Physiological and molecular predictors of cycling sprint performance.

The study aimed to identify novel muscle phenotypic factors that could determine sprint performance using linear regression models including the lean mass of the lower extremities (LLM), myosin heavy chain composition (MHC), and proteins and enzymes implicated in glycolytic and aerobic energy generation (citrate synthase, OXPHOS proteins), oxygen transport and diffusion (myoglobin), ROS sensing (Nrf2/Keap1), antioxidant enzymes, and proteins implicated in calcium handling. For this purpose, body composition (dual-energy X-ray absorptiometry) and sprint performance (isokinetic 30-s Wingate test: peak and mean power output, Wpeak and Wmean ) were measured in young physically active adults (51 males and 10 females), from which a resting muscle biopsy was obtained from the musculus vastus lateralis. Although females had a higher percentage of MHC I, SERCA2, pSer16 /Thr17 -phospholamban, and Calsequestrin 2 protein expressions (all p < 0.05), and 18.4% lower phosphofructokinase 1 protein expression than males (p < 0.05), both sexes had similar sprint performance when it was normalized to body weight or LLM. Multiple regression analysis showed that Wpeak could be predicted from LLM, SDHB, Keap1, and MHC II % (R 2 = 0.62, p < 0.001), each variable contributing to explain 46.4%, 6.3%, 4.4%, and 4.3% of the variance in Wpeak , respectively. LLM and MHC II % explained 67.5% and 2.1% of the variance in Wmean , respectively (R 2 = 0.70, p < 0.001). The present investigation shows that SDHB and Keap1, in addition to MHC II %, are relevant determinants of peak power output during sprinting.

Pulmonary ventilation and gas exchange during prolonged exercise in humans: Influence of dehydration, hyperthermia and sympathoadrenal activity.

NEW FINDINGS: What is the central question of the study? Ventilation increases during prolonged intense exercise, but the impact of dehydration and hyperthermia, with associated blunting of pulmonary circulation, and independent influences of dehydration, hyperthermia and sympathoadrenal discharge on ventilatory and pulmonary gas exchange responses remain unclear. What is the main finding and its importance? Dehydration and hyperthermia led to hyperventilation and compensatory adjustments in pulmonary CO2 and O2 exchange, such that CO2 output increased and O2 uptake remained unchanged despite the blunted circulation. Isolated hyperthermia and adrenaline infusion, but not isolated dehydration, increased ventilation to levels similar to combined dehydration and hyperthermia. Hyperthermia is the main stimulus increasing ventilation during prolonged intense exercise, partly via sympathoadrenal activation. ABSTRACT: The mechanisms driving hyperthermic hyperventilation during exercise are unclear. In a series of retrospective analyses, we evaluated the impact of combined versus isolated dehydration and hyperthermia and the effects of sympathoadrenal discharge on ventilation and pulmonary gas exchange during prolonged intense exercise. In the first study, endurance-trained males performed two submaximal cycling exercise trials in the heat. On day 1, participants cycled until volitional exhaustion (135 ± 11 min) while experiencing progressive dehydration and hyperthermia. On day 2, participants maintained euhydration and core temperature (Tc ) during a time-matched exercise (control). At rest and during the first 20 min of exercise, pulmonary ventilation ( V ̇ E ${\skew2\dot V_{\rm{E}}}$ ), arterial blood gases, CO2 output and O2 uptake were similar in both trials. At 135 ± 11 min, however, V ̇ E ${\skew2\dot V_{\rm{E}}}$ was elevated with dehydration and hyperthermia, and this was accompanied by lower arterial partial pressure of CO2 , higher breathing frequency, arterial partial pressure of O2 , arteriovenous CO2 and O2 differences, and elevated CO2 output and unchanged O2 uptake despite a reduced pulmonary circulation. The increased V ̇ E ${\skew2\dot V_{\rm{E}}}$ was closely related to the rise in Tc and circulating catecholamines (R2  ≥ 0.818, P ≤ 0.034). In three additional studies in different participants, hyperthermia independently increased V ̇ E ${\skew2\dot V_{\rm{E}}}$ to an extent similar to combined dehydration and hyperthermia, whereas prevention of hyperthermia in dehydrated individuals restored V ̇ E ${\skew2\dot V_{\rm{E}}}$ to control levels. Furthermore, adrenaline infusion during exercise elevated both Tc and V ̇ E ${\skew2\dot V_{\rm{E}}}$ . These findings indicate that: (1) adjustments in pulmonary gas exchange limit homeostatic disturbances in the face of a blunted pulmonary circulation; (2) hyperthermia is the main stimulus increasing ventilation during prolonged intense exercise; and (3) sympathoadrenal activation might partly mediate the hyperthermic hyperventilation.

