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Altered gravity affects hemodynamics and blood flow in the neck. At least one incidence of jugular venous thrombosis has been reported in an astronaut on the International Space Station. This investigation explores the impact of changes in the direction of the gravitational vector on the characteristics of the neck arteries and veins. Twelve subjects underwent graded tilt from 45° head-up to 45° head-down in 15° increments in both supine and prone positions. At each angle, the cross-sectional area of the left and right common carotid arteries (ACCA) and internal jugular veins (AIJV) were measured by ultrasound. Internal jugular venous pressure (IJVP) was also measured by compression sonography. Gravitational dose-response curves were generated from experimental data. ACCA did not show any gravitational dependence. Conversely, both AIJV and IJVP increased in a nonlinear fashion with head-down tilt. AIJV was significantly larger on the right side than the left side at all tilt angles. In addition, IJVP was significantly elevated in the prone position compared with the supine position, most likely because of raised intrathoracic pressure while prone. Dose-response curves were compared with existing experimental data from parabolic flight and spaceflight studies, showing good agreement on an acute timescale. The quantification of jugular hemodynamics as a function of changes in the gravitational vector presented here provides a terrestrial model to reference spaceflight-induced changes, contributes to the assessment of the pathogenesis of spaceflight venous thromboembolism events, and informs the development of countermeasures. [ABSTRACT FROM AUTHOR]

Weightlessness induces a cephalad shift of blood and cerebrospinal fluid that may increase intracranial pressure (ICP) during spaceflight, whereas lower body negative pressure (LBNP) may provide an opportunity to caudally redistribute fluids and lower ICP. To investigate the effects of spaceflight and LBNP on noninvasive indicators of ICP (nICP), we studied 13 crewmembers before and after spaceflight in seated, supine, and 15° head-down tilt postures, and at ~45 and ~150 days of spaceflight with and without 25 mmHg LBNP. We used four techniques to quantify nICP: cerebral and cochlear fluid pressure (CCFP), otoacoustic emissions (OAE), ultrasound measures of optic nerve sheath diameter (ONSD), and ultrasound-based internal jugular vein pressure (IJVp). On flight day 45, two nICP measures were lower than preflight supine posture [CCFP: mean difference -98.5 -nL (CI: -190.8 to -6.1 -nL), P = 0.037]; [OAE: -19.7° (CI: -10.4° to -29.1°), P < 0.001], but not significantly different from preflight seated measures. Conversely, ONSD was not different than any preflight posture, whereas IJVp was significantly greater than preflight seated measures [14.3 mmHg (CI: 10.1 to 18.5 mmHg), P < 0.001], but not significantly different than preflight supine measures. During spaceflight, acute LBNP application did not cause a significant change in nICP indicators. These data suggest that during spaceflight, nICP is not elevated above values observed in the seated posture on Earth. Invasive measures would be needed to provide absolute ICP values and more precise indications of ICP change during various phases of spaceflight. NEW & NOTEWORTHY The current study provides new evidence that intracranial pressure (ICP), as assessed with noninvasive measures, may not be elevated during long-duration spaceflight. In addition, the acute use of lower body negative pressure did not significantly reduce indicators of ICP during weightlessness. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy is a well-known consequence of spaceflight. Because of the potential significant impact of muscle atrophy and muscle dysfunction on astronauts and their mission, a thorough understanding of the mechanisms of this atrophy and the development of effective countermeasures is critical. Spaceflight-induced muscle atrophy is similar to atrophy seen in many terrestrial conditions, and therefore our understanding of this form of atrophy may also contribute to the treatment of atrophy in humans on Earth. The unique environmental features humans encounter in space include the weightlessness of microgravity, space radiation, and the distinctive aspects of living in a spacecraft. The disuse and unloading of muscles in microgravity are likely the most significant factors that mediate spaceflight-induced muscle atrophy and have been extensively studied and reviewed. However, there are numerous other direct and indirect effects on skeletal muscle that may be contributing factors to the muscle atrophy and dysfunction seen as a result of spaceflight. This review offers a novel perspective on the issue of muscle atrophy in space by providing a comprehensive overview of the unique aspects of the spaceflight environment and the various ways in which they can lead to muscle atrophy. We systematically review the potential contributions of these different mechanisms of spaceflight-induced atrophy and include findings from both actual spaceflight and ground-based models of spaceflight in humans, animals, and in vitro studies. [ABSTRACT FROM AUTHOR]

Cephalad fluid shifts in space have been hypothesized to cause the spaceflight-associated neuro-ocular syndrome (SANS) by increasing the intracranial-ocular translaminal pressure gradient. Lower body negative pressure (LBNP) can be used to shift upper-body blood and other fluids toward the legs during spaceflight. We hypothesized that microgravity would increase jugular vein volume (JVvol), portal vein cross-sectional area (PV), and intracranial venous blood velocity (MCV) and that LBNP application would return these variables toward preflight levels. Data were collected from 14 subjects (11 males) before and during long-duration International Space Station (ISS) spaceflights. Ultrasound measures of JVvol, PV, and MCV were acquired while seated and supine before flight and early during spaceflight at day 45 (FD45) and late at day 150 (FD150) with and without LBNP. JVvol increased from preflight supine and seated postures (46 ± 48% and 646 ± 595% on FD45 and 43 ± 43% and 702 ± 631% on FD150, P < 0.05), MCV increased from preflight supine (44 ± 31% on FD45 and 115 ± 116% on FD150, P < 0.05), and PV increased from preflight supine and seated (51 ± 56% on FD45 and 100 ± 74% on FD150, P < 0.05). Inflight LBNP of -25 mmHg restored JVvol and MCV to preflight supine level and PV to preflight seated level. Elevated JVvol confirms the sustained neckhead blood engorgement inflight, whereas increased PV area supports the fluid shift at the splanchnic level. Also, MCV increased potentially due to reduced lumen diameter. LBNP, returning variables to preflight levels, may be an effective countermeasure. [ABSTRACT FROM AUTHOR]

Our research described in this article was motivated by the puzzling finding of the Skylab M131 experiments: head movements made while rotating that are nauseogenic and disorienting on Earth are innocuous in a weightless, 0-g environment. We describe a series of parabolic flight experiments that directly addressed this puzzle and discovered the gravity-dependent responses to semicircular canal stimulation, consistent with the principles of velocity storage. We describe a line of research that started in a different direction, investigating dynamic balancing, but ended up pointing to the gravity dependence of angular velocity-to-position integration of semicircular canal signals. Together, these lines of research and the theoretical framework of velocity storage provide an answer to at least part of the M131 puzzle. We also describe recently discovered neural circuits by which active, dynamic vestibular, multisensory, and motor signals are interpreted as either appropriate for action and orientation or as conflicts evoking motion sickness and disorientation. [ABSTRACT FROM AUTHOR]

