Hypoxic Bed Rest Research Articles

Moderate Aerobic Exercise Reduces the Detrimental Effects of Hypoxia on Cardiac Autonomic Control in Healthy Volunteers.

Physical inactivity increases cardiometabolic risk through a variety of mechanisms, among which alterations of immunological, metabolic, and autonomic control systems may play a pivotal role. Physical inactivity is frequently associated with other factors that may further worsen prognosis. The association between physical inactivity and hypoxia is particularly interesting and characterizes several conditions-whether physiological (e.g., residing or trekking at high altitude and space flights) or pathological (e.g., chronic cardiopulmonary diseases and COVID-19). In this randomized intervention study, we investigated the combined effects of physical inactivity and hypoxia on autonomic control in eleven healthy and physically active male volunteers, both at baseline (ambulatory) conditions and, in a randomized order, hypoxic ambulatory, hypoxic bedrest, and normoxic bedrest (i.e., a simple experimental model of physical inactivity). Autoregressive spectral analysis of cardiovascular variabilities was employed to assess cardiac autonomic control. Notably, we found hypoxia to be associated with an impairment of cardiac autonomic control, especially when combined with bedrest. In particular, we observed an impairment of indices of baroreflex control, a reduction in the marker of prevalent vagal control to the SA node, and an increase in the marker of sympathetic control to vasculature.

Adult Female Sleep During Hypoxic Bed Rest.

PurposeHypobaric hypoxic habitats are currently being touted as a potential solution to minimise decompression procedures in preparation for extra vehicular activities during future space missions. Since astronauts will live in hypoxic environments for the duration of such missions, the present study sought to elucidate the separate and combined effects of inactivity [simulated with the experimental bed rest (BR) model] and hypoxia on sleep characteristics in women.MethodsTwelve women (Age = 27 ± 3 year) took part in three 10-day interventions, in a repeated measures cross-over counterbalanced design: (1) normobaric normoxic BR (NBR), (2) normobaric hypoxic BR (HBR; simulated altitude of 4,000 m), and (3) normobaric hypoxic ambulatory (HAMB; 4,000 m) confinement, during which sleep was assessed on night 1 and night 10 with polysomnography. In addition, one baseline sleep assessment was performed. This baseline assessment, although lacking a confinement aspect, was included statistically as a fourth comparison (i.e., pseudo normobaric normoxic ambulatory; pNAMB) in the present study.ResultsHypoxia decreased sleep efficiency (p = 0.019), increased N1% sleep (p = 0.030), decreased N3 sleep duration (p = 0.003), and increased apnea hypopnea index (p < 0.001). BR impaired sleep maintenance, efficiency, and architecture [e.g., N2% sleep increased (p = 0.033)]. Specifically, for N3% sleep, the effects of partial pressure of oxygen and activity interacted. Hypoxia decreased N3% sleep both when active (pNAMB vs HAMB; p < 0.001) and inactive (NBR vs HBR; p = 0.021), however, this decrease was attenuated in the inactive state (–3.8%) compared to the active state (–10.2%).ConclusionA 10-day exposure to hypoxia and BR negatively impacted sleep on multiple levels as in macrostructure, microstructure and respiratory functioning. Interestingly, hypoxia appeared to have less adverse effects on sleep macrostructure while the participants were inactive (bed ridden) compared to when ambulatory. Data were missing to some extent (i.e., 20.8%). Therefore, multiple imputation was used, and our results should be considered as exploratory.

Individual Variation Exists Within the Psychological Response to Hypoxic Bed Rest: A Retrospective Analysis.

Individual variation is of interest to Space Agency’s, which cannot be explored with astronauts due to anonymity. We retrospectively analysed data collected throughout three projects (LunHab: 10-day male, PlanHab: 21-day male, and FemHab: 10-day female) to elucidate the potentially masked individual variation in the psychological responses to bed rest. The Profile of Mood State (POMS) and Positive and Negative Affect Schedule (PANAS) – instruments used to asses psychological state – and Lake Louise Mountain Sickness (LLMS) scores were collected prior to, following and throughout three interventions: 1: normoxic bed rest 2: hypoxic bed rest and 3: hypoxic ambulatory confinement. Total Mood Disturbance (TMD) was calculated from the POMS results, positive affect (PA), and negative affect (NA) from PANAS. The three instruments were included in a latent class mixed model. TMD, NA, and LLMS were included in a four-class model, with each class representing a specific type of response (Class 1: descending, Class 2: flat, Class 3: somewhat flat, Class 4: ascending). Responses for PA were assigned to only two classes (Classes 1 and 2). 54.55% or 24 participants were included in Class 2 (TMD, NA, and LLMS), where the responses did not change and neither hypoxia or activity level had a significant effect on emotional state. The remaining participants were allotted to Class 1, 3, or 4, where hypoxia was a significant covariate, while activity (bed rest) was significant only for class 3. For PA, 84.09% or 37 participants were assigned to class 2 indicating a significant effect of hypoxia on the participants responses with no effect of physical activity. Class 1 participants (n = 7) were not affected by hypoxia, however, physical activity improved their PA. Participants undergoing confinement, hypoxia and bed rest do not exhibit a uniform emotional response and may be categorised into 2–4 distinct classes. These results indicate significant individual emotional responses, that may be masked and underreported by traditional statistical approaches like means ± SD. The emotional state of our participants is a complex construct likely influenced by past experiences and different coping mechanisms which allowed some to adapt to the experimental environment more readily.