Functional reserve and sex differences during exercise to exhaustion revealed by post-exercise ischaemia and repeated supramaximal exercise.

KEY POINTS: Females have lower fatigability than males during single limb isometric and dynamic contractions, but whether sex-differences exist during high-intensity whole-body exercise remains unknown. This study shows that males and females respond similarly to repeated supramaximal whole-body exercise, and that at task failure a large functional reserve remains in both sexes. Using post-exercise ischaemia with repeated exercise, we have shown that this functional reserve depends on the glycolytic component of substrate-level phosphorylation and is almost identical in both sexes. Metaboreflex activation during post-exercise ischaemia and the O2 debt per kg of active lean mass are also similar in males and females after supramaximal exercise. Females have a greater capacity to extract oxygen during repeated supramaximal exercise and reach lower PETCO2 , experiencing a larger drop in brain oxygenation than males, without apparent negative repercussion on performance. Females had no faster recovery of performance after accounting for sex differences in lean mass. ABSTRACT: The purpose of this study was to ascertain what mechanisms explain sex differences at task failure and to determine whether males and females have a functional reserve at exhaustion. Exercise performance, cardiorespiratory variables, oxygen deficit, and brain and muscle oxygenation were determined in 18 males and 18 females (21-36 years old) in two sessions consisting of three bouts of constant-power exercise at 120% of V̇O2max until exhaustion interspaced by 20 s recovery periods. In one of the two sessions, the circulation of both legs was occluded instantaneously (300 mmHg) during the recovery periods. Females had a higher muscle O2 extraction during fatiguing supramaximal exercise than males. Metaboreflex activation, and lean mass-adjusted O2 deficit and debt were similar in males and females. Compared to males, females reached lower PETCO2 and brain oxygenation during supramaximal exercise, without apparent negative consequences on performance. After the occlusions, males and females were able to restart exercising at 120% of V̇O2max , revealing a similar functional reserve, which depends on glycolytic component of substrate-level phosphorylation and its rate of utilization. After ischaemia, muscle O2 extraction was increased, and muscle V̇O2 was similarly reduced in males and females. The physiological response to repeated supramaximal exercise to exhaustion is remarkably similar in males and females when differences in lean mass are considered. Both sexes fatigue with a large functional reserve, which depends on the glycolytic energy supply, yet females have higher oxygen extraction capacity, but reduced PETCO2 and brain oxygenation.

Resting metabolic rate is increased in hypertensive patients with overweight or obesity: Potential mechanisms.

The purpose of this investigation was to determine whether differences in body composition, pharmacological treatment, and physical activity explain the increased resting metabolic rate (RMR) and impaired insulin sensitivity in hypertension. Resting blood pressure, RMR (indirect calorimetry), body composition (dual-energy X-ray absorptiometry), physical activity (accelerometry), maximal oxygen uptake (VO2 max) (ergospirometry), and insulin sensitivity (Matsuda index) were measured in 174 patients (88 men and 86 women; 20-68 years) with overweight or obesity. Hypertension (HTA) was present in 51 men (58%) and 42 women (49%) (p = .29). RMR was 6.9% higher in hypertensives than normotensives (1777 ± 386 and 1663 ± 383 kcal d-1 , p = .044). The double product (systolic blood pressure × heart rate) was 18% higher in hypertensive than normotensive patients (p < .001). The observed differences in absolute RMR were non-significant after adjusting for total lean mass and total fat mass (estimated means: 1702 kcal d-1 , CI: 1656-1750; and 1660 kcal d-1 , CI: 1611-1710 kcal d-1 , for the hypertensive and normotensive groups, respectively, p = .19, HTA × sex interaction p = .37). Lean mass, the double product, and age were the variables with the higher predictive value of RMR in hypertensive patients. Insulin sensitivity was lower in hypertensive than in normotensive patients, but these differences disappeared after accounting for physical activity and VO2max . In summary, hypertension is associated with increased RMR and reduced insulin sensitivity. The increased RMR is explained by an elevated myocardial oxygen consumption due to an increased resting double product, combined with differences in body composition between hypertensive and normotensive subjects.