Synthetic torpor is an induced state of deep metabolic depression (MD) in an organism that does not naturally employ regulated and reversible MD. If applied to spaceflight crewmembers, this metabolic state may theoretically mitigate numerous biological and logistical challenges of human spaceflight. These benefits have been the focus of numerous recent articles where, invariably, they are discussed in the context of hypothetical deep MD states in which the metabolism of crewmembers is profoundly depressed relative to basal rates. However, inducing these deep MD states in humans, particularly humans aboard spacecraft, is currently impossible. Here, we discuss shallow MD as a feasible first step toward synthetic torpor during spaceflight and summarize perspectives following a recent NASA-hosted workshop. We discuss methods to safely induce shallow MD (e.g., sleep and slow wave enhancement via acoustic and photoperiod stimulation; moderate sedation via dexmedetomidine), which we define as an ~20% depression of metabolic rate relative to basal levels. We also discuss different modes of shallow MD application (e.g., habitual versus targeted, whereby shallow MD is induced routinely throughout a mission or only under certain circumstances, respectively) and different spaceflight scenarios that would benefit from its use. Finally, we propose a multistep development plan toward the application of synthetic torpor to human spaceflight, highlighting shallow MD's role. As space agencies develop missions to send humans further into space than ever before, shallow MD has the potential to confer health benefits for crewmembers, reduce demands on spacecraft capacities, and serve as a testbed for deeper MD technologies. [ABSTRACT FROM AUTHOR]

As the international space community plans for manned missions to Mars, spaceflight-associated immune dysregulation has been identified as a potential risk to the health and safety of the flight crew. There is a need to determine whether salivary antimicrobial proteins, which act as a first line of innate immune defense against multiple pathogens, are altered in response to long-duration (>6 mo) missions. We collected 7 consecutive days of whole and sublingual saliva samples from eight International Space Station (ISS) crewmembers and seven ground-based control subjects at nine mission time points, ~180 and ~60 days before launch (L-180/L-60), on orbit at flight days ~10 and ~90 (FD10/FD90) and ~1 day before return (R-1), and at R+0, R+18, R+33, and R+66 days after returning to Earth. We found that salivary secretory (s)IgA, lysozyme, LL-37, and the cortisol-to-dehydroepiandrosterone ratio were elevated in the ISS crew before (L-180) and during (FD10/FD90) the mission. "Rookie" crewmembers embarking on their first spaceflight mission had lower levels of salivary sIgA but increased levels of -amylase, lysozyme, and LL-37 during and after the mission compared with the "veteran" crew who had previously flown. Latent herpesvirus reactivation was distinct to the ~6-mo mission crewmembers who performed extravehicular activity ("spacewalks"). Crewmembers who shed at least one latent virus had higher cortisol levels than those who did not shed. We conclude that long-duration spaceflight alters the concentration and/or secretion of several antimicrobial proteins in saliva, some of which are related to crewmember flight experience, biomarkers of stress, and latent viral reactivation. [ABSTRACT FROM AUTHOR]

Long-term exposure to microgravity (μG) is known to reduce the strength of a skeletal muscle contraction and the level of general physical performance in humans, while little is known about its effect on muscle architecture. Architectural and contractile properties of the triceps surae (TS) muscle were determined in vivo for male cosmonauts in response ( n = 8) to a spaceflight (213.0 ± 30.5 days). The maximal voluntary contraction (MVC), tetanic tension ( Ро), and voluntary and electrically evoked contraction times and force deficiency (Pd) were determined. The ankle was positioned at 15° dorsiflexion (-15°) and 0, 15, and 30° plantar flexion, with the knee set at 90°. At each position, longitudinal ultrasonic images of the medial (MG) and lateral (LG) gastrocnemius and soleus (SOL) muscles were obtained while the subject was relaxed. After a spaceflight, MVC and Pо decreased by 42 and 26%, respectively, and Pd increased by 50%. The rate of tension of a voluntary contraction substantially reduced but evoked contractions remained unchanged. In the passive condition, fiber length ( Lf) changed from 43, 57, and 35 mm (knee, 0°; ankle, -15°) to 34, 38, and 25 mm (knee, 0°; ankle, 30°) for MG, LG, and SOL, respectively, and Θf changed from 27, 21, and 23° (knee, 0°; ankle, -15°) to 43, 29, and 34° (knee, 0°; ankle, 30°) for MG, LG, and SOL, respectively. Different Lf and Θf, and their changes after spaceflight, might be related to differences in force-producing capabilities of the muscles and elastic characteristics of tendons and aponeuroses. NEW & NOTEWORTHY The present work was the first to combine measuring the fiber length and pennation angle (ultrasound imaging) as main determinants of mechanical force production and evaluating the muscle function after a long-duration spaceflight. The results demonstrate that muscles with different functional roles may differently respond to unloading, and this circumstance is important to consider when planning rehabilitation after unloading of any kind, paying particular attention to postural muscles. [ABSTRACT FROM AUTHOR]

Musculoskeletal deconditioning is a well-known consequence of microgravity. However, the effects of partial gravity, such as that experienced on the moon (0.16 g) or Mars (0.38 g), on musculoskeletal health remain relatively unexplored. Because Mars is being increasingly viewed as the likely next extraterrestrial site for human exploration, there is an increasing need for Earth-based models that can replicate the long-term physiological effects of microgravity. These models would also offer the opportunity to explore the potential impact of partial artificial gravity (as would be achieved by centrifugation). In this study, we describe a novel partial gravity model that can be employed in rats over extended periods of time. We demonstrate that 2 wk of partial weight bearing at 20, 40, or 70% of normal loading affects the musculoskeletal health of the animals, as evidenced by decreased trabecular bone density (ranging from -7.5 ± 2.7% at 70% of normal loading to -27.9 ± 2.9% at 20%), hindlimb muscle mass, and impaired muscle function as characterized by grip force. This new model will facilitate studies of the physiological changes occurring in partial gravity and allow for the design of potential countermeasures to mitigate these changes. NEW & NOTEWORTHY This research article describes the first quadrupedal unloading model in rats that is sustainable for investigating the physiological alterations occurring in partial gravity environments, providing a new and adaptable model for ground-based research for future space exploration. [ABSTRACT FROM AUTHOR]

Microgravity and elevated levels of CO2 are two common environmental stressors in spaceflight that may affect cognitive performance of astronauts. In this randomized, double-blind, crossover trial (SPACECOT), 6 healthy males (mean ± SD age: 41 ± 5 yr) were exposed to 0.04% (ambient air) and 0.5% CO2 concentrations during 26.5-h periods of 12° head-down tilt (HDT) bed rest with a 1-wk washout period between exposures. Subjects performed the 10 tests of the Cognition Test Battery before and on average 0.1, 5.2, and 21.0 h after the initiation of HDT bed rest. HDT in ambient air induced a change in response strategy, with increased response speed (+0.19 SD; P = 0.0254) at the expense of accuracy (-0.19 SD; P = 0.2867), resulting in comparable cognitive efficiency. The observed effects were small and statistically significant for cognitive speed only. However, even small declines in accuracy can potentially cause errors during mission-critical tasks in spaceflight. Unexpectedly, exposure to 0.5% CO2 reversed the response strategy changes observed under HDT in ambient air. This was possibly related to hypercapnia-induced cerebrovascular reactivity that favors cortical regions in general and the frontal cortex in particular, or to the CNS arousing properties of mildly to moderately increased CO2 levels. There were no statistically significant time-in-CO2 effects for any cognitive outcome. The small sample size and the small effect sizes are major limitations of this study and its findings. The results should not be generalized beyond the group of investigated subjects until they are confirmed by adequately powered follow-up studies. NEW & NOTEWORTHY Simulating microgravity with exposure to 21 h of 12° head-down tilt bed rest caused a change in response strategy on a range of cognitive tests, with a statistically significant increase in response speed at the expense of accuracy. Cognitive efficiency was not affected. The observed speed-accuracy tradeoff was small but may nevertheless be important for mission-critical tasks in spaceflight. Importantly, the change in response strategy was reversed by increasing CO2 concentrations to 0.5%. [ABSTRACT FROM AUTHOR]