Heterogeneity of Hematological Response to Hypoxia and Short-Term or Medium-Term Bed Rest.

Hematological changes are commonly observed following prolonged exposure to hypoxia and bed rest. Typically, such responses have been reported as means and standard deviations, however, investigation into the responses of individuals is insufficient. Therefore, the present study retrospectively assessed individual variation in the hematological responses to severe inactivity (bed rest) and hypoxia. The data were derived from three-bed rest projects: two 10-d (LunHab project: 8 males; FemHab project: 12 females), and one 21-d (PlanHab project: 11 males). Each project comprised a normoxic bed rest (NBR; PIO2=133mmHg) and hypoxic bed rest (HBR; PIO2=91mmHg) intervention, where the subjects were confined in the Planica facility (Rateče, Slovenia). During the HBR intervention, subjects were exposed to normobaric hypoxia equivalent to an altitude of 4,000m. NBR and HBR interventions were conducted in a random order and separated by a washout period. Blood was drawn prior to (Pre), during, and post bed rest (R1, R2, R4) to analyze the individual variation in the responses of red blood cells (RBC), erythropoietin (EPO), and reticulocytes (Rct) to bed rest and hypoxia. No significant differences were found in the mean ∆(Pre-Post) values of EPO across projects (LunHab, FemHab, and PlanHab; p>0.05), however, female EPO responses to NBR (Range - 17.39, IQR – 12.97 mIU.ml−1) and HBR (Range – 49.00, IQR – 10.91 mIU.ml−1) were larger than males (LunHab NBR Range – 4.60, IQR – 2.03; HBR Range – 7.10, IQR – 2.78; PlanHab NBR Range – 7.23, IQR – 1.37; HBR Range – 9.72, IQR – 4.91 mIU.ml−1). Bed rest duration had no impact on the heterogeneity of EPO, Rct, and RBC responses (10-d v 21-d). The resultant hematological changes that occur during NBR and HBR are not proportional to the acute EPO response. The following cascade of hematological responses to NBR and HBR suggests that the source of variability in the present data is due to mechanisms related to hypoxia as opposed to inactivity alone. Studies investigating hematological changes should structure their study design to explore these mechanistic responses and elucidate the discord between the EPO response and hematological cascade to fully assess heterogeneity.

Substantial and Reproducible Individual Variability in Skeletal Muscle Outcomes in the Cross-Over Designed Planica Bed Rest Program.

To evaluate the individual responses in skeletal muscle outcomes following bed rest, data from three studies (21-day PlanHab; 10-day FemHab and LunHab) were combined. Subjects (n = 35) participated in three cross-over campaigns within each study: normoxic (NBR) and hypoxic bed rest (HBR), and hypoxic ambulation (HAMB; used as control). Individual variability (SDIR) was investigated as √(SD–SD), where SDExp and SDCon are the standard deviations of the change score (i.e., post – pre) in the experimental (NBR and HBR) and the control (HAMB) groups, respectively. Repeatability and moderators of the individual variability were explored. Significant SDIR was detected for knee extension torque, and thigh and calf muscle area, which translated into an individual response ranging from 3 to −17% for knee extension torque, −2 to −12% for calf muscle area, and −1 to −8% for thigh muscle area. Strong correlations were found for changes in NBR vs. HBR (i.e., repeatability) in thigh and calf muscle area (r = 0.65–0.75, P < 0.0001). Change-scores in knee extension torque, and thigh and calf muscle area strongly correlated with baseline values (P < 0.001; r between −0.5 and −0.9). Orthogonal partial least squares regression analysis explored if changes in the investigated variables could predict calf muscle area alterations. This analysis indicated that 43% of the variance in calf muscle area could be attributed to changes in all of the other variables. This is the first study using a validated methodology to report clinically relevant individual variability after bed rest in knee extension torque, calf muscle area, and (to a lower extent) thigh muscle area. Baseline values emerged as a moderator of the individual response, and a global bed rest signature served as a moderately strong predictor of the individual variation in calf muscle area alterations.