Role of CaMKII and sarcolipin in muscle adaptations to strength training with different levels of fatigue in the set.

Strength training promotes a IIX-to-IIA shift in myosin heavy chain (MHC) composition, likely due to changes in sarcoplasmic [Ca2+ ] which are sensed by CaMKII. Sarcoplasmic [Ca2+ ] is in part regulated by sarcolipin (SLN), a small protein that when overexpressed in rodents stimulates mitochondrial biogenesis and a fast-to-slow fiber type shift. The purpose of this study was to determine whether CaMKII and SLN are involved in muscle phenotype and performance changes elicited by strength training. Twenty-two men followed an 8-week velocity-based resistance training program using the full squat exercise while monitoring repetition velocity. Subjects were randomly assigned to two resistance training programs differing in the repetition velocity loss allowed in each set: 20% (VL20) vs 40% (VL40). Strength training caused muscle hypertrophy, improved 1RM and increased total CaMKII protein expression, particularly of the δD isoform. Phospho-Thr287 -CaMKII δD expression increased only in VL40 (+89%), which experienced greater muscle hypertrophy, and a reduction in MHC-IIX percentage. SLN expression was increased in VL20 (+33%) remaining unaltered in VL40. The changes in phospho-Thr287 -CaMKII δD were positively associated with muscle hypertrophy and the number of repetitions during training, and negatively with the changes in MHC-IIX and SLN. Most OXPHOS proteins remained unchanged, except for NDUFB8 (Complex I), which was reduced after training (-22%) in both groups. The amount of fatigue allowed in each set critically influences muscle CaMKII and SLN responses and determines muscle phenotype changes. With lower intra-set fatigue, the IIX-to-IIA MHC shift is attenuated.

Angiotensin-Converting Enzyme 2 (SARS-CoV-2 receptor) expression in human skeletal muscle.

The study aimed to determine the levels of skeletal muscle angiotensin-converting enzyme 2 (ACE2, the SARS-CoV-2 receptor) protein expression in men and women and assess whether ACE2 expression in skeletal muscle is associated with cardiorespiratory fitness and adiposity. The level of ACE2 in vastus lateralis muscle biopsies collected in previous studies from 170 men (age: 19-65 years, weight: 56-137 kg, BMI: 23-44) and 69 women (age: 18-55 years, weight: 41-126 kg, BMI: 22-39) was analyzed in duplicate by western blot. VO2 max was determined by ergospirometry and body composition by DXA. ACE2 protein expression was 1.8-fold higher in women than men (p = 0.001, n = 239). This sex difference disappeared after accounting for the percentage of body fat (fat %), VO2 max per kg of legs lean mass (VO2 max-LLM) and age (p = 0.47). Multiple regression analysis showed that the fat % (ß = 0.47) is the main predictor of the variability in ACE2 protein expression in skeletal muscle, explaining 5.2% of the variance. VO2 max-LLM had also predictive value (ß = 0.09). There was a significant fat % by VO2 max-LLM interaction, such that for subjects with low fat %, VO2 max-LLM was positively associated with ACE2 expression while as fat % increased the slope of the positive association between VO2 max-LLM and ACE2 was reduced. In conclusion, women express higher amounts of ACE2 in their skeletal muscles than men. This sexual dimorphism is mainly explained by sex differences in fat % and cardiorespiratory fitness. The percentage of body fat is the main predictor of the variability in ACE2 protein expression in human skeletal muscle.

Increased oxygen extraction and mitochondrial protein expression after small muscle mass endurance training.

