Carsten Lundby

University of Zurich | UZH · Institut für Physiologie

Endurance exercise performance is associated with a well-developed skeletal muscle mitochondrial network, which is composed of subsarcolemmal mitochondria interconnected with intermyofibrillar mitochondria bending around the myofibrils. High-altitude exposure is typically incorporated in elite sport training regimens, but little is known about how...

Short-term heat acclimation (HA) appears adequate for maximizing sudomotor adaptations and enhancing thermal resilience in trained athletes. However, for enhanced erythropoiesis and transfer effects to exercise capacity in cooler environments, prolonged HA appears necessary. To establish the time-course for physiological adaptations and performance...

Background An increasing number of hypertensive persons travel to high altitude (HA) while using antihypertensive medications such as beta-blockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In an...

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 b...

Purpose O 2 -transport and endurance exercise performance are greatly influenced by hemoglobin mass (Hb mass ), which largely depends on lean body mass (LBM). This study investigated the effects of 8 weeks with 3 weekly sessions of conventional (3-SET: 3x10 reps) or high-volume strength training (10-SET: 5-10x10 reps) on LBM, Hb mass , muscle stren...

Introduction Fluid overload is a major challenge in hemodialysis patients and might cause hypervolemia. We speculated that hemodialysis patients reaching dry weight could have undetected hypervolemia and low hemoglobin (Hb) concentration (g/dL) due to hemodilution. Methods The study included hemodialysis patients (n = 22) and matched healthy contr...

Introduction Determination of blood volume (BV) using the dual‐isotope (e.g., 99mTc‐labeled red blood cells [99mTc‐RBC] and ¹²⁵I‐labeled human serum albumin [¹²⁵I‐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)‐rebrea...

Background and Aims Fluid overload is a major challenge in haemodialysis (HD) patients and might cause hypervolaemia. We speculated that HD patients reaching dry weight could have undetected hypervolaemia and low haemoglobin concentration (Hb) due to haemodilution. Method The study included HD patients (n = 22) and matched healthy controls (n = 22...

Heat exercise training may increase exercise performance in athletes. The underlying mechanisms remain partly unresolved, and it is unknown if female and male athletes may experience comparable gains. The aims were to investigate whether heat training (HEAT) increases hemoglobin mass (Hbmass), skeletal muscle fiber characteristics and thermoneutral...

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 m...

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...

BACKGROUND AND AIMS Blood volume (BV) is an important clinical parameter and is usually expressed relative to body weight (BW), but is inappropriate with elevated fat mass. We hypothesized that established differences in BV and hemoglobin mass (Hbmass) between male and female would vanish if expressed per lean body mass (LBM) instead of BW. We furt...

Purpose and methods: To test whether heat training performed as 5x50 min sessions/week for 5 weeks in a heat chamber (CHAMBER) or while wearing a heat suit (SUIT), in temperate conditions, increases haemoglobin mass (Hbmass) and endurance performance in elite cyclists, compared to a control group (CON-1). Furthermore, after the 5-week intervention...

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 5x50 min weekly heat suit training sessions to their regular training (HEAT; n=13, 23 ± 5 yrs, 73.9 ± 5.2 kg, 180 ± 6 cm, 76.8 ± 4.6 mL...

Background Chronic obstructive pulmonary disease (COPD) is associated with skeletal muscle mitochondrial dysfunction. Resistance exercise training (RT) is a training modality with a relatively small pulmonary demand that has been suggested to increase skeletal muscle oxidative enzyme activity in COPD. Whether a shift into a more oxidative profile f...

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...

Exercise facilitates cerebral lactate uptake, likely by increasing arterial lactate concentration and hence the diffusion gradient across the blood brain barrier. However, non-specific β-adrenergic blockade by propranolol has previously reduced the arterio-jugular venous lactate difference (AV Lac ) during exercise, suggesting β-adrenergic control...

Purpose: The present case report aimed to investigate the effects of exercise training in temperate ambient conditions while wearing a heat suit on hemoglobin mass (Hbmass). Methods: As part of their training regimens, 5 national-team members of endurance sports (3 males) performed ∼5 weekly heat suit exercise training sessions each lasting 50 m...

The objective was to compare the efficacy of three different heat acclimation protocols to improve exercise performance in the heat. Thirty four cyclists completed one of three 10-day interventions 1) 50-min cycling per day in 35°C, 2) 50-min cycling per day wearing thermal clothing, 3) 50-min cycling wearing thermal clothing plus 25 min hot water...

