Skeletal muscle mitochondria demonstrate similar respiration per cristae surface area independent of training status and sex in healthy humans.

The impact of training status and sex on intrinsic skeletal muscle mitochondrial respiratory capacity remains unclear. We examined this by analysing human skeletal muscle mitochondrial respiration relative to mitochondrial volume and cristae density across training statuses and sexes. Mitochondrial cristae density was estimated in skeletal muscle biopsies originating from previous independent studies. Participants included females (n = 12) and males (n = 41) across training statuses ranging from untrained (UT, n = 8), recreationally active (RA, n = 9), active-to-elite runners (RUN, n = 27) and cross-country skiers (XC, n = 9). The XC and RUN groups demonstrated higher mitochondrial volume density than the RA and UT groups while all active groups (RA, RUN and XC) displayed higher mass-specific capacity of oxidative phosphorylation (OXPHOS) and mitochondrial cristae density than UT. Differences in OXPHOS diminished between active groups and UT when normalising to mitochondrial volume density and were lost when normalising to muscle cristae surface area density. Moreover, active females (n = 6-9) and males (n = 15-18) did not differ in mitochondrial volume and cristae density, OXPHOS, or when normalising OXPHOS to mitochondrial volume density and muscle cristae surface area density. These findings demonstrate: (1) differences in OXPHOS between active and untrained individuals may be explained by both higher mitochondrial volume and cristae density in active individuals, with no difference in intrinsic mitochondrial respiratory capacity (OXPHOS per muscle cristae surface area density); and (2) no sex differences in mitochondrial volume and cristae density or mass-specific and normalised OXPHOS. This highlights the importance of normalising OXPHOS to muscle cristae surface area density when studying skeletal muscle mitochondrial biology. KEY POINTS: Oxidative phosphorylation is the mitochondrial process by which ATP is produced, governed by the electrochemical gradient across the inner mitochondrial membrane with infoldings named cristae. In human skeletal muscle, the mass-specific capacity of oxidative phosphorylation (OXPHOS) can change independently of shifts in mitochondrial volume density, which may be attributed to variations in cristae density. We demonstrate that differences in skeletal muscle OXPHOS between healthy females and males, ranging from untrained to elite endurance athletes, are matched by differences in cristae density. This suggests that higher OXPHOS in skeletal muscles of active individuals is attributable to an increase in the density of cristae. These findings broaden our understanding of the variability in human skeletal muscle OXPHOS and highlight the significance of cristae, specific to mitochondrial respiration.

Determinants and reference values for blood volume and total hemoglobin mass in women and men.

Blood volume (BV) is an important clinical parameter and is usually reported per kg of body mass (BM). When fat mass is elevated, this underestimates BV/BM. One aim was to study if differences in BV/BM related to sex, age, and fitness would decrease if normalized to lean body mass (LBM). The analysis included 263 women and 319 men (age: 10-93 years, body mass index: 14-41 kg/m2 ) and 107 athletes who underwent assessment of BV and hemoglobin mass (Hbmass ), body composition, and cardiorespiratory fitness. BV/BM was 25% lower (70.3 ± 11.3 and 80.3 ± 10.8 mL/kgBM ) in women than men, respectively, whereas BV/LBM was 6% higher in women (110.9 ± 12.5 and 105.3 ± 11.2 mL/kgLBM ). Hbmass /BM was 34% lower (8.9 ± 1.4 and 11.5 ± 11.2 g/kgBM ) in women than in men, respectively, but only 6% lower (14.0 ± 1.5 and 14.9 ± 1.5 g/kgLBM )/LBM. Age did not affect BV. Athlete's BV/BM was 17.2% higher than non-athletes, but decreased to only 2.5% when normalized to LBM. Of the variables analyzed, LBM was the strongest predictor for BV (R2 = .72, p < .001) and Hbmass (R2 = .81, p < .001). These data may only be valid for BV/Hbmass when assessed by CO re-breathing. Hbmass /LBM could be considered a valuable clinical matrix in medical care aiming to normalize blood homeostasis.

