Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform.

With current plans for manned missions to Mars and beyond, the need to better understand, prevent, and counteract the harmful effects of long-duration spaceflight on the body is becoming increasingly important. In this study, an automated heart-on-a-chip platform was flown to the International Space Station on a 1-mo mission during which contractile cardiac function was monitored in real-time. Upon return to Earth, engineered human heart tissues (EHTs) were further analyzed with ultrastructural imaging and RNA sequencing to investigate the impact of prolonged microgravity on cardiomyocyte function and health. Spaceflight EHTs exhibited significantly reduced twitch forces, increased incidences of arrhythmias, and increased signs of sarcomere disruption and mitochondrial damage. Transcriptomic analyses showed an up-regulation of genes and pathways associated with metabolic disorders, heart failure, oxidative stress, and inflammation, while genes related to contractility and calcium signaling showed significant down-regulation. Finally, in silico modeling revealed a potential link between oxidative stress and mitochondrial dysfunction that corresponded with RNA sequencing results. This represents an in vitro model to faithfully reproduce the adverse effects of spaceflight on three-dimensional (3D)-engineered heart tissue.

Severe Spaceflight-Associated Neuro-Ocular Syndrome in an Astronaut With 2 Predisposing Factors.

Importance: Understanding potential predisposing factors associated with spaceflight-associated neuro-ocular syndrome (SANS) may influence its management. Objective: To describe a severe case of SANS associated with 2 potentially predisposing factors. Design, Setting, and Participants: Ocular testing of and blood collections from a female astronaut were completed preflight, inflight, and postflight in the setting of the International Space Station (ISS). Exposure: Weightlessness throughout an approximately 6-month ISS mission. Mean carbon dioxide (CO2) partial pressure decreased from 2.6 to 1.3 mm Hg weeks before the astronaut's flight day (FD) 154 optical coherence tomography (OCT) session. In response to SANS, 4 B-vitamin supplements (vitamin B6, 100 mg; L-methylfolate, 5 mg; vitamin B12, 1000 µg; and riboflavin, 400 mg) were deployed, unpacked on FD153, consumed daily through FD169, and then discontinued due to gastrointestinal discomfort. Main Outcomes and Measures: Refraction, distance visual acuity (DVA), optic nerve, and macular assessment on OCT. Results: Cycloplegic refraction was -1.00 diopter in both eyes preflight and +0.50 - 0.25 × 015 in the right eye and +1.00 diopter in the left eye 3 days postflight. Uncorrected DVA was 20/30 OU preflight, 20/16 or better by FD90, and 20/15 OU 3 days postflight. Inflight peripapillary total retinal thickness (TRT) peaked between FD84 and FD126 (right eye, 401 µm preflight, 613 µm on FD84; left eye, 404 µm preflight, 636 µm on FD126), then decreased. Peripapillary choroidal folds, quantified by surface roughness, peaked at 12.7 µm in the right eye on FD154 and 15.0 µm in the left eye on FD126, then decreased. Mean choroidal thickness increased throughout the mission. Genetic analyses revealed 2 minor alleles for MTRR 66 and 2 major alleles for SHMT1 1420 (ie, 4 of 4 SANS risk alleles). One-week postflight, lumbar puncture opening pressure was normal, at 19.4 cm H2O. Conclusions and Relevance: To the authors' knowledge, no other report of SANS documented as large of a change in peripapillary TRT or hyperopic shift during a mission as in this astronaut, and this was only 1 of 4 astronauts to experience chorioretinal folds approaching the fovea. This case showed substantial inflight improvement greater than the sensitivity of the measure, possibly associated with B-vitamin supplementation and/or reduction in cabin CO2. However, as a single report, such improvement could be coincidental to these interventions, warranting further evaluation.

The aerobic dive limit: After 40 years, still rarely measured but commonly used.

The aerobic dive limit (ADL) and the hypothesis that most dives are aerobic in nature have become fundamental to the understanding of diving physiology and to the interpretation of diving behavior and foraging ecology of marine mammals and seabirds. An ADL, the dive duration associated with the onset of post-dive blood lactate accumulation, has only been documented with blood lactate analyses in five species. Applications to other species have involved behavioral estimates or use of an oxygen store / metabolic rate formula. Both approaches have limitations, but have proved useful to the evaluation of the dive behavior and ecology of many species.

Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight.

Among the physiological consequences of extended spaceflight are loss of skeletal muscle and bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis is that regulated by the secreted signaling proteins, myostatin (MSTN) and activin A. Here, we used both genetic and pharmacological approaches to investigate the effect of targeting MSTN/activin A signaling in mice that were sent to the International Space Station. Wild type mice lost significant muscle and bone mass during the 33 d spent in microgravity. Muscle weights of Mstn-/- mice, which are about twice those of wild type mice, were largely maintained during spaceflight. Systemic inhibition of MSTN/activin A signaling using a soluble form of the activin type IIB receptor (ACVR2B), which can bind each of these ligands, led to dramatic increases in both muscle and bone mass, with effects being comparable in ground and flight mice. Exposure to microgravity and treatment with the soluble receptor each led to alterations in numerous signaling pathways, which were reflected in changes in levels of key signaling components in the blood as well as their RNA expression levels in muscle and bone. These findings have implications for therapeutic strategies to combat the concomitant muscle and bone loss occurring in people afflicted with disuse atrophy on Earth as well as in astronauts in space, especially during prolonged missions.

Reduced metabolism supports hypoxic flight in the high-flying bar-headed goose (Anser indicus).

The bar-headed goose is famed for migratory flight at extreme altitude. To better understand the physiology underlying this remarkable behavior, we imprinted and trained geese, collecting the first cardiorespiratory measurements of bar-headed geese flying at simulated altitude in a wind tunnel. Metabolic rate during flight increased 16-fold from rest, supported by an increase in the estimated amount of O2 transported per heartbeat and a modest increase in heart rate. The geese appear to have ample cardiac reserves, as heart rate during hypoxic flights was not higher than in normoxic flights. We conclude that flight in hypoxia is largely achieved via the reduction in metabolic rate compared to normoxia. Arterial [Formula: see text] was maintained throughout flights. Mixed venous PO2 decreased during the initial portion of flights in hypoxia, indicative of increased tissue O2 extraction. We also discovered that mixed venous temperature decreased during flight, which may significantly increase oxygen loading to hemoglobin.

Do Bar-Headed Geese Train for High Altitude Flights?

SYNOPSIS: Exercise at high altitude is extremely challenging, largely due to hypobaric hypoxia (low oxygen levels brought about by low air pressure). In humans, the maximal rate of oxygen consumption decreases with increasing altitude, supporting progressively poorer performance. Bar-headed geese (Anser indicus) are renowned high altitude migrants and, although they appear to minimize altitude during migration where possible, they must fly over the Tibetan Plateau (mean altitude 4800 m) for much of their annual migration. This requires considerable cardiovascular effort, but no study has assessed the extent to which bar-headed geese may train prior to migration for long distances, or for high altitudes. Using implanted loggers that recorded heart rate, acceleration, pressure, and temperature, we found no evidence of training for migration in bar-headed geese. Geese showed no significant change in summed activity per day or maximal activity per day. There was also no significant change in maximum heart rate per day or minimum resting heart rate, which may be evidence of an increase in cardiac stroke volume if all other variables were to remain the same. We discuss the strategies used by bar-headed geese in the context of training undertaken by human mountaineers when preparing for high altitude, noting the differences between their respective cardiovascular physiology.

Maximum running speed of captive bar-headed geese is unaffected by severe hypoxia.

