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NASA NTRS2001

Exercise Thermoregulation Following 13 Days of Bed Rest

This investigation examined two potential mechanisms, altered skin blood flow (SBF) and sweating rate (SR) responses, that may be responsible for an elevated core temperature during exercise after bed rest (BR) and space flight. Seven healthy men (29 +/- 5 yr, 179.6 +/- 7.1 cm, 77.2 +/- 17.0kg; mean +/- SD) underwent 13 days of 6 deg head-down BR. Pre- and post-BR, subjects completed supine submaximal cycle ergometry (20 min at 40% and 20 min at 65% of pre-BR supine VO2pk) in a thermoneutral room (23.4 +/- 0.5 C, 56 +/- 8 %RH) during, heat production (VO2 ; indirect calorimetry), intestinal temperature (T(sub in) ; ingestible pill), SBF (laser Doppler velocimetry), local SR (dew point hygrometry), and total sweat loss (TSL; Delta body weight) were measured. Pre- and post- BR plasma volume (PV) was measured using I-125 dilution. After BR, T(sub in) was elevated at rest (36.99 +/- 0.14 vs. 37.30 +/- 0.06 C; p<_0.05) and at the end of exercise (37.57 +/- 0.13 vs. 37.90 +/- 0.09 C; P less than or equal to 0.05). However, the increase in T(sub in) from rest to the end of exercise was not different after BR (0.59 +/- 0.07 vs. 0.60 +/- 0.07 C). There was no difference in VO2 pre- to post-BR during rest (0.28 +/- 0.04 vs. 0.24 +/- 0.03 1 multiplied by min(exp -1) ) or 40% VO2pk (0.95 +/- 0.08 vs. 0.96 +/- 0.05 1 multiplied by min(exp -1)), but VO2 was significantly less at the end of the 65% VO2pk stage (1.53 +/- 0.09 vs. 1.42 +/- 0.11 1 multiplies by min(exp - 1); p less than or equal to 0.05). The percent change in SBF from rest to end of exercise was less after BR (211 +/- 53 vs. 96 +/- 31%; p less than or equal to 0.05), the threshold for the onset of SBF was greater (37.17 +/- 0.18vs. 37.51 +/- 0.17 C; p less than or equal to 0.05), and the slope of the response tended to be reduced (536 +/- 184 vs. 201 +/- 46 %A PC; p=0.08). TSL was not different after BR (0.42+0.06 vs. 0.44 +/- 0.08 kg), but the T in threshold at the onset of sweating was delayed significantly (37.06 +/- 0.1 1 vs. 37.34 +/- 0.06 C; p less than or equal to 0.05). However, the slope of SR was not changed after BR (3.45 +/- 1.22 vs. 2.58 +/- 0.71 mg multiplied by min(exp -1) multiplied by cm sq). PV was decreased by 11% after BR (3,259 +/- 177 vs. 2,894 +/- 138 ml; p less than or equal to 0.05). These results suggest that exercise SBF and SR responses after BR are altered, and heat production is unchanged or reduced, consistent with observations following space flight. The higher resting T(sub in) with a proportional increase in T(sub in) during exercise and delayed onset of SBF and SR suggest a centrally-mediated elevation in the thermoregulatory set point during microgravity exposure.

Lee, Stuart M. C.↗
NASA NTRS2000

Nutritional Status Assessment During the Phase IIA and Phase III Lunar/Mars Life Support Test Project

Nutrition is a critical concern for extended-duration space missions (Smith and Lane, 1999). Loss of body weight is a primary consequence of altered nutrition, and is frequently observed during space flight (Smith and Lane; 1999). Other existing dietary concerns for space flight include excessive intakes of sodium and iron, and insufficient intakes of water and vitamin D (Smith and Lane, 1999). Furthermore, dependence on closed or semi-closed food systems increases the likelihood of inadequate intakes of key nutrients. This is a significant concern for extended-duration space missions. Space nutrition research often necessitates detailed recording of all food consumption. While this yields extremely accurate data, it requires considerable time and effort, and thus is not suitable for routine medical monitoring during space flight. To alleviate this problem, a food frequency questionnaire (FFQ) was designed to provide a quick and easy, yet reasonably accurate, method for crewmembers to provide dietary intake information to the ground. We report here a study which was designed to assess nutritional status before, during, and after the 60-d and 91-d chamber stays. An additional goal of the study was to validate a food frequency questionnaire designed specifically for use with space flight food systems.