Dichotomous Responses to Chronic Fetal Hypoxia Lead to a Predetermined Aging Phenotype.

Hypoxia-induced intrauterine growth restriction increases the risk for cardiovascular, renal, and other chronic diseases in adults, representing thus a major public health problem. Still, not much is known about the fetal mechanisms that predispose these individuals to disease. Using a previously validated mouse model of fetal hypoxia and bottom-up proteomics, we characterize the response of the fetal kidney to chronic hypoxic stress. Fetal kidneys exhibit a dichotomous response to chronic hypoxia, comprising on the one hand cellular adaptations that promote survival (glycolysis, autophagy, and reduced DNA and protein synthesis), but on the other processes that induce a senescence-like phenotype (infiltration of inflammatory cells, DNA damage, and reduced proliferation). Importantly, chronic hypoxia also reduces the expression of the antiaging proteins klotho and Sirt6, a mechanism that is evolutionary conserved between mice and humans. Taken together, we uncover that predetermined aging during fetal development is a key event in chronic hypoxia, establishing a solid foundation for Barker's hypothesis of fetal programming of adult diseases. This phenotype is associated with a characteristic biomarker profile in tissue and serum samples, exploitable for detecting and targeting accelerated aging in chronic hypoxic human diseases.

Increased blood reactive oxygen species and hepcidin in obstructive sleep apnea precludes expected erythrocytosis.

Obstructive sleep apnea (OSA) causes intermittent hypoxia during sleep. Hypoxia predictably initiates an increase in the blood hemoglobin concentration (Hb); yet in our analysis of 527 patients with OSA, >98% did not have an elevated Hb. To understand why patients with OSA do not develop secondary erythrocytosis due to intermittent hypoxia, we first hypothesized that erythrocytosis occurs in these patients, but is masked by a concomitant increase in plasma volume. However, we excluded that explanation by finding that the red cell mass was normal (measured by radionuclide labeling of erythrocytes and carbon monoxide inhalation). We next studied 45 patients with OSA before and after applying continuous positive airway pressure (CPAP). We found accelerated erythropoiesis in these patients (increased erythropoietin and reticulocytosis), but it was offset by neocytolysis (lysis of erythrocytes newly generated in hypoxia upon return to normoxia). Parameters of neocytolysis included increased reactive oxygen species from expanded reticulocytes' mitochondria. The antioxidant catalase was also downregulated in these cells from hypoxia-stimulated microRNA-21. In addition, inflammation-induced hepcidin limited iron availability for erythropoiesis. After CPAP, some of these intermediaries diminished but Hb did not change. We conclude that in OSA, the absence of significant increase in red cell mass is integral to the pathogenesis, and results from hemolysis via neocytolysis combined with inflammation-mediated suppression of erythropoiesis.

Lowered muscle glycogen reduces body mass with no effect on short-term exercise performance in men.

Performance in short-duration sports is highly dependent on muscle glycogen, but the total degradation is only moderate and considering the water-binding property of glycogen, unnecessary storing of glycogen may cause an unfavorable increase in body mass. To investigate this, we determined the effect of manipulating dietary carbohydrates (CHO) on muscle glycogen content, body mass, and short-term exercise performance. In a randomized and counterbalanced cross-over design, twenty-two men completed two maximal cycle tests of either 1-min (n = 10) or 15-min (n = 12) duration with different pre-exercise muscle glycogen levels. Glycogen manipulation was initiated three days prior to the tests by exercise-induced glycogen depletion followed by ingestion of a moderate (M-CHO) or high (H-CHO) CHO-diet. Subjects were weighed before each test, and muscle glycogen content was determined in biopsies from m. vastus lateralis before and after each test. Pre-exercise muscle glycogen content was lower following M-CHO than H-CHO (367 mmol · kg-1 DW vs. 525 mmol · kg-1 DW, p < 0.00001), accompanied by a 0.7 kg lower body mass (p < 0.00001). No differences were observed in performance between diets in neither the 1-min (p = 0.33) nor the 15-min (p = 0.99) test. In conclusion, pre-exercise muscle glycogen content and body mass were lower after ingesting moderate compared with high amounts of CHO, while short-term exercise performance was unaffected. This demonstrates that adjusting pre-exercise glycogen levels to the requirements of competition may provide an attractive weight management strategy in weight-bearing sports, particularly in athletes with high resting glycogen levels.

