Cardiovascular deconditioning during long-term spaceflight through multiscale modeling.
ABSTRACT: Human spaceflight has been fascinating man for centuries, representing the intangible need to explore the unknown, challenge new frontiers, advance technology, and push scientific boundaries further. A key area of importance is cardiovascular deconditioning, that is, the collection of hemodynamic changes-from blood volume shift and reduction to altered cardiac function-induced by sustained presence in microgravity. A thorough grasp of the 0G adjustment point per se is important from a physiological viewpoint and fundamental for astronauts' safety and physical capability on long spaceflights. However, hemodynamic details of cardiovascular deconditioning are incomplete, inconsistent, and poorly measured to date; thus a computational approach can be quite valuable. We present a validated 1D-0D multiscale model to study the cardiovascular response to long-term 0G spaceflight in comparison to the 1G supine reference condition. Cardiac work, oxygen consumption, and contractility indexes, as well as central mean and pulse pressures were reduced, augmenting the cardiac deconditioning scenario. Exercise tolerance of a spaceflight traveler was found to be comparable to an untrained person with a sedentary lifestyle. At the capillary-venous level significant waveform alterations were observed which can modify the regular perfusion and average nutrient supply at the cellular level. The present study suggests special attention should be paid to future long spaceflights which demand prompt physical capacity at the time of restoration of partial gravity (e.g., Moon/Mars landing). Since spaceflight deconditioning has features similar to accelerated aging understanding deconditioning mechanisms in microgravity are also relevant to the understanding of aging physiology on the Earth.
Project description:OBJECTIVE:Spaceflight is associated with cardiovascular deregulation. However, the influence of microgravity on the cardiovascular system and its mechanisms and countermeasures remain unknown. Our previous studies have demonstrated that transcutaneous electrical acupuncture stimulation (TEAS) is effective in improving orthostatic tolerance (OT). The purpose of this study was to determine if TEAS treatment can attenuate cardiovascular deconditioning induced by a 4-day -6° head-down bed rest (HDBR). METHODS:Fourteen healthy male subjects were randomly allocated to a control group (control, n=6, 4?days HDBR without countermeasures) and a TEAS treatment group (TEAS, n=8, 4?days HDBR with TEAS at Neiguan (PC6) for 30?min each day for 4 consecutive days during HDBR). OT, plasma hormones, plasma volume and heart rate variability were assessed before and after HDBR. Cardiac function and cerebral blood flow were measured before, during and after HDBR. RESULTS:The data showed that TEAS treatment mitigated the decrease in OT that was observed in the control group and cardiac function, alleviated autonomic dysfunction, and partially prevented plasma volume reduction after HDBR. Angiotensin II and aldosterone were significantly increased by 129.3% and 133.3% after HDBR in the TEAS group (p<0.05). CONCLUSIONS:These results indicate that 30?min of daily TEAS treatment at PC6 is partially effective in maintaining OT, probably due to increased plasma volume-regulating hormones and activation of the peripheral sympathetic nervous system. TEAS treatment appears effective at reducing cardiovascular deconditioning induced by HDBR for 4?days. TRIAL REGISTRATION NUMBER:NCT02300207.
Project description:Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs.
Project description:As astronauts prepare to undertake new extra-terrestrial missions, innovative diagnostic tools are needed to better assess muscle deconditioning during periods of weightlessness and partial gravity. Electrical impedance myography (EIM) has been used to detect muscle deconditioning in rodents exposed to microgravity during spaceflight or using the standard ground-based model of hindlimb unloading via tail suspension (HU). Here, we used EIM to assess muscle changes in animals exposed to two new models: hindlimb suspension using a pelvic harness (HLS) and a partial weight-bearing (PWB) model that mimics partial gravity (including Lunar and Martian gravities). We also used a simple needle array electrode in lieu of surface or ex vivo EIM approaches previously employed. Our HLS results confirmed earlier findings obtained after spaceflight and tail suspension. Indeed, one EIM measure (i.e., phase-slope) that was previously reported as highly sensitive, was significantly decreased after HLS (day 0: 14.60 ± 0.97, day 7: 11.03 ± 0.81, and day 14: 10.13 ± 0.55 | Deg/MHz|, p < 0.0001), and was associated with a significant decrease in muscle grip force. Although EIM parameters such as 50 kHz phase, reactance, and resistance remained variable over 14 days in PWB animals, we identified major PWB-dependent effects at 7 days. Moreover, the data at both 7 and 14 days correlated to previously observed changes in rear paw grip force using the same PWB model. In conclusion, our data suggest that EIM has the potential to serve as biomarker of muscle deconditioning during exposure to both micro- and partial- gravity during future human space exploration.
