeletal muscle metabolic mRNA is dependent on relative workload was investigated. METHODS:: Trained (n = 10) and untrained (n = 8) subjects performed exhaustive intermittent cycling exercise (4 x 4 min at 85% of V O2peak, interspersed by 3 min). Trained subjects also performed the intermittent exercise at the same absolute workload as the untrained subjects, corresponding to 70% of V O2peak (n = 6). RESULTS:: Exercise at 85% of V O2peak elevated (P < 0.001) venous plasma lactate to 10.1 +/- 0.4 and 10.8 +/- 0.5 mM in the trained and untrained subjects, respectively. Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) mRNA expression was increased (P < 0.001) approximately four- to fivefold for several hours after exercise in both groups. After exercise at 70% of V O2peak, venous plasma lactate was less (P < 0.001) elevated (3.1 +/- 0.7 mM) and PGC-1alpha mRNA content was less (P < 0.05) increased (approximately threefold) than after exercise at 85% of V O2peak. Likewise, pyruvate dehydrogenase kinase 4 and hexokinase II mRNA expressions were increased (P < 0.05) only after exercise performed at 85% of V O2peak in the trained subjects. Hypoxia-inducible factor 2alpha mRNA only increased (P < 0.05) 3 h into recovery in trained subjects, with no difference between the 70% and 85% of V O2peak trial. No change in hypoxia-inducible factor 1alpha, phosphofructokinase, citrate synthase, or lactate dehydrogenase, heart and muscle isoforms, mRNA expressions was detected after any of the exercise trials. CONCLUSIONS:: The relative intensity of brief intermittent exercise is of major importance for the exercise-induced increase of several mRNA, including PGC-1alpha. [ABSTRACT FROM AUTHOR]

Recombinant human erythropoietin (EPO) increases exercise capacity by stimulating erythropoiesis and subsequently enhancing oxygen delivery to the working muscles. In a large dose, EPO crosses the BBB and may reduce central fatigue and improve cognition. In turn, this would augment exercise capacity independent of erythropoiesis. To test this hypothesis, 15 healthy young men (18-34 years old, 74 ± 7 kg) received either 3 days of high-dose (30,000 IU/day; n = 7) double-blinded placebo controlled or 3 mo of low-dose (5,000 IU/wk; n = 8) counter-balanced open but controlled administration of EPO. We recorded exercise capacity, transcranial ultrasonography-derived middle cerebral artery blood velocity, and arterial-internal jugular venous concentration differences of glucose and lactate. In addition, cognitive function, ratings of perceived exertion, ventilation, and voluntary activation by transcranial magnetic stimulation-induced twitch force were evaluated. Although EPO in a high dose increased cerebrospinal fluid EPO concentration ~20-fold and affected ventilation and cerebral glucose and lactate metabolism (P < 0.05), 3 days of high-dose EPO administration had no effect on cognition, voluntary activation, or exercise capacity, but ratings of perceived exertion increased (P < 0.05). We confirmed that 3 mo of administration of EPO increases exercise capacity, but the improvement could not be accounted for by other mechanisms than enhanced oxygen delivery. In conclusion, EPO does not attenuate central fatigue or change cognitive performance strategy, suggesting that EPO enhances exercise capacity exclusively by increased oxygen delivery to the working muscles. [ABSTRACT FROM AUTHOR]

Aim: To investigate if exercise intensity and Ca2+ signalling regulate Na+,K+ pump mRNA expression in skeletal muscle. Methods: The importance of exercise intensity was evaluated by having trained and untrained humans perform intense intermittent and prolonged exercise. The importance of Ca2+ signalling was investigated by electrical stimulation of rat soleus and extensor digitorum longus (EDL) muscles in combination with studies of cell cultures. Results: Intermittent cycling exercise at ∼85% of VO2peak increased ( P < 0.05) α1 and β1 mRNA expression ∼2-fold in untrained and trained subjects. In trained subjects, intermittent exercise at ∼70% of VO2peak resulted in a less ( P < 0.05) pronounced increase (∼1.4-fold; P < 0.05) for α1 and no change in β1 mRNA. Prolonged low intensity exercise increased ( P < 0.05) mRNA expression of α1 ∼3.0-fold and α2 ∼1.8-fold in untrained but not in trained subjects. Electrical stimulation of rat soleus, but not EDL, muscle increased ( P < 0.05) α1 mRNA expression, but not when combined with KN62 and cyclosporin A incubation. Ionomycin incubation of cultured primary rat skeletal muscle cells increased ( P < 0.05) α1 and reduced ( P < 0.001) α2 mRNA expression and these responses were abolished ( P < 0.05) by co-incubation with cyclosporin A or KN62. Conclusion: (1) Exercise-induced increases in Na+,K+ pump α1 and β1 mRNA expression in trained subjects are more pronounced after high- than after moderate- and low-intensity exercise. (2) Both prolonged low and short-duration high-intensity exercise increase α1 mRNA expression in untrained subjects. (3) Ca2+i regulates α1 mRNA expression in oxidative muscles via Ca2+/calmodulin-dependent protein kinase (CaMK) and calcineurin signalling pathways. [ABSTRACT FROM AUTHOR]