Systems View of Deconditioning During Spaceflight Simulation in the PlanHab Project: The Departure of Urine 1 H-NMR Metabolomes From Healthy State in Young Males Subjected to Bedrest Inactivity and Hypoxia.

We explored the metabolic makeup of urine in prescreened healthy male participants within the PlanHab experiment. The run-in (5 day) and the following three 21-day interventions [normoxic bedrest (NBR), hypoxic bedrest (HBR), and hypoxic ambulation (HAmb)] were executed in a crossover manner within a controlled laboratory setup (medical oversight, fluid and dietary intakes, microbial bioburden, circadian rhythm, and oxygen level). The inspired O2 (FiO2) fraction next to inspired O2 (PiO2) partial pressure were 0.209 and 133.1 ± 0.3 mmHg for the NBR variant in contrast to 0.141 ± 0.004 and 90.0 ± 0.4 mmHg (approx. 4,000 m of simulated altitude) for HBR and HAmb interventions, respectively. 1H-NMR metabolomes were processed using standard quantitative approaches. A consensus of ensemble of multivariate analyses showed that the metabolic makeup at the start of the experiment and at HAmb endpoint differed significantly from the NBR and HBR endpoints. Inactivity alone or combined with hypoxia resulted in a significant reduction of metabolic diversity and increasing number of affected metabolic pathways. Sliding window analysis (3 + 1) unraveled that metabolic changes in the NBR lagged behind those observed in the HBR. These results show that the negative effects of cessation of activity on systemic metabolism are further aggravated by additional hypoxia. The PlanHab HAmb variant that enabled ambulation, maintained vertical posture, and controlled but limited activity levels apparently prevented the development of negative physiological symptoms such as insulin resistance, low-level systemic inflammation, constipation, and depression. This indicates that exercise apparently prevented the negative spiral between the host’s metabolism, intestinal environment, microbiome physiology, and proinflammatory immune activities in the host.

Do females and males exhibit a similar sarcopenic response as a consequence of normoxic and hypoxic bed rest?

What is the central question of this study? Do females and males exhibit a similar sarcopenic response as a consequence of normoxic and hypoxic bed rest? What is the main finding and its importance? During 10-day bed rest, exposure to a simulated (normobaric hypoxia) altitude of ∼4000m does not exert additional significant structural or functional effect on the weight-bearing muscles in females compared to those noted under normoxic conditions. Whereas males and females exhibit decrements in muscle cross-sectional area and mass during normoxic and hypoxic bed rest, a concomitant strength decrement was only observed in males. This study investigated the effects of hypoxia on the known processes of adaptation of body composition and muscle function to normoxic inactivity. Females (n=12) and males (n=11) took part in the following interventions: hypoxic ambulation (HAMB; ∼4000m); hypoxic bed rest (HBR; ∼4000m) and normoxic bed rest (NBR). Prior to and immediately following each intervention, body composition, thigh and lower leg cross-sectional area (CSA) and isometric muscular strength were recorded. Participants lost body mass (HAMB: male -1.5±0.9kg, female -1.9±0.7kg; HBR: male -2.0±1.8kg, female -2.4±0.8kg; NBR: male -1.4±1.3kg, female -1.4±0.9kg) and lean mass (HAMB: male -3.9±3.0%, female -3.4±2.0%; HBR: male -4.0±4.4%, female -4.1±2.0%; NBR: male -4.0±3.4%, female -2.2±2.7%) with no between-condition or sex differences. Knee extension decreased for males in NBR compared to HAMB (HAMB: male -0.2±9.1%, female 1.3±4.9%; HBR: male -7.8±10.3%, female -3.3±10.9%; NBR: male -14.5±11%, female -3.4±6.9%). Loss of force during maximal voluntary contraction (MVC) in the knee extensors was significantly different between males and females following NBR. There were no other significant changes noted following the experimental interventions. There were no differences recorded between sexes in maximal MVC for elbow or ankle joints. Female lower leg CSA decreased following bed rest (HAMB: -4.5±2.0%; HBR: -9.9±2.6%; NBR: -8.0±1.6%). Thesefindings indicate that a 10-day hypoxic bed rest does not exert any significant additional effect on muscle atrophy when compared to NBR, except for female thigh CSA. In contrast to males, who exhibited a significant loss of muscle strength, no such decrement in strength was observed in the female participants.

The influence of a sustained 10-day hypoxic bed rest on cartilage biomarkers and subchondral bone in females: The FemHab study.