The aim of this systematic review and meta-analysis [International Prospective Register of Systematic Reviews (PROSPERO) CRD42017055619] was to assess the effects of strict prolonged bed rest (without countermeasures) on maximal oxygen uptake (V̇o2max) and to explore sources of variation therein. Since 1949, 80 studies with a total of 949 participants (>90% men) have been published with data on strict bed rest and V̇o2max. The studies were conducted mainly in young participants [median age (interquartile range) 24.5 (22.4–34.0) yr]. The duration of bed rest ranged from 1 to 90 days. V̇o2max declined linearly across bed rest duration. No statistical difference in the decline among studies reporting V̇o2max as l/min (−0.3% per day) compared with studies reporting V̇o2max normalized to body weight (ml·kg−1·min−1; −0.43% per day) was observed. Although both total body weight and lean body mass declined in response to bed rest, we did not see any associations with the decline in V̇o2max. However, 15–26% of the variation in the decline in V̇o2max was explained by the pre-bed-rest V̇o2max levels, independent of the duration of bed rest (i.e., higher pre-bed-rest V̇o2max levels were associated with larger declines in V̇o2max). Furthermore, the systematic review revealed a gap in the knowledge about the cardiovascular response to extreme physical inactivity, particularly in older subjects and women of any age group. In addition to its relevance to spaceflight, this lack of data has significant translational implications because younger women sometimes undergo prolonged periods of bed rest associated with the complications of pregnancy and the incidence of hospitalization including prolonged periods of bed rest increases with age. NEW & NOTEWORTHY Large interindividual responses of maximal oxygen uptake (V̇o2max) to aerobic exercise training exist. However, less is known about the variability in the response of V̇o2max to prolonged bed rest. This systematic review and meta-analysis showed that pre-bed-rest V̇o2max values were inversely associated with the change in V̇o2max independent of the duration of bed rest. Moreover, we identified a large knowledge gap about the causes of decline in V̇o2max, particularly in postmenopausal women, which may have clinical implications. [ABSTRACT FROM AUTHOR]

Long-term spaceflight induces a near visual acuity change in ~50% of astronauts. In some crew members, postflight cerebrospinal fluid (CSF) opening pressures by lumbar puncture are as high as 20.9 mmHg; these members demonstrated optic disc edema. CSF communicates through the cochlear aqueduct to affect perilymphatic pressure and tympanic membrane motion. We hypothesized that 50 mmHg of lower-body negative pressure (LBNP) during 15° head-down tilt (HDT) would mitigate elevations in internal jugular vein cross-sectional area (IJV CSA) and intracranial pressure (ICP). Fifteen healthy adult volunteers were positioned in sitting (5 min), supine (5 min), 15° HDT (5 min), and 15° HDT with LBNP (10 min) postures for data collection. Evoked tympanic membrane displacements (TMD) quantified ICP noninvasively. IJV CSA was measured using standard ultrasound techniques. ICP and IJV CSA increased significantly from the seated upright to the 15° HDT posture (P < 0.05), and LBNP mitigated these increases. LBNP at 25 mmHg reduced ICP during HDT (TMD of 322.13 ± 419.17 nl) to 232.38 ± 445.85 nl, and at 50 mmHg ICP was reduced further to TMD of 199.76 ± 429.69 nl. In addition, 50 mmHg LBNP significantly reduced IJV CSA (1.50 ± 0.33 cm2) during 15° HDT to 0.83 ± 0.42 cm2. LBNP counteracts the headward fluid shift elevation of ICP and IJV CSA experienced during microgravity as simulated by15° HDT. These data provide quantitative evidence that LBNP shifts cephalic fluid to the lower body, reducing IJV CSA and ICP. NEW & NOTEWORTHY The current study provides new evidence that 25 or 50 mmHg of lower body negative pressure reduces jugular venous pooling and intracranial pressure during simulated microgravity. Therefore, spaceflight countermeasures that sequester fluid to the lower body may mitigate cephalic venous congestion and vision impairment. NEW & NOTEWORTHY The current study provides new evidence that 25 or 50 mmHg of lower body negative pressure reduces jugular venous pooling and intracranial pressure during simulated microgravity. Therefore, spaceflight countermeasures that sequester fluid to the lower body may mitigate cephalic venous congestion and vision impairment. [ABSTRACT FROM AUTHOR]

Exposure to the microgravity environment results in various adaptive and maladaptive physiological changes in the human body, with notable ophthalmic abnormalities developing during 6-mo missions on the International Space Station (ISS). These findings have led to the hypothesis that the loss of gravity induces a cephalad fluid shift, decreased cerebral venous outflow, and increased intracranial pressure, which may be further exacerbated by increased ambient carbon dioxide (CO2) levels on the ISS. Here we describe the SPACECOT study (studying the physiological and anatomical cerebral effects of CO2 during head-down tilt), a randomized, doubleblind crossover design study with two conditions: 29 h of 12° head-down tilt (HDT) with ambient air and 29 h of 12° HDT with 0.5% CO2. The internationally collaborative SPACECOT study utilized an innovative approach to study the effects of headward fluid shifting induced by 12° HDT and increased ambient CO2 as well as their interaction with a focus on cerebral and ocular anatomy and physiology. Here we provide an in-depth overview of this new approach including the subjects, study design, and implementation, as well as the standardization plan for nutritional intake, environmental parameters, and bed rest procedures. NEW & NOTEWORTHY A new approach for investigating the combined effects of cephalad fluid shifting and increased ambient carbon dioxide (CO2) is presented. This may be useful for studying the neuroophthalmic and cerebral effects of spaceflight where cephalad fluid shifts occur in an elevated CO2 environment. [ABSTRACT FROM AUTHOR]