When exercising with a small muscle mass, the mass-specific O2 delivery exceeds the muscle oxidative capacity resulting in a lower O2 extraction compared with whole-body exercise. We elevated the muscle oxidative capacity and tested its impact on O2 extraction during small muscle mass exercise. Nine individuals conducted six weeks of one-legged knee extension (1L-KE) endurance training. After training, the trained leg (TL) displayed 45% higher citrate synthase and COX-IV protein content in vastus lateralis and 15%-22% higher pulmonary oxygen uptake ( V ˙ O 2 peak ) and peak power output ( W ˙ peak ) during 1L-KE than the control leg (CON; all P < .05). Leg O2 extraction (catheters) and blood flow (ultrasound Doppler) were measured while both legs exercised simultaneously during 2L-KE at the same submaximal power outputs (real-time feedback-controlled). TL displayed higher O2 extraction than CON (main effect: 1.7 ± 1.6% points; P = .010; 40%-83% of W ˙ peak ) with the largest between-leg difference at 83% of W ˙ peak (O2 extraction: 3.2 ± 2.2% points; arteriovenous O2 difference: 7.1 ± 4.8 mL· L-1 ; P < .001). At 83% of W ˙ peak , muscle O2 conductance (DM O2 ; Fick law of diffusion) and the equilibration index Y were higher in TL (P < .01), indicating reduced diffusion limitations. The between-leg difference in O2 extraction correlated with the between-leg ratio of citrate synthase and COX-IV (r = .72-.73; P = .03), but not with the difference in the capillary-to-fiber ratio (P = .965). In conclusion, endurance training improves O2 extraction during small muscle mass exercise by elevating the muscle oxidative capacity and the recruitment of DM O2, especially evident during high-intensity exercise exploiting a larger fraction of the muscle oxidative capacity.

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise.

Sarcolipin (SLN) is a SERCA uncoupling protein associated with exercise performance and lower adiposity in mice. To determine SLN protein expression in human skeletal muscle and its relationship with adiposity, resting energy expenditure (REE), and performance, SLN was assessed by Western blot in 199 biopsies from two previous studies. In one study, 15 overweight volunteers underwent a pretest followed by 4 days of caloric restriction and exercise (45-minute one-arm cranking + 8-hour walking), and 3 days on a control diet. Muscle biopsies were obtained from the trained and non-exercised deltoid, and vastus lateralis (VL). In another study, 16 men performed seven sessions of 4-6 × 30-sec all-out sprints on the cycle ergometer with both limbs, and their VL and triceps brachii biopsied pre- and post-training. SLN expression was twofold and 44% higher in the VL than in the deltoids and triceps brachii, respectively. SLN was associated with neither adiposity nor REE, and was not altered by a severe energy deficit (5500 kcal/day). SLN and cortisol changes after the energy deficit were correlated (r = .38, P = .039). SLN was not altered by low-intensity exercise in the overweight subjects, whereas it was reduced after sprint training in the other group. The changes in SLN with sprint training were inversely associated with the changes in gross efficiency (r = -.59, P = .016). No association was observed between aerobic or anaerobic performance and SLN expression. In conclusion, sarcolipin appears to play no role in regulating the fat mass of men. Sprint training reduces sarcolipin expression, which may improve muscle efficiency.

Protein synthesis signaling in skeletal muscle is refractory to whey protein ingestion during a severe energy deficit evoked by prolonged exercise and caloric restriction.

BACKGROUND: Exercise and protein ingestion preserve muscle mass during moderate energy deficits. OBJECTIVE: To determine the molecular mechanisms by which exercise and protein ingestion may spare muscle mass during severe energy deficit (5500 kcal/day). DESIGN: Fifteen overweight, but otherwise healthy men, underwent a pre-test (PRE), caloric restriction (3.2 kcals/kg body weight/day) + exercise (45 min one-arm cranking + 8 h walking) for 4 days (CRE), followed by a control diet (CD) for 3 days, with a caloric content similar to pre-intervention while exercise was reduced to less than 10,000 steps per day. During CRE, participants ingested either whey protein (PRO, n = 8) or sucrose (SU, n = 7) (0.8 g/kg body weight/day). Muscle biopsies were obtained from the trained and untrained deltoid, and vastus lateralis. RESULTS: Following CRE and CD, serum concentrations of leptin, insulin, and testosterone were reduced, whereas cortisol and the catabolic index (cortisol/total testosterone) increased. The Akt/mTor/p70S6K pathway and total eIF2α were unchanged, while total 4E-BP1 and Thr37/464E-BP1 were higher. After CRE, plasma BCAA and EAA were elevated, with a greater response in PRO group, and total GSK3ß, pSer9GSK3ß, pSer51eIF2α, and pSer51eIF2α/total eIF2α were reduced, with a greater response of pSer9GSK3ß in the PRO group. The changes in signaling were associated with the changes in leptin, insulin, amino acids, cortisol, cortisol/total testosterone, and lean mass. CONCLUSIONS: During severe energy deficit, pSer9GSK3ß levels are reduced and human skeletal muscle becomes refractory to the anabolic effects of whey protein ingestion, regardless of contractile activity. These effects are associated with the changes in lean mass and serum insulin, testosterone, and cortisol concentrations.