Project description:Dry immersion (DI) is a Russian-developed, ground-based model to study the physiological effects of microgravity. It accurately reproduces environmental conditions of weightlessness, such as enhanced physical inactivity, suppression of hydrostatic pressure and supportlessness. We aimed to study the integrative physiological responses to a 3-day strict DI protocol in 12 healthy men, and to assess the extent of multi-system deconditioning. We recorded general clinical data, biological data and evaluated body fluid changes. Cardiovascular deconditioning was evaluated using orthostatic tolerance tests (Lower Body Negative Pressure + tilt and progressive tilt). Metabolic state was tested with oral glucose tolerance test. Muscular deconditioning was assessed via muscle tone measurement. Results: Orthostatic tolerance time dropped from 27 ± 1 to 9 ± 2 min after DI. Significant impairment in glucose tolerance was observed. Net insulin response increased by 72 ± 23% on the third day of DI compared to baseline. Global leg muscle tone was approximately 10% reduced under immersion. Day-night changes in temperature, heart rate and blood pressure were preserved on the third day of DI. Day-night variations of urinary K+ diminished, beginning at the second day of immersion, while 24-h K+ excretion remained stable throughout. Urinary cortisol and melatonin metabolite increased with DI, although within normal limits. A positive correlation was observed between lumbar pain intensity, estimated on the second day of DI, and mean 24-h urinary cortisol under DI. In conclusion, DI represents an accurate and rapid model of gravitational deconditioning. The extent of glucose tolerance impairment may be linked to constant enhanced muscle inactivity. Muscle tone reduction may reflect the reaction of postural muscles to withdrawal of support. Relatively modest increases in cortisol suggest that DI induces a moderate stress effect. In prospect, this advanced ground-based model is extremely suited to test countermeasures for microgravity-induced deconditioning and physical inactivity-related pathologies.
Project description:INTRODUCTION:This study investigated the safety and effectiveness of a new integrated aerobic and resistance exercise training prescription (SPRINT) using two different sets of exercise equipment: a suite of large International Space Station-like exercise equipment similar to what is found on the International Space Station and a single device with aerobic and resistance exercise capability in the spaceflight analog of bed rest (BR). METHODS:Subjects (n = 34) completed 70 d of 6° head down tilt BR: 9 were randomized to remain sedentary (CONT), 9 to exercise training using traditional equipment (EX), 8 to exercise using traditional equipment and low-dose testosterone supplementation (ExT), and 8 to exercise using a combined resistance and aerobic flywheel device. Peak aerobic capacity, ventilatory threshold, cardiac morphology and function (echocardiography), muscle mass (magnetic resonance imaging) and strength/power (isokinetic, leg press, and vertical jump), and bone health (bone mineral density, blood and urine bone markers) were assessed before and after BR. RESULTS:The SPRINT protocol mitigated BR-induced muscle and cardiac deconditioning regardless of the exercise device used. Molecular markers of bone did not change in the CONT or EX groups. Peak aerobic capacity was maintained from pre- to post-BR in all exercise groups similarly, whereas significant declines were observed in the CONT group (~10%). Significant interaction effects between the CONT group and all EX groups were observed for muscle performance including leg press total work, isokinetic upper and lower leg strength, vertical jump power, and maximal jump height as well as muscle size. CONCLUSIONS:This is the first trial to evaluate multisystem deconditioning and the role of an integrated exercise countermeasure. These findings have important implications for the design and implementation of exercise-based countermeasures on future long-duration spaceflight missions.
Project description:Exposure to microgravity conditions causes cardiovascular deconditioning in astronauts during spaceflight. Until now, no specific drugs are available for countermeasure, since the underlying mechanism is largely unknown. Endothelial cells (ECs) and smooth muscle cells (SMCs) play key roles in various vascular functions, many of which are regulated by purinergic 2 (P2) receptors. However, their function in ECs and SMCs under microgravity conditions is still unclear. In this study, primary ECs and SMCs were isolated from bovine aorta and verified with specific markers. We show for the first time that the P2 receptor expression pattern is altered in ECs and SMCs after 24?h exposure to simulated microgravity using a clinostat. However, conditioned medium compensates this change in specific P2 receptors, for example, P2X7. Notably, P2 receptors such as P2X7 might be the important players during the paracrine interaction. Additionally, ECs and SMCs secreted different cytokines under simulated microgravity, leading into a pathogenic proliferation and migration. In conclusion, our data indicate P2 receptors might be important players responding to gravity changes in ECs and SMCs. Since some artificial P2 receptor ligands are applied as drugs, it is reasonable to assume that they might be promising candidates against cardiovascular deconditioning in the future.