We have previously predicted that the decrease in maximal oxygen uptake (V̇o2max) that accompanies time in microgravity reflects decrements in both convective and diffusive O2 transport to the mitochondria of the contracting myocytes. The aim of this investigation was therefore to quantify the relative changes in convective O2 transport (Q̇o2) and O2 diffusing capacity (Do2) following long-duration spaceflight. In nine astronauts, resting hemoglobin concentration ([Hb]), V̇o2max, maximal cardiac output (Q̇Tmax), and differences in arterial and venous O2 contents (CaO2-CvO2) were obtained retrospectively for International Space Station Increments 19–33 (April 2009–November 2012). Q̇o2 and Do2 were calculated from these variables via integration of Fick’s Principle of Mass Conservation and Fick’s Law of Diffusion. V̇o2max significantly decreased from pre- to postflight (−53.9 ± 45.5%, P = 0.008). The significant decrease in Q̇Tmax (−7.8 ± 9.1%, P = 0.05), despite an unchanged [Hb], resulted in a significantly decreased Q̇o2 (−11.4 ± 10.5%, P = 0.02). Do2 significantly decreased from pre- to postflight by −27.5 ± 24.5% (P = 0.04), as did the peak CaO2-CvO2 (−9.2 ± 7.5%, P = 0.007). With the use of linear regression analysis, changes in V̇o2max were significantly correlated with changes in Do2 (R2 = 0.47; P = 0.04). These data suggest that spaceflight decreases both convective and diffusive O2 transport. These results have practical implications for future long-duration space missions and highlight the need to resolve the specific mechanisms underlying these spaceflight-induced changes along the O2 transport pathway. NEW & NOTEWORTHY Long-duration spaceflight elicited a significant decrease in maximal oxygen uptake. Given the adverse physiological adaptations to microgravity along the O2 transport pathway that have been reported, an integrative approach to the determinants of postflight maximal oxygen uptake is needed. We demonstrate that both convective and diffusive oxygen transport are decreased following ~6 mo International Space Station missions. [ABSTRACT FROM AUTHOR]

As metabolic changes in human skeletal muscle after long-term (simulated) spaceflight are not well understood, this study examined the effects of long-term microgravity, with and without concurrent resistance exercise, on skeletal muscle oxidative and glycolytic capacity. Twenty-one men were subjected to 84 days head-down tilt bed rest with (BRE; n = 9) or without (BR; n = 12) concurrent flywheel resistance exercise. Activity and gene expression of glycogen synthase, glycogen phosphorylase (GPh), hexokinase, phosphofructokinase- 1 (PFK-1), and citrate synthase (CS), as well as gene expression of succinate dehydrogenase (SDH), vascular endothelial growth factor (VEFG), peroxisome proliferator-activated receptor gamma coactivator- 1 (PGC-1α), and myostatin, were analyzed in samples from m. vastus lateralis collected before and after bed rest. Activity and gene expression of enzymes controlling oxidative metabolism (CS, SDH) decreased in BR but were partially maintained in BRE. Activity of enzymes regulating anaerobic glycolysis (GPh, PFK-1) was unchanged in BR. Resistance exercise increased the activity of GPh. PGC-1α and VEGF expression decreased in both BR and BRE. Myostatin increased in BR but decreased in BRE after bed rest. The analyses of these unique samples indicate that long-term microgravity induces marked alterations in the oxidative, but not the glycolytic, energy system. The proposed flywheel resistance exercise was effective in counteracting some of the metabolic alterations triggered by 84-day bed rest. Given the disparity between gene expression vs. enzyme activity in several key metabolic markers, posttranscriptional mechanisms should be explored to fully evaluate metabolic adaptations to long-term microgravity with/without exercise countermeasures in human skeletal muscle. [ABSTRACT FROM AUTHOR]

Groundbased analog facilities have had wide use in mimicking some of the features of spaceflight in a more-controlled and less-expensive manner. One such analog is parabolic flight, in which an aircraft flies repeated parabolic trajectories that provide short-duration periods of free fall (0 g) alternating with high-g pullout or recovery phases. Parabolic flight is unique in being able to provide true 0 g in a ground-based facility. Accordingly, it lends itself well to the investigation of specific areas of human spaceflight that can benefit from this capability, which predominantly includes neurovestibular effects, but also others such as human factors, locomotion, and medical procedures. Applications to research in artificial gravity and to effects likely to occur in upcoming commercial suborbital flights are also possible. [ABSTRACT FROM AUTHOR]

The information coming from the vestibular otolith organs is important for the brain when reflexively making appropriate visual and spinal corrections to maintain balance. Symptoms related to failed balance control and navigation are commonly observed in astronauts returning from space. To investigate the effect of microgravity exposure on the otoliths, we studied the otolith-mediated responses elicited by centrifugation in a group of 25 astronauts before and after 6 mo of spaceflight. Ocular counterrolling (OCR) is an otolith-driven reflex that is sensitive to head tilt with regard to gravity and tilts of the gravito-inertial acceleration vector during centrifugation. When comparing pre- and postflight OCR, we found a statistically significant decrease of the OCR response upon return. Nine days after return, the OCR was back at preflight level, indicating a full recovery. Our large study sample allows for more general physiological conclusions about the effect of prolonged microgravity on the otolith system. A deconditioned otolith system is thought to be the cause of several of the negative effects seen in returning astronauts, such as spatial disorientation and orthostatic intolerance. This knowledge should be taken into account for future long-term space missions. [ABSTRACT FROM AUTHOR]

Microgravity-induced lumbar paraspinal muscle deconditioning may contribute to back pain commonly experienced by astronauts and may increase the risk of postflight injury. We hypothesized that a combined resistive and aerobic exercise countermeasure protocol that included spinal loading would mitigate lumbar paraspinal muscle deconditioning during 60 days of bed rest in women. Sixteen women underwent 60-day, 6° head-downtilt bed rest (BR) and were randomized into control and exercise groups. During bed rest the control group performed no exercise. The exercise group performed supine treadmill exercise within lower body negative pressure (LBNP) for 3-4 days/wk and flywheel resistive exercise for 2-3 days/wk. Paraspinal muscle cross-sectional area (CSA) was measured using a lumbar spine MRI sequence before and after BR. In addition, isokinetic spinal flexion and extension strengths were measured before and after BR. Data are presented as means SD. Total lumbar paraspinal muscle CSA decreased significantly more in controls (10.9±3.4%) than in exercisers (4.3±3.4%; P±0.05). The erector spinae was the primary contributor (76%) to total lumbar paraspinal muscle loss. Moreover, exercise attenuated isokinetic spinal extension loss (4.3±4.5%), compared with controls (16.6±11.2%; P±0.05). In conclusion, LBNP treadmill and flywheel resistive exercises during simulated microgravity mitigate decrements in lumbar paraspinal muscle structure and spine function. Therefore spaceflight exercise countermeasures that attempt to reproduce spinal loads experienced on Earth may mitigate spinal deconditioning during long-duration space travel. [ABSTRACT FROM AUTHOR]