Impact of data averaging strategies on V̇O2max assessment: Mathematical modeling and reliability.

BACKGROUND: No consensus exists on how to average data to optimize V ˙ O2max assessment. Although the V ˙ O2max value is reduced with larger averaging blocks, no mathematical procedure is available to account for the effect of the length of the averaging block on V ˙ O2max. AIMS: To determine the effect that the number of breaths or seconds included in the averaging block has on the V ˙ O2max value and its reproducibility and to develop correction equations to standardize V ˙ O2max values obtained with different averaging strategies. METHODS: Eighty-four subjects performed duplicate incremental tests to exhaustion (IE) in the cycle ergometer and/or treadmill using two metabolic carts (Vyntus and Vmax N29). Rolling breath averages and fixed time averages were calculated from breath-by-breath data from 6 to 60 breaths or seconds. RESULTS: V ˙ O2max decayed from 6 to 60 breath averages by 10% in low fit ( V ˙ O2max  < 40 mL kg-1  min-1 ) and 6.7% in trained subjects. The V ˙ O2max averaged from a similar number of breaths or seconds was highly concordant (CCC > 0.97). There was a linear-log relationship between the number of breaths or seconds in the averaging block and V ˙ O2max (R2  > 0.99, P < 0.001), and specific equations were developed to standardize V ˙ O2max values to a fixed number of breaths or seconds. Reproducibility was higher in trained than low-fit subjects and not influenced by the averaging strategy, exercise mode, maximal respiratory rate, or IE protocol. CONCLUSIONS: The V ˙ O2max decreases following a linear-log function with the number of breaths or seconds included in the averaging block and can be corrected with specific equations as those developed here.

Antioxidants Facilitate High-intensity Exercise IL-15 Expression in Skeletal Muscle.

Interleukin (IL)-15 stimulates mitochondrial biogenesis, fat oxidation, glucose uptake and myogenesis in skeletal muscle. However, the mechanisms by which exercise triggers IL-15 expression remain to be elucidated in humans. This study aimed at determining whether high-intensity exercise and exercise-induced RONS stimulate IL-15/IL-15Rα expression and its signaling pathway (STAT3) in human skeletal muscle. Nine volunteers performed a 30-s Wingate test in normoxia and hypoxia (PIO2=75 mmHg), 2 h after placebo or antioxidant administration (α-lipoic acid, vitamin C and E) in a randomized double-blind design. Blood samples and muscle biopsies (vastus lateralis) were obtained before, immediately after, and 30 and 120 min post-exercise. Sprint exercise upregulated skeletal muscle IL-15 protein expression (ANOVA, P=0.05), an effect accentuated by antioxidant administration in hypoxia (ANOVA, P=0.022). In antioxidant conditions, the increased IL-15 expression at 120 min post-exercise (33%; P=0.017) was associated with the oxygen deficit caused by the sprint (r=-0.54; P=0.020); while, IL-15 and Tyr705-STAT3 AUCs were also related (r=0.50; P=0.036). Antioxidant administration promotes IL-15 protein expression in human skeletal muscle after sprint exercise, particularly in severe acute hypoxia. Therefore, during intense muscle contraction, a reduced PO2 and glycolytic rate, and possibly, an attenuated RONS generation may facilitate IL-15 production, accompanied by STAT3 activation, in a process that does not require AMPK phosphorylation.