While bar-headed geese are renowned for migration at high altitude over the Himalayas, previous work on captive birds suggested that these geese are unable to maintain rates of oxygen consumption while running in severely hypoxic conditions. To investigate this paradox, we re-examined the running performance and heart rates of bar-headed geese and barnacle geese (a low altitude species) during exercise in hypoxia. Bar-headed geese (n = 7) were able to run at maximum speeds (determined in normoxia) for 15 minutes in severe hypoxia (7% O2; simulating the hypoxia at 8500 m) with mean heart rates of 466±8 beats min-1. Barnacle geese (n = 10), on the other hand, were unable to complete similar trials in severe hypoxia and their mean heart rate (316 beats.min-1) was significantly lower than bar-headed geese. In bar-headed geese, partial pressures of oxygen and carbon dioxide in both arterial and mixed venous blood were significantly lower during hypoxia than normoxia, both at rest and while running. However, measurements of blood lactate in bar-headed geese suggested that anaerobic metabolism was not a major energy source during running in hypoxia. We combined these data with values taken from the literature to estimate (i) oxygen supply, using the Fick equation and (ii) oxygen demand using aerodynamic theory for bar-headed geese flying aerobically, and under their own power, at altitude. This analysis predicts that the maximum altitude at which geese can transport enough oxygen to fly without environmental assistance ranges from 6,800 m to 8,900 m altitude, depending on the parameters used in the model but that such flights should be rare.

Blood oxygen depletion is independent of dive function in a deep diving vertebrate, the northern elephant seal.

Although energetics is fundamental to animal ecology, traditional methods of determining metabolic rate are neither direct nor instantaneous. Recently, continuous blood oxygen (O2) measurements were used to assess energy expenditure in diving elephant seals (Mirounga angustirostris), demonstrating that an exceptional hypoxemic tolerance and exquisite management of blood O2 stores underlie the extraordinary diving capability of this consummate diver. As the detailed relationship of energy expenditure and dive behavior remains unknown, we integrated behavior, ecology, and physiology to characterize the costs of different types of dives of elephant seals. Elephant seal dive profiles were analyzed and O2 utilization was classified according to dive type (overall function of dive: transit, foraging, food processing/rest). This is the first account linking behavior at this level with in vivo blood O2 measurements in an animal freely diving at sea, allowing us to assess patterns of O2 utilization and energy expenditure between various behaviors and activities in an animal in the wild. In routine dives of elephant seals, the blood O2 store was significantly depleted to a similar range irrespective of dive function, suggesting that all dive types have equal costs in terms of blood O2 depletion. Here, we present the first physiological evidence that all dive types have similarly high blood O2 demands, supporting an energy balance strategy achieved by devoting one major task to a given dive, thereby separating dive functions into distinct dive types. This strategy may optimize O2 store utilization and recovery, consequently maximizing time underwater and allowing these animals to take full advantage of their underwater resources. This approach may be important to optimizing energy expenditure throughout a dive bout or at-sea foraging trip and is well suited to the lifestyle of an elephant seal, which spends > 90% of its time at sea submerged making diving its most "natural" state.

High thermal sensitivity of blood enhances oxygen delivery in the high-flying bar-headed goose.

The bar-headed goose (Anser indicus) crosses the Himalaya twice a year at altitudes where oxygen (O2) levels are less than half those at sea level and temperatures are below -20°C. Although it has been known for over three decades that the major hemoglobin (Hb) component of bar-headed geese has an increased affinity for O2, enhancing O2 uptake, the effects of temperature and interactions between temperature and pH on bar-headed goose Hb-O2 affinity have not previously been determined. An increase in breathing of the hypoxic and extremely cold air experienced by a bar-headed goose at altitude (due to the enhanced hypoxic ventilatory response in this species) could result in both reduced temperature and reduced levels of CO2 at the blood-gas interface in the lungs, enhancing O2 loading. In addition, given the strenuous nature of flapping flight, particularly in thin air, blood leaving the exercising muscle should be warm and acidotic, facilitating O2 unloading. To explore the possibility that features of blood biochemistry in this species could further enhance O2 delivery, we determined the P50 (the partial pressure of O2 at which Hb is 50% saturated) of whole blood from bar-headed geese under conditions of varying temperature and [CO2]. We found that blood-O2 affinity was highly temperature sensitive in bar-headed geese compared with other birds and mammals. Based on our analysis, temperature and pH effects acting on blood-O2 affinity (cold alkalotic lungs and warm acidotic muscle) could increase O2 delivery by twofold during sustained flapping flight at high altitudes compared with what would be delivered by blood at constant temperature and pH.