Validation of a clinically applicable device for fast and accurate quantification of blood volume.

INTRODUCTION: Determination of blood volume (BV) using the dual-isotope (e.g., 99m Tc-labeled red blood cells [99m Tc-RBC] and 125 I-labeled human serum albumin [125 I-HSA]) injection method is limited in medicine due to the long isotope half-life. However, BV has been determined in laboratory settings for 100 years using the carbon monoxide (CO)-rebreathing-based procedure, which allows frequent BV measurements. METHODS: We investigated the reliability and accuracy of a semi-automated CO-rebreathing device by comparing it against the dual-isotope methodology and its ability to detect a known blood removal. In study A, BV was determined three times in ~2 h; twice using the device with rebreathing protocols lasting 2 (CO2min ) and 10 min (CO10min ) and once with the dual-isotope technique. In study B, the accuracy of the device was assessed by its ability to detect a 2% removal of BV. RESULTS: A good correlation was observed between both the CO-rebreathing protocols (r2 = 0.89-0.98; p < 0.001) and the dual-isotope approach (r2 = 0.89-0.95; p < 0.001). In absolute terms BV was 425 ± 263 mL and 491 ± 388 mL lower (p < 0.001) when quantified with the dual-isotope compared to the CO-rebreathing protocols. When reducing BV by 132 ± 25 mL (2%), the device quantified a lower (p < 0.001) BV of 150 ± 45 mL. CONCLUSION: This study emphasizes that the semi-automated device accurately determines small changes (i.e., 2%) in BV and that a high correlation with the dual-isotope methodology exists. The findings are clinically relevant owing to the method's simple and fast nature (the absence of radioactive tracers and reduced time requirements, i.e., ~15 min vs. ~180 min) and the possibility for repeated measurements within a single day.

High or hot-Perspectives on altitude camps and heat-acclimation training as preparation for prolonged stage races.

Adaptation to heat stress and hypoxia are relevant for athletes participating in Tour de France or similar cycling races taking place during the summertime in landscapes with varying altitude. Both to minimize detrimental performance effects associated with arterial desaturation occurring at moderate altitudes in elite athletes, respectively, reduce the risk of hyperthermia on hot days, but also as a pre-competition acclimatization strategy to boost blood volume in already highly adapted athletes. The hematological adaptations require weeks of exposure to manifest, but are attractive as an augmented hemoglobin mass may improve arterial oxygen delivery and hence benefit prolonged performances. Altitude training camps have in this context a long history in exercise physiology and are still common practice in elite cycling. However, heat-acclimation training provides an attractive alternative for some athletes either as a stand-alone approach or in combination with altitude. The present paper provides an update and practical perspectives on the potential to utilize hypoxia and heat exposure to optimize hematological adaptations. Furthermore, we will consider temporal aspects both in terms of onset and decay of the adaptations relevant for improved thermoregulatory capacity and respiratory adaptations to abate arterial desaturation during altitude exposure. From focus on involved physiological mechanisms, time course, and responsiveness in elite athletes, we will provide guidance based on our experience from practical implementation in cyclists preparing for prolonged stage races such as the Tour de France.

Heat suit training increases hemoglobin mass in elite cross-country skiers.