The core musculature in male prepubescent tennis players and untrained counterparts: a volumetric MRI study.

The effects of exercise on the core musculature have not been investigated in prepubescents. The main purpose of the present study was to determine the volume and degree of asymmetry of rectus abdominis, obliques and transversus abdominis, quadratus lumborum, iliopsoas, gluteus and paravertebralis muscles in prepubescent tennis players and in untrained boys. The muscle volume was determined using magnetic resonance imaging (MRI) in 7 male prepubescent tennis players and 10 untrained controls (mean age 11.0 ± 0.8 years, Tanner 1-2). After accounting for height and body weight as covariates, the tennis players had 14-34% greater volume than the controls in all the muscles analysed (P < 0.05) except in paravertebralis, dominant quadratus lumborum and non-dominant gluteus, which had similar volumes in both groups (P = NS). Compared to controls, the tennis players displayed a greater degree of asymmetry in quadratus lumborum and rectus abdominis (3% vs. 15%, P < 0.01 and 8% vs. 17%, P = 0.06, respectively). The level of asymmetry of obliques and transversus abdominis, iliopsoas, gluteus and paravertebralis muscles was similar in both groups (P = NS). In conclusion, tennis playing at prepubertal ages induces a selective hypertrophy of the core musculature and exaggerates the degree of asymmetry of quadratus lumborum and rectus abdominis compared to untrained boys.

Effect of regional muscle location but not adiposity on mitochondrial biogenesis-regulating proteins.

PURPOSE: The aim of this study was to determine if the expression of the mitochondrial biogenesis-regulating proteins SIRT1, SIRT3 and PGC-1alpha in human skeletal muscle is influenced by adiposity. METHOD: Twenty-nine male subjects were recruited into three groups: control (n = 10), obese (n = 10) and post-obese (n = 9). Intentionally, groups were matched by age, aerobic capacity and in addition the control and post-obese groups also by BMI. Muscle biopsies were obtained from the m. deltoid and vastus lateralis. PGC-1alpha, SIRT1 and SIRT3 protein expression was analyzed by Western blot. RESULT: PGC-1alpha, SIRT1 and SIRT3 protein expression was similar regardless of the level of adiposity. Only a main effect of group on SIRT1 protein showed a trend toward higher expression in post-obese than control and obese (P = 0.09). Despite similar muscle fiber-type composition (previously reported), PGC-1alpha, SIRT1 and SIRT3 protein expression was higher in leg compared to arm muscle in all groups (P < 0.05). CONCLUSION: This study shows that PGC-1alpha, SIRT1 and SIRT3 protein expression in basal conditions was not altered in humans with different levels of adiposity but similar aerobic capacity. The expression of PGC-1alpha, SIRT1 and SIRT3 was higher in vastus lateralis than in deltoid muscle, indicating that local rather than systemic factors prevail in regulating the level of expression of these proteins.

Why Are High-Altitude Natives So Strong at Altitude? Maximal Oxygen Transport to the Muscle Cell in Altitude Natives.

In hypoxia aerobic exercise performance of high-altitude natives is suggested to be superior to that of lowlanders; i.e., for a given altitude natives are reported to have higher maximal oxygen uptake (VO2max). The likely basis for this is a higher pulmonary diffusion capacity, which in turn ensures higher arterial O2 saturation (SaO2) and therefore also potentially a higher delivery of O2 to the exercising muscles. This review focuses on O2 transport in high-altitude Aymara. We have quantified femoral artery O2 delivery, arterial O2 extraction and calculated leg VO2 in Aymara, and compared their values with that of acclimatizing Danish lowlanders. All subjects were studied at 4100 m. At maximal exercise SaO2 dropped tremendously in the lowlanders, but did not change in the Aymara. Therefore arterial O2 content was also higher in the Aymara. At maximal exercise however, fractional O2 extraction was lower in the Aymara, and the a-vO2 difference was similar in both populations. The lower extraction levels in the Aymara were associated with lower muscle O2 conductance (a measure of muscle diffusion capacity). At any given submaximal exercise intensity, leg VO2 was always of similar magnitude in both groups, but at maximal exercise the lowlanders had higher leg blood flow, and hence also higher maximum leg VO2. With the induction of acute normoxia fractional arterial O2 extraction fell in the highlanders, but remained unchanged in the lowlanders. Hence high-altitude natives seem to be more diffusion limited at the muscle level as compared to lowlanders. In conclusion Aymara preserve very high SaO2 during hypoxic exercise (likely due to a higher lung diffusion capacity), but the effect on VO2max is reduced by a lower ability to extract O2 at the muscle level.