This study assessed the influence of a 10‐day hypoxic bed rest on cartilage biomarkers and subchondral bone density across the patellofemoral joint (PFJ). Within clinical settings hypoxic tissue may arise in several types of disorders. Furthermore, a hypoxic environment is being considered for space flight habitats in the near future. Female participants (N = 12) participated in this study comprising three 10‐day interventions: hypoxic ambulation (HAMB), normoxic bed rest (NBR), and hypoxic bed rest (HBR). Venous samples were collected prior to (day −2: Pre) and during the intervention (days 2 and 5), immediately before reambulation (D11) and 24 hr post intervention (R1). Blood samples were analyzed for: aggrecan, hyaluronan, Type IIA procollagen amino terminal propeptide (PIIANP), and cartilage oligomeric matrix protein (COMP). Total bone mineral density (BMD) in eight regions (2 mm × 10 mm) across the PFJ was determined. The three interventions (HAMB, HBR, and NBR) did not induce any significant changes in the cartilage biomarkers of hyaluronan or PIIANP. Aggrecan increased during the HAMB trial to 2.02 fold the Pre value. COMP decreased significantly in both NBR & HBR compared to HAMB on D5. There were significant differences in BMD measured across the PFJ from cortical patellar bone (735 to 800 mg/cm3) to femur trabecular (195 to 226 mg/cm3). However, there were no significant changes in BMD from Pre to Post bed rest. These results indicate that there were no significant detectable effects of inactivity/unloading on subchondral bone density. The biomarker of cartilage, COMP, decreased on D5, whereas the addition of hypoxia to bed rest had no effect, it appears that hypoxia in combination with ambulation counteracted this decrease.

The LunHab project: Muscle and bone alterations in male participants following a 10day lunar habitat simulation.

What is the central question of this study? It is well established that muscle and bone atrophy in conditions of inactivity or unloading, but there is little information regarding the effect of a hypoxic environment on the time course of these deconditioning physiological systems. What is the main finding and its importance? The main finding is that a horizontal 10 day bed rest in normoxia results in typical muscle atrophy, which is not aggravated by hypoxia. Changes in bone mineral content or in metabolism were not detected after either normoxic or hypoxic bed rest. Musculoskeletal atrophy constitutes a typical adaptation to inactivity and unloading of weightbearing bones. The reduced-gravity environment in future Moon and Mars habitats is likely to be hypobaric hypoxic, and there is an urgent need to understand the effect of hypoxia on the process of inactivity-induced musculoskeletal atrophy. This was the principal aim of the present study. Eleven males participated in three 10day interventions: (i) hypoxic ambulatory confinement; (ii) hypoxic bed rest; and (iii) normoxic bed rest. Before and after the interventions, the muscle strength (isometric maximal voluntary contraction), mass (lean mass, by dual-energy X-ray absorptiometry), cross-sectional area and total bone mineral content (determined with peripheral quantitative computed tomography) of the participants were measured. Blood and urine samples were collected before and on the 1st, 4th and 10th day of the intervention and analysed for biomarkers of bone resorption and formation. There was a significant reduction in thigh and lower leg muscle mass and volume after both normoxic and hypoxic bed rests. Muscle strength loss was proportionately greater than the loss in muscle mass for both thigh and lower leg. There was no indication of bone loss. Furthermore, the biomarkers of resorption and formation were not affected by any of the interventions. There was no significant effect of hypoxia on the musculoskeletal variables. Short-term normoxic (10day) bed rest resulted in muscular deconditioning, but not in the loss of bone mineral content or changes in bone metabolism. Hypoxia did not modify these results.

Effects of Hypoxia and Bed Rest on Markers of Cardiometabolic Risk: Compensatory Changes in Circulating TRAIL and Glutathione Redox Capacity.

In chronic diseases, hypoxia and physical inactivity are associated with atherosclerosis progression. In contrast, a lower mortality from coronary artery disease and stroke is observed in healthy humans residing at high altitude in hypoxic environments. Eleven young, male volunteers completed the following 10-day campaigns in a randomized order: hypoxic ambulatory, hypoxic bed rest and normoxic bed rest. Before intervention, subjects were evaluated in normoxic ambulatory condition. Normobaric hypoxia was achieved in a hypoxic facility simulating 4000 m of altitude. Following hypoxia, either in bed rest or ambulatory condition, markers of cardiometabolic risk shifted toward a more atherogenic pattern consisting of: (a) lower levels of total HDL cholesterol and HDL2 sub-fraction and decreased hepatic lipase; (b) activation of systemic inflammation, as determined by C-reactive protein and serum amyloid A; (c) increased plasma homocysteine; (d) decreased delta-5 desaturase index in cell membrane fatty acids, a marker of insulin sensitivity. Bed rest and hypoxia additively decreased total HDL and delta-5 desaturase index. In parallel to the pro-atherogenic effects, hypoxia activated selected anti-atherogenic pathways, consisting of increased circulating TNF-related apoptosis-inducing ligand (TRAIL), a protective factor against atherosclerosis, membrane omega-3 index and erythrocyte glutathione availability. Hypoxia mediated changes in TRAIL concentrations and redox glutathione capacity (i.e., GSH/GSSG ratio) were greater in ambulatory conditions (+34 ± 6% and +87 ± 31%, respectively) than in bed rest (+17 ± 7% and +2 ± 27% respectively). Hypoxia-induced cardiometabolic risk is blunted by moderate level of physical activity as compared to bed rest. TRAIL and glutathione redox capacity may contribute to the positive interaction between physical activity and hypoxia.Highlights:– Hypoxia and bed rest activate metabolic and inflammatory markers of atherogenesis.– Hypoxia and physical activity activate selected anti-atherogenic pathways.– Hypoxia and physical activity positive interaction involves TRAIL and glutathione.