Aims. Total haemoglobin mass (tot-Hb) increases during high altitude acclimatization. Normalization of tot-Hb upon descent is thought to occur via neocytolysis, the selective destruction of newly formed erythrocytes. Because convincing experimental proof of neocytolysis is lacking, we performed a prospective study on erythrocyte survival after a st...

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...

The diagnosis of chronic mountain sickness (CMS) is based on a score including 7 clinical features (breathlessness, sleep disturbance, cyanosis, venous dilatation, paresthesia, headache, and tinnitus) in the setting of extreme erythrocytosis. Examining individuals in La Rinconada, Peru, the highest city in the world, the authors demonstrated that C...

New findings: What is the central question of this study? We set out to test the hypothesis that hemoglobin mass and red blood cell volume would become increased in elite cyclists training in a hot environment compared to control group training in normal temperature. What is the main finding and its importance? We demonstrate that five weeks of he...

Recombinant human erythropoietin (rhEpo) can improve human performance, but misuse remains difficult to detect. C‐terminal fibroblast growth factor 23 (cFGF23) was recently demonstrated to increase following injection of a single high dose rhEpo, but the effect of more frequent low doses is unknown. Using a randomized double‐blind placebo‐controlle...

Introduction Treatment of fluid overload and anemia remains a challenge in patients undergoing hemodialysis. Hypervolemia can be evaluated using a carbon monoxide (CO) rebreathing method by which blood volume (BV), plasma volume (PV), and red blood cell volumes (RBCV) can be determined. We hypothesized that recurrent hypervolemia would cause hemogl...

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 =...

The iron chelator Deferasirox (DFX) causes severe toxicity in patients for reasons that were previously unexplained. Here, using the kidney as a clinically relevant in vivo model for toxicity together with a broad range of experimental techniques, including live cell imaging and in vitro biophysical models, we show that DFX causes partial uncouplin...

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 physiologi...

Many endurance athletes use altitude training to improve their physical performance. In this chapter, we briefly present the main altitude training methods and we evaluate from the existing scientific data their potential effectiveness on endurance performance at sea level. Live high—train high (LHTH) at natural altitude has not been demonstrated t...

Introduction: Notwithstanding recent progress on molecular mechanisms underlying heart failure with preserved ejection fraction (HFpEF), multiple pathophysiological aspects of this condition including the basis of anemia and other hematological disorders remain unresolved. In this study, we sought to determine the relationship of plasma volume (PV...

Heat acclimation is associated with plasma volume (PV) expansion that occurs within the first week of exposure. However, prolonged effects on hemoglobin mass (Hbmass) are unclear as intervention periods in previous studies have not allowed sufficient time for erythropoiesis to manifest. Therefore, Hbmass, intravascular volumes, and blood volume (BV...

Heat acclimation (HA) involves physiological adaptations that directly promote exercise performance in hot environments. However, for endurance-athletes it is unclear if adaptations also improve aerobic capacity and performance in cool conditions, partly because previous randomized controlled trial (RCT) studies have been restricted to short interv...

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...

It has been appreciated for more than a century that maximal oxygen uptake (VO2max ) increases with endurance training (ET). A question that has emerged in our community is why that is so? More specifically, what is the main target of biological signals induced by endurance exercise? It must be assumed that mechanical and chemical signals leading t...

This paper reports temporal changes in physiological measurements of exercise performance in a young man transitioning from alpine skiing until he became a world junior champion time trial cyclist after only 3 yr of bike-specific training. At the time he became World Champion he also achieved among the highest reported maximal oxygen uptake (V̇o 2m...

Blood volume is an integral component of the cardiovascular system, and fundamental to discerning the pathophysiology of multiple cardiovascular conditions leading to exercise intolerance. Based on a systematic search of controlled studies assessing blood volume, in this Personal View we describe how hypovolaemia is a prevalent characteristic of pa...

Despite growing research interest in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), it remains unknown whether central hemodynamic alterations inherently present in this condition do affect blood pressure and blood volume (BV) regulation. The present study sought to determine hemodynamic and endocrine responses to pr...

Hypervolemia is a hallmark of endurance training (ET) and manifests by similar elevations in plasma (PV) and red blood cell volume (RBCV) so that hematocrit largely remains unaltered following weeks/months of training. While the mechanisms facilitating PV expansion with ET have been previously reviewed extensively this is not the case for RBCV. End...

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 plasm...

Hypoxia increases heart rate (HR) in humans by sympathetic activation and vagal withdrawal. However, in anaesthetized dogs hypoxia increases vagal activity and reduces HR if pulmonary ventilation does not increase and we evaluated whether that observation applies to awake humans. Ten healthy males were exposed to 15 min of normoxia and hypoxia (10....