Integrative Conductance of Oxygen During Exercise at Altitude.

In the oxygen (O2) cascade downstream steps can never achieve higher flows of O2 than the preceding ones. At the lung the transfer of O2 is determined by the O2 gradient between the alveolar space and the lung capillaries and the O2 diffusing capacity (DLO2). While DLO2 may be increased several times during exercise by recruiting more lung capillaries and by increasing the oxygen carrying capacity of blood due to higher peripheral extraction of O2, the capacity to enhance the alveolocapillary PO2 gradient is more limited. The transfer of oxygen from the alveolar space to the hemoglobin (Hb) must overcome first the resistance offered by the alveolocapillary membrane (1/DM) and the capillary blood (1/θVc). The fractional contribution of each of these two components to DLO2 remains unknown. During exercise these resistances are reduced by the recruitment of lung capillaries. The factors that reduce the slope of the oxygen dissociation curve of the Hb (ODC) (i.e., lactic acidosis and hyperthermia) increase 1/θVc contributing to limit DLO2. These effects are accentuated in hypoxia. Reducing the size of the active muscle mass improves pulmonary gas exchange during exercise and reduces the rightward shift of the ODC. The flow of oxygen from the muscle capillaries to the mitochondria is pressumably limited by muscle O2 conductance (DmcO2) (an estimation of muscle oxygen diffusing capacity). However, during maximal whole body exercise in normoxia, a higher flow of O2 is achieved at the same pressure gradients after increasing blood [Hb], implying that in healthy humans exercising in normoxia there is a functional reserve in DmcO2. This conclusion is supported by the fact that during small muscle exercise in chronic hypoxia, peak exercise DmcO2 is similar to that observed during exercise in normoxia despite a markedly lower O2 pressure gradient driving diffusion.

What limits performance during whole-body incremental exercise to exhaustion in humans?

To determine the mechanisms causing task failure during incremental exercise to exhaustion (IE), sprint performance (10 s all-out isokinetic) and muscle metabolites were measured before (control) and immediately after IE in normoxia (P(IO2) 143 mmHg) and hypoxia (P(IO2): 73 mmHg) in 22 men (22 ± 3 years). After IE, subjects recovered for either 10 or 60 s, with open circulation or bilateral leg occlusion (300 mmHg) in random order. This was followed by a 10 s sprint with open circulation. Post-IE peak power output (W(peak)) was higher than the power output reached at exhaustion during IE (P < 0.05). After 10 and 60 s recovery in normoxia, W(peak) was reduced by 38 ± 9 and 22 ± 10% without occlusion, and 61 ± 8 and 47 ± 10% with occlusion (P < 0.05). Following 10 s occlusion, W(peak) was 20% higher in hypoxia than normoxia (P < 0.05), despite similar muscle lactate accumulation ([La]) and phosphocreatine and ATP reduction. Sprint performance and anaerobic ATP resynthesis were greater after 60 s compared with 10 s occlusions, despite the higher [La] and [H(+)] after 60 s compared with 10 s occlusion recovery (P < 0.05). The mean rate of ATP turnover during the 60 s occlusion was 0.180 ± 0.133 mmol (kg wet wt)(-1) s(-1), i.e. equivalent to 32% of leg peak O2 uptake (the energy expended by the ion pumps). A greater degree of recovery is achieved, however, without occlusion. In conclusion, during incremental exercise task failure is not due to metabolite accumulation or lack of energy resources. Anaerobic metabolism, despite the accumulation of lactate and H(+), facilitates early recovery even in anoxia. This points to central mechanisms as the principal determinants of task failure both in normoxia and hypoxia, with lower peripheral contribution in hypoxia.