Hypoxia Worsens Affective Responses and Feeling of Fatigue During Prolonged Bed Rest.

Previous research, although limited, suggests that both hypoxia and bed rest influence psychological responses by exaggerating negative psychological responses and attenuating positive emotions. The present study investigated the effect of a 21-day prolonged exposure to normobaric hypoxia and bed rest on affective responses and fatigue. Eleven healthy participants underwent three 21-day interventions using a cross-over design: (1) normobaric hypoxic ambulatory confinement (HAMB), (2) normobaric hypoxic bed rest (HBR) and (3) normoxic bed rest (NBR). Affective and fatigue responses were investigated using the Activation Deactivation Adjective Check List, and the Multidimensional Fatigue Inventory, which were completed before (Pre), during (Day 7, Day 14, and Day 21) and after (Post) the interventions. The most negative psychological profile appeared during the HBR intervention. Specifically, tiredness, tension, general and physical fatigue significantly increased on days 7, 14, and 21, as well as at Post. After the HBR intervention, general and physical fatigue remained higher compared to Pre values. Additionally, a deterioration of psychological responses was also noted following HAMB and NBR. In particular, both hypoxia and BR per se induced subjective fatigue and negative affective responses. BR seems to exert a moderate negative effect on the sensation of fatigue, whereas exercise attenuates the negative effects of hypoxia as noted during the HAMB condition. In conclusion, our data suggest that the addition of hypoxia to bed rest-induced inactivity significantly worsens affective responses and feeling of fatigue.

Intestinal Metagenomes and Metabolomes in Healthy Young Males: Inactivity and Hypoxia Generated Negative Physiological Symptoms Precede Microbial Dysbiosis.

We explored the metagenomic, metabolomic and trace metal makeup of intestinal microbiota and environment in healthy male participants during the run-in (5 day) and the following three 21-day interventions: normoxic bedrest (NBR), hypoxic bedrest (HBR) and hypoxic ambulation (HAmb) which were carried out within a controlled laboratory environment (circadian rhythm, fluid and dietary intakes, microbial bioburden, oxygen level, exercise). The fraction of inspired O2 (FiO2) and partial pressure of inspired O2 (PiO2) were 0.209 and 133.1 ± 0.3 mmHg for the NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg (~4,000 m simulated altitude) for HBR and HAmb interventions, respectively. Shotgun metagenomes were analyzed at various taxonomic and functional levels, 1H- and 13C -metabolomes were processed using standard quantitative and human expert approaches, whereas metals were assessed using X-ray fluorescence spectrometry. Inactivity and hypoxia resulted in a significant increase in the genus Bacteroides in HBR, in genes coding for proteins involved in iron acquisition and metabolism, cell wall, capsule, virulence, defense and mucin degradation, such as beta-galactosidase (EC3.2.1.23), α-L-fucosidase (EC3.2.1.51), Sialidase (EC3.2.1.18), and α-N-acetylglucosaminidase (EC3.2.1.50). In contrast, the microbial metabolomes, intestinal element and metal profiles, the diversity of bacterial, archaeal and fungal microbial communities were not significantly affected. The observed progressive decrease in defecation frequency and concomitant increase in the electrical conductivity (EC) preceded or took place in absence of significant changes at the taxonomic, functional gene, metabolome and intestinal metal profile levels. The fact that the genus Bacteroides and proteins involved in iron acquisition and metabolism, cell wall, capsule, virulence and mucin degradation were enriched at the end of HBR suggest that both constipation and EC decreased intestinal metal availability leading to modified expression of co-regulated genes in Bacteroides genomes. Bayesian network analysis was used to derive the first hierarchical model of initial inactivity mediated deconditioning steps over time. The PlanHab wash-out period corresponded to a profound life-style change (i.e., reintroduction of exercise) that resulted in stepwise amelioration of the negative physiological symptoms, indicating that exercise apparently prevented the crosstalk between the microbial physiology, mucin degradation and proinflammatory immune activities in the host.