PURPOSE: The primary purpose was to test the effect of heat suit training on hemoglobin mass (Hbmass ) in elite cross-country (XC) skiers. METHODS: Twenty-five male XC-skiers were divided into a group that added 5 × 50 min weekly heat suit training sessions to their regular training (HEAT; n = 13, 23 ± 5 years, 73.9 ± 5.2 kg, 180 ± 6 cm, 76.8 ± 4.6 ml·min-1 ·kg-1 ) or to a control group matched for training volume and intensity distribution (CON; n = 12, 23 ± 4 years, 78.4 ± 5.8 kg, 184 ± 4 cm, 75.2 ± 3.4 ml·min-1 ·kg-1 ) during the five-week intervention period. Hbmass , endurance performance and factors determining endurance performance were assessed before and after the intervention. RESULTS: HEAT led to 30 g greater Hbmass (95% CI: [8.5, 51.7], p = 0.009) and 157 ml greater red blood cell volume ([29, 285], p = 0.018) post-intervention, compared to CON when adjusted for baseline values. In contrast, no group differences were observed for changes in work economy, running velocity, and fractional utilization of maximal oxygen uptake (V̇O2max ) at 4 mmol·L-1 blood lactate, V̇O2max or 15-min running distance performance trial during the intervention. CONCLUSION: HEAT induced a larger increase in Hbmass and red blood cell volume after five weeks with five weekly heat suit training sessions than CON, but with no detectable group differences on physiological determinants of endurance performance or actual endurance performance in elite CX skiers.

Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure.

The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coordinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hepcidin synthesis by inhibiting hepatic BMP/SMAD signaling, evidence for the role of ERFE in humans is limited. To investigate the role of ERFE as a physiological erythroid regulator in humans, we conducted two studies: first, 24 males received six injections of saline (placebo), recombinant Epo (rhEpo) 20 UI kg-1 (micro-dose) or 50 UI kg-1 (low-dose). Second, we quantified ERFE in 22 subjects exposed to high altitude (3800 m) for 15 hours. In the first study, total hemoglobin mass (Hbmass) increased after low- but not after micro-dose injections, when compared to placebo. Serum ERFE levels were enhanced by rhEpo, remaining higher than after placebo for 48 (micro-dose) or 72 hours (low-dose) post-injections. Conversely, hepcidin levels decreased when Epo and ERFE arose, before any changes in serum iron parameters occurred. In the second study, serum Epo and ERFE increased at high altitude. The present results demonstrate that in healthy humans ERFE responds to slightly increased Epo levels not associated with Hbmass expansion and down-regulates hepcidin in an apparently iron-independent way. Notably, ERFE flags micro-dose Epo, thus holding promise as novel anti-doping biomarker.

Five weeks of heat training increases haemoglobin mass in elite cyclists.

NEW FINDINGS: What is the central question of this study? Do haemoglobin mass and red blood cell volume increase in elite cyclists training in a hot environment compared to a control group training at normal temperature? What is the main finding and its importance? Five weeks of heat training increases haemoglobin mass in elite cyclists. There are small to intermediate effect sizes for exercise parameters favouring heat training. ABSTRACT: In this study we tested the hypothesis that performing 1 h of regular light exercise in a heat chamber (HEAT; 37.8 ± 0.5°C; 65.4 ± 1.8% humidity) 5 times week-1 for a total of 5 weeks increases haemoglobin mass (Hbmass ) and exercise performance in elite cyclists ( V̇O2max  = 76.2 ± 7.6 ml min-1  kg-1 ). Twenty-three male volunteers were assigned to HEAT (n = 11) or CON (n = 12; 15.5 ± 0.1°C; 25.1 ± 0.0% humidity) training groups. Hbmass was determined before and after the intervention period in conjunction with an extensive exercise test protocol (conducted at 16-19°C). HEAT increased (P < 0.05) Hbmass by 42 g from 893 ± 78 to 935 ± 108 g whereas Hbmass remained unchanged (+6 g) in CON. Furthermore, statistical analysis revealed a time-group interaction (P < 0.05). The greater increase in Hbmass in HEAT, however, did not manifest in a greater increase in V̇O2max (225 ± 274 ml min-1 in HEAT and 161 ± 202 ml min-1 in CON). While HEAT reduced (P < 0.05) lactate levels during some of the submaximal exercise tests, there was no statistical difference between other performance parameters. There were, however, small to intermediate effect sizes favouring HEAT for lactate threshold power output (2.8 ± 3.9 vs. -0.4 ± 5.1% change, effect size (ES) = 0.34), gross economy in the fatigued state (0.19 ± 0.42 vs. -0.12 ± 0.49%-point change, ES = 0.52) and 15 min mean power (6.9 ± 8.4 vs. 3.4 ± 5.1% increase, ES = 0.22). This study demonstrates an increase in Hbmass and small to intermediate effect sizes on exercise variables in elite cyclists following a 5-week heat training intervention.