Anemia is defined according to decreased blood hemoglobin concentration ([Hb]), which is considered a marker of low total red blood cell volume (RBCV). Alterations of plasma volume (PV) may also modify [Hb] without concomitant changes in RBCV. Since anemia and fluid retention are frequent complications of chronic kidney disease (CKD), we hypothesiz...

High altitude hypoxia causes sympathoexcitation in humans, but the underlying mechanisms remain unclear. In this study we tested the hypothesis that muscle sympathetic nerve activity (MSNA) would be lowered at high altitude when carotid chemoreceptor activity is reduced by intravenous dopamine infusion. Nine healthy individuals (mean [SD]; 26 [4] y...

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 f...

Bed rest leads to impaired glucose tolerance. Whether this is linked to maladaptation's in skeletal muscle mitochondrial function and in particular to the level of reactive oxygen species (ROS) is at present unknown. The aim of this longitudinal study was to quantify skeletal muscle mitochondrial function (respiratory capacity and ROS production) t...

Physical inactivity alters glucose homeostasis in skeletal muscle, potentially developing into overt metabolic disease. The present study sought to investigate the role of skeletal muscle capillarization in glucose tolerance and insulin sensitivity (IS) using a classic human model of physical inactivity. Thirteen healthy males (age = 23 ± 2 years)...

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 pri...

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...

Background Mitochondrial dysfunction may represent a pathogenic factor in Huntington disease (HD). Physical exercise leads to enhanced mitochondrial function in healthy participants. However, data on effects of physical exercise on HD skeletal muscle remains scarce. We aimed at investigating adaptations of the skeletal muscle mitochondria to endura...

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...

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 calci...

Combined results from different independent studies suggest that acclimatization to high altitude induces a slowly developing sympathetic activation, even at levels of hypoxia that cause no acute chemoreflex-mediated sympathoexcitation. We here provide direct neurophysiological evidence for this phenomenon. In eight Danish lowlanders, we quantified...

We reassessed data from a previous study on the transcerebral net exchange of large neutral amino acids (LNAAs) using a novel mathematical model of blood–brain barrier (BBB) transport. The study included twelve healthy volunteers who received a 4-h intravenous lipopolysaccharide (LPS) infusion (total dose: 0·3 ng/kg), a human experimental model of...

In this CORP article we present the theory and practical aspects of the carbon monoxide (CO) rebreathing method for the determination of total hemoglobin mass in humans. With CO rebreathing, a small quantity of CO is diluted in O2 and rebreathed for a specified time period, during which most of the CO is absorbed and bound to circulating hemoglobin...

Aims: 1) determine whether exercise induced increases in muscle mitochondrial volume density (MitoVD ) is related to enlargement of existing mitochondria or de novo biogenesis, 2) establish if measures of mitochondrial-specific enzymatic activities are valid biomarkers for exercise induced increases in MitoVD . Method: Skeletal muscle samples we...

Humans ascending to high altitude (HA) experience a reduction in arterial oxyhemoglobin saturation and, as a result, arterial O2 content (CaO2). As HA exposure extends, this reduction in CaO2 is counteracted by an increase in arterial hemoglobin concentration. Initially, hemoconcentration is exclusively related to a reduction in plasma volume (PV),...

Arterial distensibility, an independent predictor of cardiovascular events, is transiently increased with acute hyperglycemia (AHG) in healthy individuals. Whether this response interacts with physical inactivity remains unknown. We examined the effects of short-term bed rest (BR) on the response of carotid artery distensibility (CD) to AHG, and th...

Background: Anemia in heart failure (HF) is commonly diagnosed according to hemoglobin concentration [Hb], hence may be the result of hemodilution or true red blood cell volume (RBCV) deficit. Whether true (nonhemodilutional) anemia in HF can or cannot be generally inferred by [Hb] measurements and clinical correlates remains unclear. The purpose...

The purpose of the present study was to characterize the progression of red blood cell volume (RBCV) expansion and potential volumetric and endocrine regulators of erythropoiesis during endurance training (ET). Nine healthy untrained volunteers (age=27±4 years) underwent supervised ET consisting of 3-4 × 60 min cycle ergometry sessions per week for...

Carbon monoxide (CO) increases middle cerebral artery mean flow velocity (MCAVmean), but the effect of CO on the near-infrared spectroscopy (NIRS) determined cerebral oxygenation (ScO2) is not detailed. In our study, 11 non-smoking subjects breathed 100% O2 through a closed circuit. A CO2 scrubber with CO (1.5 mL kg−1) was added to the circuit. Two...