Hypoxia Exacerbates Negative Emotional State during Inactivity: The Effect of 21 Days Hypoxic Bed Rest and Confinement.

Hypoxia and confinement have both been shown to influence emotional state. It is envisaged that the inhabitants of future planetary habitats will be exposed to concomitant confinement, reduced gravity and hypoxia. We examined the independent and combined effects of a 21-day inactivity/unloading and normobaric hypoxia under confined conditions on various psychological factors. Eleven healthy men participated in three 21-day experimental campaigns designed in a cross-over manner: (1) Normobaric hypoxic ambulatory confinement, (2) Normobaric hypoxic bed rest and (3) Normobaric normoxic bed rest. The Profile of Mood States, and the Positive and Negative Affect Schedule were employed to assess the participants' psychological responses before (Pre), during (Day 7, Day 14, and Day 21) and after (Post) the confinements. The most negative psychological profile appeared on days 14 and 21 of the hypoxic bed rest campaign. A significant increase in depression, tension, and confusion was noted on days 14 and 21 of the hypoxic bed rest condition. Concomitantly, a decrease, albeit not statistically significant, in positive psychological responses was observed. The psychological profile returned to the initial level at Post following all confinements. These data suggest that the combined effect of hypoxia and bed rest induced the most negative effects on an individual's mood. However, significant intra- and inter-individual differences in psychological responses were noted and should be taken into consideration.

PlanHab Study: Consequences of combined normobaric hypoxia and bed rest on adenosine kinetics

Adenosine plays a role in the energy supply of cells and provokes differential, hormone-like functions in circulating cells and various tissues. Its release is importantly regulated by oxygen tension. This renders adenosine and its kinetics interesting to investigate in humans subjected to low oxygen conditions. Especially for space exploration scenarios, hypoxic conditions – together with reduced gravity - represent two foreseen living conditions when planning manned long-duration space missions or planetary habitats. The PlanHab study investigated microgravity through inactivity in bed rest and normobaric hypoxia to examine their independent or combined effect on adenosine and its kinetics. Healthy male subjects (n = 14) completed three 21-day interventions: hypoxic bed rest (HBR); hypoxic ambulatory confinement (HAMB); normoxic bed rest (NBR). The interventions were separated by 4 months. Our hypothesis of a hypoxia-triggered increase in adenosine was confirmed in HAMB but unexpectedly also in NBR. However, the highest adenosine levels were noted following HBR. Furthermore, the percentage of hemolysis was elevated in HBR whereas endothelial integrity markers stayed low in all three interventions. In summary, these data suggest that neocytolysis accounts for these effects while we could reduce evidence for microcirculatory changes.

Hypoxia and inactivity related physiological changes precede or take place in absence of significant rearrangements in bacterial community structure: The PlanHab randomized trial pilot study.

We explored the assembly of intestinal microbiota in healthy male participants during the randomized crossover design of run-in (5 day) and experimental phases (21-day normoxic bed rest (NBR), hypoxic bed rest (HBR) and hypoxic ambulation (HAmb) in a strictly controlled laboratory environment, with balanced fluid and dietary intakes, controlled circadian rhythm, microbial ambiental burden and 24/7 medical surveillance. The fraction of inspired O2 (FiO2) and partial pressure of inspired O2 (PiO2) were 0.209 and 133.1 ± 0.3 mmHg for NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg for both hypoxic variants (HBR and HAmb; ~4000 m simulated altitude), respectively. A number of parameters linked to intestinal environment such as defecation frequency, intestinal electrical conductivity (IEC), sterol and polyphenol content and diversity, indole, aromaticity and spectral characteristics of dissolved organic matter (DOM) were measured (64 variables). The structure and diversity of bacterial microbial community was assessed using 16S rRNA amplicon sequencing. Inactivity negatively affected frequency of defecation and in combination with hypoxia increased IEC (p < 0.05). In contrast, sterol and polyphenol diversity and content, various characteristics of DOM and aromatic compounds, the structure and diversity of bacterial microbial community were not significantly affected over time. A new in-house PlanHab database was established to integrate all measured variables on host physiology, diet, experiment, immune and metabolic markers (n = 231). The observed progressive decrease in defecation frequency and concomitant increase in IEC suggested that the transition from healthy physiological state towards the developed symptoms of low magnitude obesity-related syndromes was dose dependent on the extent of time spent in inactivity and preceded or took place in absence of significant rearrangements in bacterial microbial community. Species B. thetaiotamicron, B. fragilis, B. dorei and other Bacteroides with reported relevance for dysbiotic medical conditions were significantly enriched in HBR, characterized with most severe inflammation symptoms, indicating a shift towards host mucin degradation and proinflammatory immune crosstalk.