Reproducibility of the CO rebreathing technique with a lower CO dose and a shorter rebreathing duration at sea level and at 2320 m of altitude.

Total hemoglobin mass (Hbmass) is routinely assessed in studies by the carbon monoxide (CO) rebreathing. Its clinical application is often hindered due to the consequent rise in carboxyhemoglobin (%HbCO) and the concern of CO toxicity. We tested the reproducibility of the CO rebreathing with a CO dose of 0.5 mL/kg body mass (CO0.5) compared to 1.5 mL/kg (CO1.5) and when shortening the CO rebreathing protocol. Therefore, CO rebreathing was performed 1×/day in eight healthy individuals on four consecutive days. On each day, either CO0.5 (CO0.5-1 and CO0.5-2) or CO1.5 (CO1.5-1 and CO1.5-2) was administered. Venous blood samples to determine %HbCO and quantify Hbmass were obtained prior to, and at 6 (T6), 8 (T8) and 10 min (T10) of CO rebreathing. This protocol was tested at sea level and at 2320 m to investigate the altitude-related measurement error. At sea level, the mean difference (95% limits of agreement) in Hbmass between CO0.5-1 and CO0.5-2 was 26 g (-26; 79 g) and between CO1.5-1 and CO1.5-2, it was 17 g (-18; 52 g). The respective typical error (TE) corresponded to 2.4% (CO0.5) and 1.5% (CO1.5), while it was 6.5% and 3.0% at 2320 m. With CO0.5, shortening the CO rebreathing resulted in a TE for Hbmass of 4.4% (T8 vs. T10) and 14.1% (T6 vs T10) and with CO1.5, TE was 1.6% and 5.8%. In conclusion, the CO dose and rebreathing time for the CO rebreathing procedure can be decreased at the cost of a measurement error ranging from 1.5-14.1%.

Superior performance improvements in elite cyclists following short-interval vs effort-matched long-interval training.

The purpose of this study was to compare the effects of 3 weeks with three weekly sessions (ie, nine sessions in total) of short intervals (SI; n = 9; 3 series with 13 × 30-second work intervals interspersed with 15-second recovery and 3-minutes recovery between series) against effort-matched (rate of perceived effort based) long intervals (LI; n = 9; 4 series of 5-minute work intervals with 2.5-minutes recovery between series) on performance parameters in elite cyclists ( V ˙ O 2max 73 ± 4 mL min-1  kg-1 ). There were no differences between groups in total volume and intensity distribution of training during the intervention period. SI achieved a larger (P < .05) relative improvement in peak aerobic power output than LI (3.7 ± 4.3% vs -0.3 ± 2.8%, respectively), fractional utilization of V ˙ O 2max at 4 mmol L-1 [La- ] (3.0 ± 5.8 percent points vs -3.5 ± 2.7 percent points, respectively), and larger relative increase in power output at 4 mmol L-1 [La- ] (2.0 ± 6.7% vs -2.8 ± 3.4, respectively), while there was no group difference in change of V ˙ O 2max . Improvements in performance measured as mean power output during 20-minute cycling test were greater (P < .01) in SI compared with LI (4.7 ± 4.4% vs -1.4 ± 2.2%, respectively). Mean effect size of the improvement in the above variables revealed a small to large effect of SI training vs LI training. The data thus demonstrate that the present SI protocol induces superior training adaptations compared with the present LI protocol in elite cyclists.