The main aim of the present study was to quantify the magnitude of differences introduced when estimating a given blood volume compartment (e.g. plasma volume) through the direct determination of another compartment (e.g. red cell volume) by multiplication of venous haematocrit and/or haemoglobin concentration. However, since whole body haematocrit...

Cerebral blood flow (CBF) is regulated to secure brain O2 delivery while simultaneously avoiding hyperperfusion; however, both requisites may conflict during sprint exercise. To determine whether brain O2 delivery or CBF is prioritized, young men performed sprint exercise in normoxia and hypoxia (PIO2 = 73 mmHg). During the sprints, cardiac output...

Inter-individual variation in running and cycling exercise economy (EE) remains unexplained although studied for more than a century. This study is the first to comprehensively evaluate the importance of biochemical, structural, physiological, anthropometric, and biomechanical influences on running and cycling EE within a single study. In 22 health...

Key points: The prevalence of cardiorespiratory fitness (CRF) non-response gradually declines in healthy individuals exercising 60, 120, 180, 240 or 300 min per week for 6 weeks. Following a successive identical 6-week training period but comprising 120 min of additional exercise per week, CRF non-response is universally abolished. The magnitude o...

Introduction: The carbon monoxide (CO) rebreathing method used for the determination of haemoglobin mass (Hbmass ) is associated with blood sample analysis (in this study: Radiometer ABL800). As an alternative hereto the aim of the present study was to evaluate the use of a portable and non-invasive CO pulse oximeter (Rad-57). Method: With simul...

Introduction Inflammatory bowel disease (IBD) is a chronic intestinal disorder, often leading to an impaired quality of life in affected patients. The importance of environmental factors in the pathogenesis of IBD, including their disease-modifying potential, is increasingly recognised. Hypoxia seems to be an important driver of inflammation, as ha...

Key points: Heart rate is increased in chronic hypoxia and we tested whether this is the result of increased sympathetic nervous activity, reduced parasympathetic nervous activity, or a non-autonomic mechanism. In seven lowlanders, heart rate was measured at sea level and after 2 weeks at high altitude after individual and combined pharmacological...

Purpose: Cerebral blood flow (CBF) increases ~20% during whole body exercise although a Kety-Schmidt-determined CBF is reported to remain stable; a discrepancy that could reflect evaluation of arterial vs. internal jugular venous (IJV) flow and/or that CBF is influenced by posture. Here we test the hypothesis that IJV flow, as determined by retrog...

Background Exercise training (ExT) prompts multiple beneficial adaptations associated with vascular health, such as increases in skeletal muscle capillarization and vascular dilator function and decreases in arterial stiffness. However, whether ExT performed in hypoxic conditions induces enhanced effects is unclear. Objective We sought to systemati...

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 inter-individual variability: 1) Training induced increases in VO2max are largely facilitated by expansion of red blood cell volume and an associated improvement in stroke volume,...

Anemia, as defined by hemoglobin concentration < 12.0 and < 13.0 g/dl in women and men, respectively, affects more than 150 million elderly people worldwide and even when mild is associated with increased disability, morbidity, and mortality (Ezekowitz et al., 2003; Penninx et al., 2004; De Benoist et al., 2008). The causes of anemia remain unresol...

Introduction and Methods: Acute exposure to high altitude increases pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR). The evolution of Ppa and PVR with continuous hypoxic exposure remains, however, elusive. To test the hypothesis that altitude exposure leads to a persistent elevation in Ppa and PVR throughout acclimatization...

Bed rest leads to rapid impairments in glucose tolerance. Plasma volume and thus dilution space for glucose is 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 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 capillar...

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 therefor...

Background: Erythropoiesis is partly regulated through classic feedback pathways that govern blood volume (BV) as sensed by veno-atrial but also arterial stretch receptors. Hence, the total volume of red blood cells (RBCV) could be associated with arterial stiffness (AS), although such hypothesis has not yet been tested. Therefore, we sought to in...

New Findings What is the topic of this review? The aim is to evaluate the effectiveness of various altitude training strategies as investigated within the last few years. What advances does it highlight? Based on the available literature, the foundation to recommend altitude training to athletes is weak. Athletes may use one of the various altitud...

Purpose: Few recent studies indicate that short-term repeated sprint training in hypoxia (RSH) improves repeated sprint (RS) performance compared with identical training under normoxic conditions (RSN) in endurance-trained subjects. Herein, we sought to determine the effects of RSH against RSN on RS performance under normoxic and moderate hypoxic...

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,...