This study was performed to test the hypothesis that administration of recombinant human erythropoietin (rHuEpo) in humans increases maximal oxygen consumption by augmenting the maximal oxygen carrying capacity of blood. Systemic and leg oxygen delivery and oxygen uptake were studied during exercise in eight subjects before and after 13 wk of rHuEpo treatment and after isovolemic hemodilution to the same hemoglobin concentration observed before the start of rHuEpo administration. At peak exercise, leg oxygen delivery was increased from 1,777.0 ± 102.0 mI/mm before rHuEpo treatment to 2,079.8 ± 120.7 mI/mm after treatment. After hemodilution, oxygen delivery was decreased to the pretreatment value (1,710.3 ± 138.1 mI/mm). Fractional leg arterial oxygen extraction was unaffected at maximal exercise; hence, maximal leg oxygen uptake increased from 1,511.0 ± 130.1 ml/min before treatment to 1,793.0 ± 148.7 ml/min with rHuEpo and decreased after hemodilution to 1,428.0 ± 111.6 mI/mm. Pulmonary oxygen uptake at peak exercise increased from 3,950.0 ± 160.7 before administration to 4,254.5 ± 178.4 mI/mm with rHuEpo and decreased to 4,059.0 ± 161.1 mI/mm with hemodilution (P = 0.22, compared with values before rHuEpo treatment). Blood buffer capacity remained unaffected by rHuEpo treatment and hemodilution. The augmented hematocrit did not compromise peak cardiac output. In summary, in healthy humans, rHuEpo increases maximal oxygen consumption due to augmented systemic and muscular peak oxygen delivery. [ABSTRACT FROM AUTHOR]

Adaptations to chronic hypoxia involve changes in membrane transport proteins. The underlying mechanism of this response may be related to concomitant occurring changes in erythropoietin (Epo) levels. We therefore tested the direct effects of recombinant human erythropoietin (rHuEpo) treatment on the expression of muscle membrane transport proteins. Likewise, improvements in performance may involve upregulation of metabolic enzymes. Since Epo is known to augment performance we tested the effect of rHuEpo on some marker enzymes that are related to aerobic capacity. For these purposes eight subjects received 5,000 IU rHuEpo every second day for 14 days, and subsequently a single dose of 5,000 IU weekly for 12 weeks. Muscle biopsies were obtained before and after 14 weeks of rHuEpo treatment. The treatment increased hematocrit (from 44.7 to 48.8%), maximal oxygen uptake by 8.1%, and submaximal performance by approximately 54%. Membrane transport systems and carbonic anhydrases involved in pH regulation remained unchanged. Of the Na+, K+-pump isoforms only the density of the α2 subunit was decreased (by 22%) after treatment. The marker enzymes cytochrom c and hexokinase remained unchanged with the treatment. In conclusion, changes in muscle membrane transport proteins and selected muscle enzymes do not contribute to the Epo-induced improvement in performance. [ABSTRACT FROM AUTHOR]

During maximal whole body exercise V̇o2peak is limited by O2 delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2 delivery and leg V̇o2 during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 μg·kg body mass-1·min-1. During near-maximal exercise (92% of V̇o2 peak), the infusion of ATP increased leg vascular conductance (+43%, P < 0.05), leg blood flow (+20%, 1.7 l/min, P < 0.05), and leg O2 delivery (+20%, 0.3 l/min, P < 0.05). No effects were observed on leg or systemic V̇o2. Leg O2 fractional extraction was decreased from 85 ± 3 (control) to 78 ± 4% (ATP) in the infused leg (P < 0.05), while it remained unchanged in the left leg (84 ± 2 and 83 ± 2%; control and ATP; n = 3). ATP infusion at maximal exercise increased leg vascular conductance by 17% (P < 0.05), while leg blood flow tended to be elevated by 0.8 l/min (P = 0.08). However, neither systemic nor leg peak Vo2 values where enhanced due to a reduction of O2 extraction from 84 ± 4 to 76 ± 4%, in the control and ATP conditions, respectively (P < 0.05). In summary, the V̇o2 of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2 extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active muscle fibers of the exercising limb. [ABSTRACT FROM AUTHOR]