Bed Rest and Hypoxic Exposure Affect Sleep Architecture and Breathing Stability.

Objective: Despite over 50 years of research on the physiological effects of sustained bed rest, data characterizing its effects on sleep macrostructure and breathing stability in humans are scarce. This study was conducted to determine the effects of continuous exposure to hypoxia and sustained best rest, both individually and combined, on nocturnal sleep and breathing stability.Methods: Eleven participants completed three randomized, counter-balanced, 21-days trials of: (1) normoxic bed rest (NBR, PIO2 = 133.1 ± 0.3), (2) hypoxic ambulatory confinement (HAMB, PIO2 = 90.0 ± 0.4) and (3) hypoxic bed rest (HBR, PIO2 = 90.0 ± 0.4; ~4,000 m equivalent altitude). Full objective polysomnography was performed at baseline, on Night 1 and Night 21 in each condition.Results: In NBR Night 1, more time was spent in light sleep (10 ± 2%) compared to baseline (8 ± 2%; p = 0.028); Slow-wave sleep (SWS) was reduced from baseline in the hypoxic-only trial by 18% (HAMB Night 21, p = 0.028) and further reduced by 33% (HBR Night 1, p = 0.010), and 36% (HBR Night 21, p = 0.008) when combined with bed rest. The apnea-hypopnea index doubled from Night 1 to Night 21 in HBR (32–62 events·h−1) and HAMB (31–59 events·h−1; p = 0.002). Those who experienced greatest breathing instability from Night 1 to Night 21 (NBR) were correlated to unchanged or higher (+1%) night SpO2 concentrations (R2 = 0.471, p = 0.020).Conclusion: Bed rest negatively affects sleep macrostructure, increases the apnea-hypopnea index, and worsens breathing stability, each independently exacerbated by continuous exposure to hypoxia.

LunHab: interactive effects of a 10day sustained exposure to hypoxia and bedrest on aerobic exercise capacity in male lowlanders.

What is the central question of this study? What are the distinct and interactive effects of a 10day exposure to hypoxia and horizontal bedrest on the whole-body peak oxygen uptake and on the regional cerebral and skeletal muscle tissue oxygenation during upright cycle ergometry in male lowlanders? What is the main finding and its importance? A 10day sustained exposure to hypoxia aggravates the bedrest-induced reduction in peak oxygen uptake during dynamic exercise engaging large muscle groups, but mitigates the skeletal muscle oxidative capacity impairment elicited by bedrest. The study examined the interactive effects of a 10day exposure to hypoxia and bedrest on the whole-body peak oxygen uptake (V̇O2 peak ) during maximal exercise and on skeletal muscle and cerebral oxygenation during submaximal exercise. Nine males underwent three 10day confinements, in a Latin-square order, as follows: (i) a normoxic bedrest [NBR; partial pressure of inspired O2 (PI,O2)=134.2±0.7mmHg]; (ii) a hypoxic bedrest (HBR; PI,O2=102.9±0.1mmHg at day1, 91.5±1.2mmHg at days3-10); and (iii) a hypoxic ambulation (HAMB; PI,O2 as in HBR). Before, 1 (R+1) and 3days (R+3) after each confinement, subjects performed exhaustive, incremental-load and moderate-intensity constant-load (CLTs) cycle-ergometry trials, while breathing either room air or a hypoxic gas mixture. During the CLTs, changes in the regional oxygenation of the cerebral frontal cortex and the vastus lateralis and intercostal muscles were monitored with near-infrared spectroscopy. At R+1, the confinement-related impairment in V̇O2 peak was greater after HBR than after NBR or HAMB, regardless of whether the trial was performed in room air or hypoxia (HBR, -16.2%; NBR, -8.3%; HAMB, -4.1%; P=0.001). During the CLTs, bedrest aggravated the exercise-induced reduction in locomotor and respiratory muscle oxygenation (P≤0.05); an effect that was less after HBR than after NBR (P≤0.05). The hypoxic exercise-induced cerebral vasodilatory response was blunted by HBR, probably because of the marked hyperventilation-dependent hypocapnia, attendant to the sustained hypoxic stimulus. Hence, short-term exposure to hypoxia potentiates the reduction in V̇O2 peak , but it mitigates the impairment in skeletal muscle oxidative capacity induced by bedrest.

Hypoxia and Inactivity Related Physiological Changes (Constipation, Inflammation) Are Not Reflected at the Level of Gut Metabolites and Butyrate Producing Microbial Community: The PlanHab Study.