Arterial oxygen content regulates plasma erythropoietin independent of arterial oxygen tension: a blinded crossover study.

The production of erythropoietin (Epo) is modulated by renal tissue oxygen tension, which in principle depends on both arterial oxygen content (CaO2) and arterial oxygen tension (PaO2). Uncontrolled observational studies suggest that alterations in CaO2 fundamentally regulate Epo synthesis. We sought to establish whether reduced CaO2 enhances plasma Epo concentration independently of PaO2. In a blinded crossover study, 8 healthy young subjects were exposed to three conditions: room air (normoxia); 11% oxygen balanced in nitrogen, which lowers both CaO2 and PaO2 (hypoxia); and carbon monoxide plus normoxia, which decreases CaO2 to the same degree as hypoxia while preserving PaO2 (hypoxemia). Arterial blood samples were obtained prior to and throughout the 5 hours of exposure to each condition. In the hypoxic conditions, average CaO2 was reduced to similar levels, whereas PaO2 was only decreased with exposure to hypoxia. Plasma Epo concentration was increased in both hypoxic conditions relative to normoxia after 150 min of exposure and was augmented more than two-fold after 300 min, with no difference between hypoxic conditions. Reduced CaO2 induces similar increases in circulating Epo concentration irrespective of PaO2 manipulation, demonstrating that CaO2 is the critical variable regulating Epo production.

Transcerebral exchange kinetics of large neutral amino acids during acute inspiratory hypoxia in humans.

Hypoxaemia is present in many critically ill patients, and may contribute to encephalopathy. Changes in the passage of large neutral amino acids (LNAAs) across the blood-brain barrier (BBB) with an increased cerebral influx of aromatic amino acids into the brain may concurrently be present and also contribute to encephalopathy, but it has not been established whether hypoxaemia per se may trigger such changes. We measured cerebral blood flow (CBF) in 11 healthy men using the Kety-Schmidt technique and obtained paired arterial and jugular-venous blood samples for the determination of LNAAs by high performance liquid chromatography at baseline and after 9 hours of poikilocapnic normobaric hypoxia (12% O2). Transcerebral net exchange was determined by the Fick principle, and transport of LNAAs across the BBB was determined mathematically. Hypoxia increased both the systemic and corresponding cerebral delivery of the aromatic amino acid phenylalanine, and the branched-chain amino acids leucine and isoleucine. Despite this, the transcerebral net exchange values and mathematically derived brain extracellular concentrations for all LNAAs were unaffected. In conclusion, the observed changes in circulating LNAAs triggered by hypoxaemia do not affect the transcerebral exchange kinetics of LNAAs to such an extent that their brain extracellular concentrations are affected.

Carotid chemoreceptor control of muscle sympathetic nerve activity in hypobaric hypoxia.