The unilateral lower limb suspension (ULLS) method was developed, introduced, and validated in the quest for a simple, effective, and highly reliable human analog to study the consequences of spaceflight on muscle size and function. Because withdrawal of weight bearing for no more than 2-3 days is sufficient to inflict disturbances in protein metabolism of postural muscles, it is imperative ULLS serves as a very powerful method to manifest skeletal muscle adaptations similar to those experienced in 0 g. Thus the rate of global muscle loss appears rather constant over the first 2 mo, amounting to about 2-3% per week. At the microscopic level, these changes are accompanied by a corresponding decrease in individual muscle fiber size. ULLS alters metabolism favoring more carbohydrate over fat substrate utilization. Altogether, these changes result in impaired work and endurance capacity of muscles being subjected to ULLS. Maximal voluntary force decreases out of proportion to the muscle loss, suggesting motor control is modified. Past reviews offer near exhaustive information on ULLS-induced responses with regard to the above changes. Hence, the current brief review describes more broadly the evolution of the ULLS model, from issues of subject recruitment and compliance control, to recent advances unraveling molecular mechanisms facilitating unloading-induced muscle wasting. Such knowledge is critical in designing future studies aimed at exploring and developing exercise countermeasures or other means to combat the debilitating effects on muscle experienced by astronauts during longhaul missions in Orbit. [ABSTRACT FROM AUTHOR]

The rodent hindlimb unloading (HU) model was developed in the 1980s to make it possible to study mechanisms, responses, and treatments for the adverse consequences of spaceflight. Decades before development of the HU model, weightlessness was predicted to yield deficits in the principal tissues responsible for structure and movement on Earth, primarily muscle and bone. Indeed, results from early spaceflight and HU experiments confirmed the expected sensitivity of the musculoskeletal system to gravity loading. Results from human and animal spaceflight and HU experiments show that nearly all organ systems and tissues studied display some measurable changes, albeit sometimes minor and of uncertain relevance to astronaut health. The focus of this review is to examine key HU results for various organ systems including those related to stress; the immune, cardiovascular, and nervous systems; vision changes; and wound healing. Analysis of the validity of the HU model is important given its potential value for both hypothesis testing and countermeasure development. [ABSTRACT FROM AUTHOR]

Bed rest, a ground-based spaceflight analog, induces robust atrophy of skeletal muscle, an effect that is exacerbated with increasing age. We examined the effect of 14 days of bed rest on skeletal muscle satellite cell content and fiber type atrophy in middle-aged adults, an understudied age demographic with few overt signs of muscle aging that is representative of astronauts who perform long-duration spaceflight. Muscle biopsies were obtained from the vastus lateralis of healthy middle-aged adults [n = 7 (4 male, 3 female); age: 51 ± 1 yr] before (Pre-BR) and after (Post-BR) 14 days of bed rest. Immunohistochemical analyses were used to quantify myosin heavy chain (MyHC) isoform expression, cross-sectional area (CSA), satellite cell and myonuclear content, and capillary density. Peak oxygen consumption, knee extensor strength, and body composition were also measured Pre-BR and Post-BR. Post-BR MyHC type 2a fiber percentage was reduced, and mean CSA decreased in all fiber types (-24 ± 5%; P < 0.05). Satellite cell content was also reduced Post-BR (-39 ± 9%; P < 0.05), and the change in satellite cell content was significantly correlated with the change in mean fiber CSA (r2 = 0.60; P < 0.05). A decline in capillary density was observed Post-BR (-23±6%; P<0.05), and Post-BR capillary content was significantly associated with Post-BR peak aerobic capacity (r2 = 0.59; P < 0.05). A subtle decline in myonuclear content occurred during bed rest (-5 ± 1%; P < 0.05). The rapid maladaptation of skeletal muscle to 14 days of mechanical unloading in middle-aged adults emphasizes the need for robust countermeasures to preserve muscle function in astronauts. [ABSTRACT FROM AUTHOR]

Countermeasures are defined as solutions to prevent the undesirable physiologic outcomes associated with spaceflight. Spaceflight analogs provide a valuable opportunity for the evaluation of countermeasures because they allow for the evaluation of more subjects, more experimental control, and are considerably less expensive than actual spaceflight. The various human analogs have differing strengths and weaknesses with respect to the development and evaluation of countermeasures. The human analogs are briefly reviewed with a focus on their suitability for countermeasure evaluation. Bed rest is the most commonly used analog for evaluating countermeasures. While countermeasures are typically developed to target one or maybe two particular physiologic issues, it is increasingly important to evaluate all of the organ systems to discern whether they might be unintended consequences on nontargeted tissues. In preparation for Mars exploration it will be necessary to fully integrate countermeasures to protect all organ systems. The synergistic and antagonistic effects of multiple countermeasures needs to be the focus of future work. [ABSTRACT FROM AUTHOR]

Removal of the normal head-to-foot gravity vector and chronic weightlessness during spaceflight might induce cardiovascular and metabolic adaptations related to changes in arterial pressure and reduction in physical activity. We tested hypotheses that stiffness of arteries located above the heart would be increased postflight, and that blood biomarkers inflight would be consistent with changes in vascular function. Possible sex differences in responses were explored in four male and four female astronauts who lived on the International Space Station for 6 mo. Carotid artery distensibility coefficient (P = 0.005) and (3-stiffness index (P = 0.006) reflected 17-30% increases in arterial stiffness when measured within 38 h of return to Earth compared with preflight. Spaceflight-by-sex interaction effects were found with greater changes in (3-stiffness index in women (P = 0.017), but greater changes in pulse wave transit time in men (P = 0.006). Several blood biomarkers were changed from preflight to inflight, including an increase in an index of insulin resistance (P < 0.001) with a spaceflight-by-sex term suggesting greater change in men (P = 0.034). Spaceflight-by-sex interactions forrenin (P = 0.016) and aldosterone (P = 0.010) indicated greater increases in women than men. Six-month spaceflight caused increased arterial stiffness. Altered hydrostatic arterial pressure gradients as well as changes in insulin resistance and other biomarkers might have contributed to alterations in arterial properties, including sex differences between male and female astronauts. [ABSTRACT FROM AUTHOR]

Spaceflight has profound effects on vascular function as a result of weightlessness that may be further compounded by radiation exposure. The purpose of the present study was to assess the individual and combined effects of hindlimb unloading (HU) and radiation (Rad) on vasodilator responses in the skeletal muscle vasculature. Adult male C57BL/6J mice were randomized to one of four groups: control (Con), HU (tail suspension for 15 days), Rad (200 cGy of 137Cs), and HU-Rad (15-day tail suspension and 200 cGy of 137Cs). Endotheliumdependent vasodilation of gastrocnemius feed arteries was assessed in vitro using acetylcholine (ACh, 10-9-10-4 M) and inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX). Endotheliumindependent vasodilation was assessed using Dea-NONOate (10-9-10-4 M). Endothelium-dependent and -independent vasodilator responses were impaired relative to Con responses in all treatment groups; however, there was no further impairment from the combination of treatments (HU-Rad) relative to that in the HU and Rad groups. The NOS-mediated contribution to endothelium-dependent vasodilation was depressed with HU and Rad. This impairment in NOS signaling may have been partially compensated for by an enhancement of PGI2-mediated dilation. Changes in endotheliumdependent vasodilation were also associated with decrements in trabecular bone volume in the proximal tibia metaphysis. These data demonstrate that the simulated space environment (i.e., radiation exposure and unloading of muscle and bone) significantly impairs skeletal muscle artery vasodilation, mediated through endothelium-dependent reductions in NOS signaling and decrements in vascular smooth muscle cell responsiveness to NO. [ABSTRACT FROM AUTHOR]