We explored the assembly of intestinal microbiota in healthy male participants during the run-in (5 day) and experimental phases [21-day normoxic bed rest (NBR), hypoxic bedrest (HBR)], and hypoxic ambulation (HAmb) in a strictly controlled laboratory environment, balanced fluid, and dietary intakes, controlled circadian rhythm, microbial ambiental burden, and 24/7 medical surveillance. The fraction of inspired O2 (FiO2) and partial pressure of inspired O2 (PiO2) were 0.209 and 133.1 ± 0.3 mmHg for NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg for both hypoxic variants (HBR and HAmb; ~4,000 m simulated altitude), respectively. A number of parameters linked to intestinal transit spanning Bristol Stool Scale, defecation rates, zonulin, α1-antitrypsin, eosinophil derived neurotoxin, bile acids, reducing sugars, short chain fatty acids, total soluble organic carbon, water content, diet composition, and food intake were measured (167 variables). The abundance, structure, and diversity of butyrate producing microbial community were assessed using the two primary bacterial butyrate synthesis pathways, butyryl-CoA: acetate CoA-transferase (but) and butyrate kinase (buk) genes. Inactivity negatively affected fecal consistency and in combination with hypoxia aggravated the state of gut inflammation (p < 0.05). In contrast, gut permeability, various metabolic markers, the structure, diversity, and abundance of butyrate producing microbial community were not significantly affected. Rearrangements in the butyrate producing microbial community structure were explained by experimental setup (13.4%), experimentally structured metabolites (12.8%), and gut metabolite-immunological markers (11.9%), with 61.9% remaining unexplained. Many of the measured parameters were found to be correlated and were hence omitted from further analyses. The observed progressive increase in two immunological intestinal markers suggested that the transition from healthy physiological state toward the developed symptoms of low magnitude obesity-related syndromes was primarily driven by the onset of inactivity (lack of exercise in NBR) that were exacerbated by systemic hypoxia (HBR) and significantly alleviated by exercise, despite hypoxia (HAmb). Butyrate producing community in colon exhibited apparent resilience toward short-term modifications in host exercise or hypoxia. Progressive constipation (decreased intestinal motility) and increased local inflammation marker suggest that changes in microbial colonization and metabolism were taking place at the location of small intestine.

Commentaries on Viewpoint: Standardization of bed rest studies in the spaceflight contextCommentaries on Viewpoint: Standardization of bed rest studies in the spaceflight contextCommentaries on Viewpoint: Standardization of bed rest studies in the spaceflight contextCommentaries on Viewpoint: Standardization of bed rest studies in the spaceflight contextCommentaries on Viewpoint: Standardization of bed rest studies in the spaceflight context

to the editor: The work presented by Sundblad et al. ([5][1]) is important and is likely to improve present international efforts to develop countermeasures against, for example, cardiovascular deconditioning during spaceflight. However, one aspect that is not addressed to a sufficient extent is the

PlanHab: hypoxia exaggerates the bed-rest-induced reduction in peak oxygen uptake during upright cycle ergometry.

The study examined the effects of hypoxia and horizontal bed rest, separately and in combination, on peak oxygen uptake (V̇o2 peak) during upright cycle ergometry. Ten male lowlanders underwent three 21-day confinement periods in a counterbalanced order: 1) normoxic bed rest [NBR; partial pressure of inspired O2 (PiO2 ) = 133.1 ± 0.3 mmHg]; 2) hypoxic bed rest (HBR; PiO2 = 90.0 ± 0.4 mmHg), and 3) hypoxic ambulation (HAMB; PiO2 = 90.0 ± 0.4 mmHg). Before and after each confinement, subjects performed two incremental-load trials to exhaustion, while inspiring either room air (AIR), or a hypoxic gas (HYPO; PiO2 = 90.0 ± 0.4 mmHg). Changes in regional oxygenation of the vastus lateralis muscle and the frontal cerebral cortex were monitored with near-infrared spectroscopy. Cardiac output (CO) was recorded using a bioimpedance method. The AIR V̇o2 peak was decreased by both HBR (∼13.5%; P ≤ 0.001) and NBR (∼8.6%; P ≤ 0.001), with greater drop after HBR (P = 0.01). The HYPO V̇o2 peak was also reduced by HBR (-9.7%; P ≤ 0.001) and NBR (-6.1%; P ≤ 0.001). Peak CO was lower after both bed-rest interventions, and especially after HBR (HBR: ∼13%, NBR: ∼7%; P ≤ 0.05). Exercise-induced alterations in muscle and cerebral oxygenation were blunted in a similar manner after both bed-rest confinements. No changes were observed in HAMB. Hence, the bed-rest-induced decrease in V̇o2 peak was exaggerated by hypoxia, most likely due to a reduction in convective O2 transport, as indicated by the lower peak values of CO.