Limitations to oxygen transport and utilization during sprint exercise in humans: evidence for a functional reserve in muscle O2 diffusing capacity.

To determine the contribution of convective and diffusive limitations to V̇(O2peak) during exercise in humans, oxygen transport and haemodynamics were measured in 11 men (22 ± 2 years) during incremental (IE) and 30 s all-out cycling sprints (Wingate test, WgT), in normoxia (Nx, P(IO2): 143 mmHg) and hypoxia (Hyp, P(IO2): 73 mmHg). Carboxyhaemoglobin (COHb) was increased to 6-7% before both WgTs to left-shift the oxyhaemoglobin dissociation curve. Leg V̇(O2) was measured by the Fick method and leg blood flow (BF) with thermodilution, and muscle O2 diffusing capacity (D(MO2)) was calculated. In the WgT mean power output, leg BF, leg O2 delivery and leg V̇(O2) were 7, 5, 28 and 23% lower in Hyp than Nx (P < 0.05); however, peak WgT D(MO2) was higher in Hyp (51.5 ± 9.7) than Nx (20.5 ± 3.0 ml min(-1) mmHg(-1), P < 0.05). Despite a similar P(aO2) (33.3 ± 2.4 and 34.1 ± 3.3 mmHg), mean capillary P(O2) (16.7 ± 1.2 and 17.1 ± 1.6 mmHg), and peak perfusion during IE and WgT in Hyp, D(MO2) and leg V̇(O2) were 12 and 14% higher, respectively, during WgT than IE in Hyp (both P < 0.05). D(MO2) was insensitive to COHb (COHb: 0.7 vs. 7%, in IE Hyp and WgT Hyp). At exhaustion, the Y equilibration index was well above 1.0 in both conditions, reflecting greater convective than diffusive limitation to the O2 transfer in both Nx and Hyp. In conclusion, muscle V̇(O2) during sprint exercise is not limited by O2 delivery, O2 offloading from haemoglobin or structure-dependent diffusion constraints in the skeletal muscle. These findings reveal a remarkable functional reserve in muscle O2 diffusing capacity.

Blood temperature and perfusion to exercising and non-exercising human limbs.

NEW FINDINGS: What is the central question of this study? Temperature-sensitive mechanisms are thought to contribute to blood-flow regulation, but the relationship between exercising and non-exercising limb perfusion and blood temperature is not established. What is the main finding and its importance? The close coupling among perfusion, blood temperature and aerobic metabolism in exercising and non-exercising extremities across different exercise modalities and activity levels and the tight association between limb vasodilatation and increases in plasma ATP suggest that both temperature- and metabolism-sensitive mechanisms are important for the control of human limb perfusion, possibly by activating ATP release from the erythrocytes. Temperature-sensitive mechanisms may contribute to blood-flow regulation, but the influence of temperature on perfusion to exercising and non-exercising human limbs is not established. Blood temperature (TB ), blood flow and oxygen uptake (V̇O2) in the legs and arms were measured in 16 healthy humans during 90 min of leg and arm exercise and during exhaustive incremental leg or arm exercise. During prolonged exercise, leg blood flow (LBF) was fourfold higher than arm blood flow (ABF) in association with higher TB and limb V̇O2. Leg and arm vascular conductance during exercise compared with rest was related closely to TB (r(2) = 0.91; P < 0.05), plasma ATP (r(2) = 0.94; P < 0.05) and limb V̇O2 (r(2) = 0.99; P < 0.05). During incremental leg exercise, LBF increased in association with elevations in TB and limb V̇O2, whereas ABF, arm TB and V̇O2 remained largely unchanged. During incremental arm exercise, both ABF and LBF increased in relationship to similar increases in V̇O2. In 12 trained males, increases in femoral TB and LBF during incremental leg exercise were mirrored by similar pulmonary artery TB and cardiac output dynamics, suggesting that processes in active limbs dominate central temperature and perfusion responses. The present data reveal a close coupling among perfusion, TB and aerobic metabolism in exercising and non-exercising extremities and a tight association between limb vasodilatation and increases in plasma ATP. These findings suggest that temperature and V̇O2 contribute to the regulation of limb perfusion through control of intravascular ATP.