NEW FINDINGS: What is the central question of this study? High-altitude hypoxia increases muscle sympathetic nerve activity (MSNA), but whether intravenous infusion of dopamine, to blunt the responsiveness of the carotid chemoreceptors, reduces MSNA at high altitude is not known. What is the main finding and its importance? Muscle sympathetic nerve activity was elevated after 15-17 days of high-altitude hypoxia (3454 m) compared with values at 'sea level' (432 m). However, intravenous dopamine infusion to blunt the responsiveness of the carotid chemoreceptors did not significantly decrease MSNA either at sea level or at high altitude, suggesting that high-altitude sympathoexcitation arises via a different mechanism. High-altitude hypoxia causes pronounced sympathoexcitation, but the underlying mechanisms remain unclear. We tested the hypothesis that i.v. infusion of dopamine to attenuate carotid chemoreceptor responsiveness would reduce muscle sympathetic nerve activity (MSNA) at high altitude. Nine healthy individuals [mean (SD); 26 (4) years of age] were studied at 'sea level' (SL; Zurich) and at high altitude (ALT; 3454 m; 15-17 days after arrival), both while breathing the ambient air and during an acute incremental hypoxia test (eight 3 min stages; partial pressure of end-tidal O2 90-45 mmHg). Intravenous infusions of dopamine (3 µg kg-1  min-1 ) and placebo (saline) were administered on both study days, according to a single-blind randomized cross-over design. Sojourn to high altitude decreased the partial pressure of end-tidal O2 (to ∼60 mmHg) and increased minute ventilation [V̇E; mean ± SEM, SL versus ALT: saline, 8.6 ± 0.5 versus 11.3 ± 0.6 l min-1 ; dopamine, 8.2 ± 0.5 versus 10.6 ± 0.8 l min-1 ; P < 0.05] and MSNA burst frequency by ∼80% [SL versus ALT: saline, 16 ± 3 versus 28 ± 4 bursts min-1 ; dopamine, 16 ± 4 versus 31 ± 4 bursts min-1 ; P < 0.05) when breathing the ambient air, but were not different with dopamine. Increases in MSNA burst frequency and V̇E during the acute incremental hypoxia test were greater at ALT than SL (P < 0.05). Dopamine did not affect the magnitude of the MSNA burst frequency response to acute incremental hypoxia at either SL or ALT. However, V̇E was lower with dopamine than saline administration throughout the acute incremental hypoxia test at ALT. These data indicate that i.v. infusion of low-dose dopamine to blunt the responsiveness of the carotid chemoreceptors does not significantly decrease MSNA at high altitude.

Sexual dimorphism of substrate utilization: Differences in skeletal muscle mitochondrial volume density and function.

NEW FINDINGS: What is the central question of this study? Females rely to a greater extent than males on fat oxidation during exercise. Whether any difference in skeletal muscle mitochondrial phenotype and oxidative capacity contributes to this sexual dimorphism remains incompletely explored. What is the main finding and its importance? Female prioritization of fat during exercise occurs in parallel to augmented mitochondrial volume density and intrinsic fatty acid and lactate oxidation in skeletal muscle fibres compared with males, independently of aerobic exercise capacity. The enlarged metabolic machinery in skeletal muscle of females is associated with lower body size and leg mass. ABSTRACT: Fat oxidation during exercise is greater in females than in males. We sought to determine whether sex differences in substrate metabolism are paralleled by distinct skeletal muscle mitochondrial volume density and oxidative capacity. Whole-body substrate (fat and carbohydrate) utilization during submaximal treadmill running was assessed, and skeletal muscle biopsies were taken to determine mitochondrial volume density and function in healthy young females (n = 12) and males (n = 12) matched by aerobic exercise capacity and exercise performance. Females presented a lower respiratory exchange ratio (0.87 ± 0.04 versus 0.91 ± 0.04, P = 0.023) and whole-body carbohydrate oxidation (27.8 ± 8.3 versus 35.8 ± 6.5 mg kg-1  min-1 , P = 0.027), whereas fat oxidation was higher (8.7 ± 2.8 versus 5.9 ± 2.6 mg kg-1  min-1 , P = 0.034) during submaximal exercise compared with males. In skeletal muscle biopsies, females demonstrated augmented mitochondrial volume density (7.51 ± 1.77 versus 5.90 ± 1.72%, P = 0.035) and oxidative capacity for fatty acid [36.6 ± 12.8 versus 24.5 ± 7.3 pmol O2  s-1  (mg wet weight)-1 , P = 0.009] and lactate [71.1 ± 24.4 versus 53.2 ± 14.6 pmol O2  s-1  (mg wet weight)-1 , P = 0.040]. No sex differences in respiratory exchange ratio, whole-body fat oxidation and skeletal muscle variables were detected when adjusted for anthropometric variables including body mass or leg mass, which were lower in females. In conclusion, female prioritization of fat over carbohydrate oxidation during exercise is underpinned by augmented body size-related mitochondrial volume density, fatty acid and lactate oxidative capacity in skeletal muscle fibres.