Skeletal unloading and cephalic fluid shifts in microgravity may alter the bone microvascular flow and may be associated with the 1-2% bone loss per month during spaceflight. The purpose of this study was to determine if lower-body negative pressure (LBNP) can prevent mi-crogravity-induced alterations of tibial microvascular flow. Head-down tilt (HDT) simulates the cephalad fluid shift and microvascular flow responses that may occur in microgravity. We hypothesized that LBNP prevents HDT-induced increases in tibial microvascular flow. Tibial bone microvascular flow, oxygenation, and calf circumference were measured during 5 min sitting, 5 min supine, 5 min 15° HDT, and 10 min 15° HDT with 25 mmHg LBNP using photoplethysmog-raphy (PPG), near-infrared spectroscopy (NIRS), and strain-gauge plethysmography (SGP). Measurements were made simultaneously. Tibial microvascular flow increased by 36% with 5 min 15° HDT [2.2 ± 1.1 V; repeated-measures ANOVA (RMANOVA) P < 0.0001] from supine (1.4 ± 0.8 V). After 10 min of LBNP in the 15° HDT position, tibial microvascular flow returned to supine levels (1.1 ± 0.5 V; RMANOVA P < 0.001). Tibial oxygenation did not change significantly during sitting, supine, HDT, or HDT with LBNP. However, calf circumference decreased with 5 min 15° HDT (-0.7 ± 0.4 V; RMANOVA P < 0.0001) from supine (-0.5 ± 0.4 V). However, with LBNP calf circumference returned to supine levels (-0.4 ± 0.1 V; RMANOVA P = 0.002). These data establish that simulated microgravity increases tibial microvascular flow and LBNP prevents these increases. The results suggest that LBNP may provide a suitable countermeasure to normalize the bone microvascular flow during spaceflight. [ABSTRACT FROM AUTHOR]

The innate immune system as one key element of immunity and a prerequisite for an adequate host defense is of emerging interest in space research to ensure crew health and thus mission success. In ground-based studies, spaceflight-associated specifics such as confinement caused altered immune functions paralleled by changes in stress hormone levels. In this study, six men were confined for 105 days to a space module of ~500 m³ mimicking conditions of a long-term space mission. Psychic stress was surveyed by different questionnaires. Blood, saliva, and urine samples were taken before, during, and after confinement to determine quantitative and qualitative immune responses by analyzing enumerative assays and quantifying microbicide and phagocytic functions. Additionally, expression and shedding of L-selectin (CD62L) on granulocytes and different plasma cytokine levels were measured. Cortisol and catecholamine levels were analyzed in saliva and urine. Psychic stress or an activation of the psychoneuroendocrine system could not be testified. White blood cell counts were not significantly altered, but innate immune functions showed increased cytotoxic and reduced microbicide capabilities. Furthermore, a significantly enhanced shedding of CD62L might be a hint at increased migratory capabilities. However, this was observed in the absence of any acute inflammatory state, and no rise in plasma cytokine levels was detected. In summary, confinement for 105 days caused changes in innate immune functions. Whether these changes result from an alert immune state in preparation for further immune challenges or from a normal adaptive process during confinement remains to be clarified in future research. [ABSTRACT FROM AUTHOR]

Few studies have investigated the impact of alterations in gravity on mammalian transcriptomes. Here, we describe the impact of spaceflight on mammary transcriptome of late pregnant rats and the effect of hypergravity exposure on mammary, liver, and adipose transcriptomes in late pregnancy and at the onset of lactation. RNA was isolated from mammary collected on pregnancy day 20 from rats exposed to spaceflight from days 11 to 20 of gestation. To measure the impact of hypergravity on mammary, liver, and adipose transcriptomes we isolated RNA from tissues collected on P20 and lactation day 1 from rats exposed to hypergravity beginning on pregnancy day 9. Gene expression was measured with Affymetrix GeneChips. Microarray analysis of variance revealed alterations in gravity affected the expression of genes that regulate circadian clocks and activate mechanotransduction pathways. Changes in these systems may explain global gene expression changes in immune response, metabolism, and cell proliferation. Expression of genes that modify chromatin structure and methylation was affected, suggesting adaptation to gravity alterations may proceed through epigenetic change. Altered gravity experiments offer insights into the role of forces omnipresent on Earth that shape genomes in heritable ways. Our study is the first to analyze the impact of alterations in gravity on transcriptomes of pregnant and lactating mammals. Findings provide insight into systems that sense gravity and the way in which they affect phenotype, as well as the possibility of sustaining life beyond Earth's orbit. [ABSTRACT FROM AUTHOR]

The objectives of this study were to evaluate the efficacy of two separate countermeasures, exercise and protein supplementation, to prevent muscle strength and lean tissue mass losses during 60 days of bed rest (BR) in women and whether countermeasure efficacy was influenced by pre-BR muscular fitness (strength, endurance, tissue mass). Twenty-four women were assigned to an exercise (EX, n = 8), a no-exercise control (CON, n = 8), or a no-exercise protein supplementation group (PROT, n = 8). EX performed supine treadmill exercise within lower body negative pressure 3-4 days/wk and maximal concentric and eccentric supine leg- and calf-press exercises 2-4 days/wk. PROT consumed a diet with elevated protein content compared with CON and EX (1.6 vs. 1.0 g·kg(-1)·day(-1)). Knee and calf isokinetic strength and endurance, isotonic leg-press strength, and leg lean mass were measured before and after BR. Post-BR knee extensor strength and endurance, ankle strength, and leg lean mass were significantly greater and leg-press strength tended to be higher in EX than in CON and PROT. Post-BR measures in PROT were not different than those in CON. Exercise countermeasure efficacy was less, and strength, endurance, and leg lean mass losses in CON and PROT were greater, in subjects who were more fit pre-BR. An exercise protocol combining resistive and aerobic exercise training protects against losses in strength, endurance, and leg lean mass in women during BR, while a nutritional countermeasure without exercise was not effective. Exercise countermeasures may require individualization to protect higher levels of strength and endurance. [ABSTRACT FROM AUTHOR]

The impact of prolonged bed rest on the cervical and upper thoracic spine is unknown. In the 2nd Berlin BedRest Study (BBR2-2), 24 male subjects underwent 60-day bed rest and performed either no exercise, resistive exercise, or resistive exercise with whole body vibration. Subjects were followed for 2 yr after bed rest. On axial cervical magnetic resonance images from the skull to T3, the volumes of the semispinalis capitis, splenius capitis, spinalis cervicis, longus capitis, longus colli, levator scapulae, sternocleidomastoid, middle and posterior scalenes, and anterior scalenes were measured. Disc height, anteroposterior width, and volume were measured from C2/3 to T6/7 on sagittal images. The volume of all muscles, with the exception of semispinalis capitis, increased during bed rest (P < 0.025). There were no significant differences between the groups for changes in the muscles. Increased upper and midthoracic spine disc height and volume (P < 0.001) was seen during bed rest, and disc height increases persisted at least 6 mo after bed rest. Increases in thoracic disc height were greater (P = 0.003) in the resistive vibration exercise group than in control. On radiological review, two subjects showed new injuries to the mid-lower thoracic spine. One of these subjects reported a midthoracic pain incident during maximal strength testing before bed rest and the other after countermeasure exercise on day 3 of bed rest. We conclude that bed rest is associated with increased disc size in the thoracic region and increases in muscle volume at the neck. The exercise device needs to be modified to ensure that load is distributed in a more physiological fashion. [ABSTRACT FROM AUTHOR]