Project description:Microgravity induces a number of significant physiological changes in the cardiovascular, nervous, immune systems, as well as the bone tissue of astronauts. Changes in cell adhesion properties are one aspect affected during long-term spaceflights in mammalian cells. Cellular adhesion behaviors can be divided into cell-cell and cell-matrix adhesion. These behaviors trigger cell-cell recognition, conjugation, migration, cytoskeletal rearrangement, and signal transduction. Cellular adhesion molecule (CAM) is a general term for macromolecules that mediate the contact and binding between cells or between cells and the extracellular matrix (ECM). In this review, we summarize the four major classes of adhesion molecules that regulate cell adhesion, including integrins, immunoglobulin superfamily (Ig-SF), cadherins, and selectin. Moreover, we discuss the effects of spaceflight and simulated microgravity on the adhesion of endothelial cells, immune cells, tumor cells, stem cells, osteoblasts, muscle cells, and other types of cells. Further studies on the effects of microgravity on cell adhesion and the corresponding physiological behaviors may help increase the safety and improve the health of astronauts in space.
Project description:Exposure to microgravity causes alterations in multiple physiological systems, potentially impacting the ability of astronauts to perform critical mission tasks. The goal of this study was to determine the effects of spaceflight on functional task performance and to identify the key physiological factors contributing to their deficits.A test battery comprised of seven functional tests and 15 physiological measures was used to investigate the sensorimotor, cardiovascular, and neuromuscular adaptations to spaceflight. Astronauts were tested before and after 6-month spaceflights. Subjects were also tested before and after 70 d of 6° head-down bed rest, a spaceflight analog, to examine the role of axial body unloading on the spaceflight results. These subjects included control and exercise groups to examine the effects of exercise during bed rest.Spaceflight subjects showed the greatest decrement in performance during functional tasks that required the greatest demand for dynamic control of postural equilibrium which was paralleled by similar decrements in sensorimotor tests that assessed postural and dynamic gait control. Other changes included reduced lower limb muscle performance and increased HR to maintain blood pressure. Exercise performed during bed rest prevented detrimental change in neuromuscular and cardiovascular function; however, both bed rest groups experienced functional and balance deficits similar to spaceflight subjects.Bed rest data indicate that body support unloading experienced during spaceflight contributes to postflight postural control dysfunction. Further, the bed rest results in the exercise group of subjects confirm that resistance and aerobic exercises performed during spaceflight can play an integral role in maintaining neuromuscular and cardiovascular functions, which can help in reducing decrements in functional performance. These results indicate that a countermeasure to mitigate postflight postural control dysfunction is required to maintain functional performance.
Project description:Most astronauts experience back pain after spaceflight, primarily located in the lumbar region. Intervertebral disc herniations have been observed after real and simulated microgravity. Spinal deconditioning after exposure to microgravity has been described, but the underlying mechanisms are not well understood. The dry immersion (DI) model of microgravity was used with eighteen male volunteers. Half of the participants wore thigh cuffs as a potential countermeasure. The spinal changes and intervertebral disc (IVD) content changes were investigated using magnetic resonance imaging (MRI) analyses with T1-T2 mapping sequences. IVD water content was estimated by the apparent diffusion coefficient (ADC), with proteoglycan content measured using MRI T1-mapping sequences centered in the nucleus pulposus. The use of thigh cuffs had no effect on any of the spinal variables measured. There was significant spinal lengthening for all of the subjects. The ADC and IVD proteoglycan content both increased significantly with DI (7.34 ± 2.23% and 10.09 ± 1.39%, respectively; mean ± standard deviation), p < 0.05). The ADC changes suggest dynamic and rapid water diffusion inside IVDs, linked to gravitational unloading. Further investigation is needed to determine whether similar changes occur in the cervical IVDs. A better understanding of the mechanisms involved in spinal deconditioning with spaceflight would assist in the development of alternative countermeasures to prevent IVD herniation.
Project description:To date, hampered physiological function after exposure to microgravity has been primarily attributed to deprived peripheral neuro-sensory systems. For the first time, this study elucidates alterations in human brain function after long-duration spaceflight. More specifically, we found significant differences in resting-state functional connectivity between motor cortex and cerebellum, as well as changes within the default mode network. In addition, the cosmonaut showed changes in the supplementary motor areas during a motor imagery task. These results highlight the underlying neural basis for the observed physiological deconditioning due to spaceflight and are relevant for future interplanetary missions and vestibular patients.