Concepts About V˙O2max and Trainability Are Context Dependent.

Some individuals show little or no increase in maximal oxygen consumption (V˙O2max) in response to training programs consistent with public health guidelines. However, results from studies using more intense programs challenge the concept that some humans have limited trainability. We explore the implications of these divergent observations on the biology of trainability and propose a new set of twin studies to explore them.

Transcerebral net exchange of vasoactive peptides and catecholamines during lipopolysaccharide-induced systemic inflammation in healthy humans.

The systemic inflammatory response triggered by lipopolysaccharide (LPS) is associated with cerebral vasoconstriction, but the underlying mechanisms are unknown. We therefore examined whether a 4-hour intravenous LPS infusion (0.3 ng·kg-1) induces any changes in the transcerebral net exchange of the vasoactive peptides endothelin-1 (ET-1) and calcitonin-gene related peptide (CGRP) and catecholamines in human volunteers. Cerebral blood flow was measured by the Kety-Schmidt technique, and paired arterial-to-jugular venous blood samples were obtained for estimating the transcerebral exchange of ET-1, CGRP, and catecholamines by the Fick principle in 12 volunteers before and after LPS infusion. The cerebrovascular release of ET-1 was enhanced, whereas the transcerebral net exchange of CGRP and catecholamines was unaffected. Our findings thus point towards locally produced ET-1 within the cerebrovasculature as a contributor to cerebral vasoconstriction after LPS infusion.

Determinants of maximal whole-body fat oxidation in elite cross-country skiers: Role of skeletal muscle mitochondria.

Elite endurance athletes possess a high capacity for whole-body maximal fat oxidation (MFO). The aim was to investigate the determinants of a high MFO in endurance athletes. The hypotheses were that augmented MFO in endurance athletes is related to concomitantly increments of skeletal muscle mitochondrial volume density (MitoVD ) and mitochondrial fatty acid oxidation (FAOp ), that is, quantitative mitochondrial adaptations as well as intrinsic FAOp per mitochondria, that is, qualitative adaptations. Eight competitive male cross-country skiers and eight untrained controls were compared in the study. A graded exercise test was performed to determine MFO, the intensity where MFO occurs (FatMax ), and V ˙ O 2 Max . Skeletal muscle biopsies were obtained to determine MitoVD (electron microscopy), FAOp , and OXPHOSp (high-resolution respirometry). The following were higher (P < 0.05) in endurance athletes compared to controls: MFO (mean [95% confidence intervals]) (0.60 g/min [0.50-0.70] vs 0.32 [0.24-0.39]), FatMax (46% V ˙ O 2 Max [44-47] vs 35 [34-37]), V ˙ O 2 Max (71 mL/min/kg [69-72] vs 48 [47-49]), MitoVD (7.8% [7.2-8.5] vs 6.0 [5.3-6.8]), FAOp (34 pmol/s/mg muscle ww [27-40] vs 21 [17-25]), and OXPHOSp (108 pmol/s/mg muscle ww [104-112] vs 69 [68-71]). Intrinsic FAOp (4.0 pmol/s/mg muscle w.w/MitoVD [2.7-5.3] vs 3.3 [2.7-3.9]) and OXPHOSp (14 pmol/s/mg muscle ww/MitoVD [13-15] vs 11 [10-13]) were, however, similar in the endurance athletes and untrained controls. MFO and MitoVD correlated (r2  = 0.504, P < 0.05) in the endurance athletes. A strong correlation between MitoVD and MFO suggests that expansion of MitoVD might be rate-limiting for MFO in the endurance athletes. In contrast, intrinsic mitochondrial changes were not associated with augmented MFO.