Spaceflight-induced orthostatic intolerance has been studied for decades. Although ~22% of the astronaut corps are women, most mechanistic studies use mostly male subjects, despite known sex differences in autonomic control and postflight orthostatic intolerance. We studied adrenergic, baroreflex, and autonomic indexes during continuous infusions of vasoactive drugs in men and women during a 60-day head-down bed rest. Volunteers were tested before bed rest (20 men and 10 women) and around day 30 (20 men and 10 women) and day 60 (16 men and 8 women) of bed rest. Three increasing doses of phenylephrine (PE) and sodium nitroprusside were infused for 10 min after an infusion of normal saline. A 20-min rest period separated the phenylephrine and sodium nitroprusside infusions. Autonomic activity was approximated by spectral indexes of heart rate and blood pressure variability, and baroreflex sensitivity was measured by the spontaneous baroreflex slope. Parasympathetic modulation and baroreflex sensitivity decreased with bed rest, with women experiencing a larger decrease in baroreflex sensitivity by day 30 than men. The sympathetic activation of men and parasympathetic responsiveness of women in blood pressure control during physiological stress were preserved throughout bed rest. During PE infusions, women experienced saturation of the R-R interval at high frequency, whereas men did not, revealing a sex difference in the parabolic relationship between high-frequency R-R interval, a measurement of respiratory sinus arrhythmia, and R-R interval. These sex differences in blood pressure control during simulated microgravity reveal the need to study sex differences in long-duration spaceflight to ensure the health and safety of the entire astronaut corps. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that reduction in cerebral blood flow (CBF) during orthostatic stress after bed rest can be ameliorated with volume loading, exercise, or both. Transcranial Doppler was used to measure changes in CBF velocity during lower body negative pressure (LBNP) before and after an 18-day bed rest in 33 healthy subjects. Subjects were assigned into four groups with similar age and sex: 1) supine cycling during bed rest (Exercise group; n = 7), 2) volume loading with Dextran infusion after bed rest to restore reduced left ventricular filling pressure (Dextran group; n = 7), 3) exercise combined with volume loading to prevent orthostatic intolerance (Ex-Dex group; n = 7), and 4) a control group (n = 12). LBNP tolerance was measured using a cumulative stress index (CSI). After bed rest, CBF velocity was reduced at a lower level of LBNP in the Control group, and the magnitude of reduction was greater in the Ex-Dex group. However, reduction in orthostatic tolerance was prevented in the Ex-Dex group. Notably, volume loading alone prevented greater reductions in CBF velocity after bed rest, but CSI was reduced still by 25%. Finally, decreases in CBF velocity during LBNP were correlated with reduction in cardiac output under all conditions (r2 = 0.86; P = < 0.001). Taken together, these findings demonstrate that volume loading alone can ameliorate reductions in CBF during LBNP. However, the lack of associations between changes in CBF velocity and orthostatic tolerance suggests that reductions in CBF during LBNP under steady-state conditions by itself are unlikely to be a primary factor leading to orthostatic intolerance. [ABSTRACT FROM AUTHOR]

As part of the nutrition-countermeasures (NUC) study in Cologne, Germany in 2010, seven healthy male subjects underwent 21 days of head-down tilt bed rest and returned 153 days later to undergo a second bout of 21-day bed rest. As part of this model, we aimed to examine the recovery of the lumbar intervertebral discs and muscle cross-sectional area (CSA) after bed rest using magnetic resonance imaging and conduct a pilot study on the effects of bed rest in lumbar muscle activation, as measured by signal intensity changes in T2-weighted images after a standardized isometric spinal extension loading task. The changes in intervertebral disc volume, anterior and posterior disc height, and intervertebral length seen after bed rest did not return to prebed-rest values 153 days later. While recovery of muscle CSA occurred after bed rest, increases (P ≤ 0.016) in multifidus, psoas, and quadratus lumborum muscle CSA were seen 153 days after bed rest. A trend was seen for greater activation of the erector spinae and multifidus muscles in the standardized loading task after bed rest. Greater reductions of multifidus and psoas CSA muscle and greater increases in multifidus signal intensity with loading were associated with incidence of low back pain in the first 28 days after bed rest (P ≤ 0.044). The current study contributes to our understanding of the recovery of the lumbar spine after 21-day bed rest, and the main finding was that a decrease in spinal extensor muscle CSA recovers within 5 mo after bed rest but that changes in the intervertebral discs persist. [ABSTRACT FROM AUTHOR]

To evaluate the effect of short-duration, high-load resistive exercise, with and without whole body vibration on lumbar muscle size, intervertebral disk and spinal morphology changes, and low back pain (LBP) incidence during prolonged bed rest, 24 subjects underwent 60 days of head-down tilt bed rest and performed either resistive vibration exercise (n = 7), resistive exercise only (n = 8), or no exercise (n = 9; 2nd Berlin Bed-Rest Study). Discal and spinal shape was measured from sagittal plane magnetic resonance images. Cross-sectional areas (CSAs) of the multifidus, erector spinae, quadratus lumborum, and psoas were measured on para-axial magnetic resonance images. LBP incidence was assessed with questionnaires at regular intervals. The countermeasures reduced CSA loss in the multifidus, lumbar erector spinae and quadratus lumborum muscles, with greater increases in psoas muscle CSA seen in the countermeasure groups (P ≥ 0.004). There was little statistical evidence for an additional effect of whole body vibration above resistive exercise alone on these muscle changes. Exercise subjects reported LBP more frequently in the first week of bed rest, but this was only significant in resistive exercise only (P = 0.011 vs. control, resistive vibration exercise vs. control: P = 0.56). No effect of the countermeasures on changes in spinal morphology was seen (P ≤ 0.22). The results suggest that high-load resistive exercise, with or without whole body vibration, performed 3 days/wk can reduce lumbar muscle atrophy, but further countermeasure optimization is required. [ABSTRACT FROM AUTHOR]

Entering weightlessness affects central circulation in humans by enhancing venous return and cardiac output. We tested whether the operational point of neural cardiovascular regulation in space sets accordingly to adopt a level close to that found in the ground-based horizontal position. Heart rate (HR), finger blood and brachial blood pressure (BP), and respiratory frequency were collected in 11 astronauts from nine space missions. Recordings were made in supine and standing positions at least 10 days before launch and during spaceflight (days 5-19,45-67, 77-116, 146-180). Cross-correlation analyses of HR and systolic BP were used to measure three complementary aspects of cardiac baroreflex modulation: 1) baroreflex sensitivity, 2) number of effective baroreflex estimates, and 3) baroreflex time delay. A fixed breathing protocol was performed to measure respiratory sinus arrhythmia and low-frequency power of systolic BP variability. We found that HR and mean arterial pressure did not differ from preflight supine values for up to 6 mo in space. Respiration frequency tended to decrease during prolonged spaceflight. Concerning neural markers of cardiovascular regulation, we observed in-flight adaptations toward homeostatic conditions similar to those found in the ground-based supine position. Surprisingly, this was not the case for baroreflex time delay distribution, which had somewhat longer latencies in space. Except for this finding, our results confirm that the operational point of neural cardiovascular regulation in space sets to a level close to that of an Earth-based supine position. This adaptation level suggests that circulation is chronically relaxed for at least 6 mo in space. [ABSTRACT FROM AUTHOR]

Exposure of astronauts in space to radiation during weightlessness may contribute to subsequent bone loss. Gamma irradiation of postpubertal mice rapidly increases the number of bone-resorbing osteoclasts and causes bone loss in cancellous tissue; similar changes occur in skeletal diseases associated with oxidative stress. Therefore, we hypothesized that increased oxidative stress mediates radiation-induced bone loss and that musculoskeletal disuse changes the sensitivity of cancellous tissue to radiation exposure. Musculoskeletal disuse by hindlimb unloading (1 or 2 wk) or total body gamma irradiation (1 or 2 Gy of 137Cs) of 4-mo-old, male C57BL/6 mice each decreased cancellous bone volume fraction in the proximal tibiae and lumbar vertebrae. The extent of radiation-induced acute cancellous bone loss in tibiae and lumbar vertebrae was similar in normally loaded and hindlimbunloaded mice. Similarly, osteoclast surface in the tibiae increased 46% as a result of irradiation, 47% as a result of hindlimb unloading, and 64% as a result of irradiation + hindlimb unloading compared with normally loaded mice. Irradiation, but not hindlimb unloading, reduced viability and increased apoptosis of marrow cells and caused oxidative damage to lipids within mineralized tissue. Irradiation also stimulated generation of reactive oxygen species in marrow cells. Furthermore, injection of α-lipoic acid, an antioxidant, mitigated the acute bone loss caused by irradiation. Together, these results showed that disuse and gamma irradiation, alone or in combination, caused a similar degree of acute cancellous bone loss and shared a common cellular mechanism of increased bone resorption. Furthermore, irradiation, but not disuse, may increase the number of osteoclasts and the extent of acute bone loss via increased reactive oxygen species production and ensuing oxidative damage, implying different molecular mechanisms. The finding that α-lipoic acid protected cancellous tissue from the detrimental effects of irradiation has potential relevance to astronauts and radiotherapy patients. [ABSTRACT FROM AUTHOR]

We sought to determine the effects of longitudinal loading (artificial gravity) on skeletal muscle protein kinetics in 15 healthy young males after 21 days of 6° head-down tilt bed rest [experimental treatment (Exp) group: n = 8, 31 ± 1 yr; control (Con) group; n = 7, 28 ± 1 yr, means ± SEI. On days 1 and 21 of bed rest, postabsorptive venous blood samples and muscle biopsies (vastus lateralis and soleus) were obtained during a 1-h pulse bolus infusion protocol (0 min, L-[ring-13C6]phenylalanine, 35 μmol/kg; 30 mm, L-[ring-15N]phenylalanine, 35 μmol/kg). Outcome measures included mixed muscle fractional synthesis (FSR) and breakdown rates (FBR). The Exp group experienced 1 h of longitudinal loading (2.5G at the feet) via a short-radius centrifuge during each day of bed rest. Mixed muscle FSR in the Con group was reduced by 48.5% (day 1, 0.081 ± 0.000%/h vs. day 21, 0.042 ± 0.000%/h; P = 0.001) in vastus lateralis after 21 days of bed rest, whereas the Exp group maintained their rate of protein synthesis. A similar but nonsignificant change in FSR was noted for the soleus muscle (Exp, -7%; Con, -22%). No changes in muscle protein breakdown were observed. In conclusion, 1 h of daily exposure to artificial gravity maintained the rate of protein synthesis of the vastus lateralis and may represent an effective adjunct countermeasure to combat the loss of muscle mass and functional during extended spaceflight. [ABSTRACT FROM AUTHOR]

We have shown previously that treadmill exercise within lower body negative pressure (LBNPex) maintains upright exercise capacity (peak oxygen consumption, V̇O2peak) in men after 5, 15, and 30 days of bed rest (BR). We hypothesized that LBNPex protects treadmill V̇O2peak and sprint speed in women during a 30-day BR. Seven sets of female monozygous twins volunteered to participate. Within each twin set, one was randomly assigned to a control group (Con) and performed no countermeasures, and the other was assigned to an exercise group (Ex) and performed a 40-min interval (40-80% pre-BR V̇O2peak) LBNPex (51 ± 5 mmHg) protocol, plus 5 min of static LBNP, 6 days per week. Before and immediately after BR, subjects completed a 30.5-m sprint test and an upright graded treadmill test to volitional fatigue. These results in women were compared with previously reported reductions in V̇O2peak and sprint speed in male twins after BR. In women, sprint speed (-8 ± 2%) and V̇O2peak (-6 ± 2%) were not different after BR in the Ex group. In contrast, both sprint speed (-24 ± 5%) and VO2peak (-16 ± 3%) were significantly less after BR in the Con group. The effect of BR on sprint speed and VO2peak after BR was not different between women and men. We conclude that treadmill exercise within LBNP protects against BR-induced reductions in VO2peak and sprint speed in women and should prove effective during long-duration spaceflight. [ABSTRACT FROM AUTHOR]

Spaceflight and bed rest (BR) result in losses of muscle mass and strength. Resistance training (RT) and amino acid (AA) supplementation are potential countermeasures to minimize these losses. However, it is unknown if timing of supplementation with exercise can optimize benefits, particularly with energy deficit. We examined the effect of these countermeasures on body composition, strength, and insulin levels in 31 men (ages 3 1-55 yr) during BR (28 days) followed by active recovery (14 days). Subjects were randomly assigned to essential AA supplementation (AA group, n = 7); RT with AA given 3 h after training (RT group, n = 12); or RT with AA given 5 mm before training (AART group, n = 12). Energy intake was reduced by 8 ± 6%. Midthigh muscle area declined with BR for the AA > RT > AART groups: -11%, -3%, -4% (P = 0.05). Similarly, greatest losses in lower body muscle strength were seen in the AA group (-22%). These were attenuated in the exercising groups [RT (-8%) and AART (-6%; P < 0.05)]. Fat mass and midthigh intramuscular fat increased after BR in the AA group (+3% and + 14%, respectively), and decreased in the RT (-5% and -4%) and AART groups (-1 and -5%; P = 0.05). Muscle mass and strength returned toward baseline after recovery, but the AA group showed the lowest regains. Combined resistance training with AA supplementation pre- or postexercise attenuated the losses in muscle mass and strength by approximately two-thirds compared with AA supplement alone during BR and energy deficit. These data support the efficacy of combined AA and RT as a countermeasure against muscle wasting due to low gravity. [ABSTRACT FROM AUTHOR]