Smith, Scott M.↗
NASA NTRS2001

Alendronate and Resistive Exercise Countermeasures Against Bed Rest-Induced Bone Loss: Biochemical Markers of Bone and Calcium Metabolism

Weightlessness-induced bone loss must be counteracted to ensure crew health during extendedduration space missions. Studies were conducted to assess two bone loss countermeasures in a ground-based model: horizontal bed rest. Following a 3-wk ambulatory adaptation period, male and female subjects (aged 21-56 y) completed a 17-wk bed rest protocol. Subjects were assigned to one of three treatments: alendronate (ALEN; 10 mg/d, n=6), resistive exercise (RE; 1.5 h/d, 6 d/wk, n=8), or control (CN; no countermeasure, n=8). Dietary intake was adjusted to maintain body weight. Endocrine and biochemical indices were measured in blood and urine using standard laboratory methods. All data reported are expressed as percent change from individual pre-bedrest data. Serum calcium changed little during bed rest, and tended to decrease (4-8%) in ALEN subjects. In RE subjects, bone alkaline phosphatase and osteocalcin were increased >65 and >30%, respectively, during bed rest, while these were unchanged or decreased in ALEN and CN subjects. Urinary calcium was increased 50% in CN subjects, but was unchanged or decreased in both ALEN and RE groups. Urinary n-telopeptide excretion was increased 40-50% in CN and RE subjects, but decreased 20% in ALEN subjects. Pyridinium crosslink and deoxypyridinoline excretion were increased 20-50% during bed rest. These data suggest that RE countermeasures are effective at increasing markers of bone formation in an analog of weightlessness, while ALEN reduces markers of bone resorption. Counteracting the bone loss of space flight may require both pharmacologic and exercise countermeasures.

Smith, Scott M.↗
NASA NTRS2010

Decline in Aerobic Fitness After Long-Term Stays on the International Space Station

U.S. and non-Russian International Partner astronauts who participate in long-term International Space Station (ISS) expeditions perform submaximal cycle exercise tests before, during, and after space flight. The heart rate (HR) and oxygen uptake (VO2) responses to exercise are used to estimate peak VO2 (EVO2pk). Purpose: To determine if the following factors are associated with the preflight-to-post flight change in EVO2pk: gender, age, body weight (BW), number of aerobic exercise sessions/wk- during flight, length of flight, EVO2pk measured before and late during the flight, ISS Expedition number and time between landing and the first post flight test. Methods: Records of 37 ISS astronauts (30 male, BW=81.6 plus or minus 8.6 kg; 7 female BW=66.1 plus or minus 4.9 kg [mean plus or minus SD]), age 46 plus or minus 4 years, were retrospectively examined. Peak HR and VO2 were measured approximately 9 months before flight to establish the test protocol. The submaximal cycle test consisted of three 5-minute stages designed to elicit 25, 50, and 75% of VO2pk. EVO2pk was calculated using linear least-squares extrapolation of average HR and VO2 during the last minute of each stage to predict VO2 at maximal HR. VO2 was not measured during flight and was assumed to not be different from preflight. Testing was performed 45 days before launch, late during flight, and during the week after landing. A random-intercept multivariate model was used to determine which characteristics significantly contributed to post flight EVO2pk. Results: In-flight aerobic exercise averaged 5.4 plus or minus 1.2 sessions/wk. ISS flight duration averaged 163 plus or minus 39 d. Mean EVO2pk values were 3.41 plus or minus 0.64 L (raised dot) per minute before flight, 3.09 plus or minus 0.57 L (raised dot) per minute late in flight, and 3.02 plus or minus 0.65 L (raised dot) per minute after flight. Late- and after-flight values were lower (p less than 0.05) than preflight values and did not differ from each other. Time between landing and post flight testing was 4.5 plus or minus 1.6 days. The only factor significantly associated with the post flight EVO2pk value was the late-flight EVO2pk score. Conclusion: Testing performed late during a mission provides a prediction of EVO2pk after landing. This approach may be implemented during longer missions.

Lynn, Peggy A.↗
NASA NTRS2010

Gender Differences in Isokinetic Strength after 60 and 90 d Bed Rest

Recent reports suggest that changes in muscle strength following disuse may differ between males and females. PURPOSE: To examine potential gender differences in strength changes following 60 and 90 d of experimental bed rest. METHODS: Isokinetic extensor and flexor strength of the knee (60deg and 180deg/s, concentric only), ankle (30deg/s, concentric and eccentric), and trunk (60deg/s, concentric only) were measured following 60 d (males: n=4, 34.5+/-9.6 y; females: n=4, 35.5+/-8.2 y) and 90 d (males: n=10, 31.4+/-4.8 y; females: n=5, 37.6+/-9.9 y) of 6-degree head-down-tilt bed rest (BR; N=23). Subjects were fed a controlled diet (55%/15%/ 30%, CHO/PRO/FAT) that maintained body weight within 3% of the weight recorded on Day 3 of bed rest. After a familiarization session, testing was conducted 6 d before BR and 2 d after BR completion. Peak torque and total work were calculated for the tests performed. To allow us to combine data from both 60- and 90-d subjects, we used a mixed-model statistical analysis in which time and gender were fixed effects and bed rest duration was a random effect. Log-transformations of strength measures were utilized when necessary in order to meet statistical assumptions. RESULTS: Main effects were seen for both time and gender (p<0.05), showing decreased strength in response to bed rest for both males and females, and males stronger than females for most strength measures. Only one interaction effect was observed: females exhibited a greater loss of trunk extensor peak torque at 60 d versus pre-BR, relative to males (p=0.004). CONCLUSION: Sixty and 90 d of BR induced significant losses in isokinetic muscle strength of the locomotor and postural muscles of the knee, ankle, and trunk. Although males were stronger than females for most of the strength measures that we examined, only changes in trunk extensor peak torque were greater for females than males at day 60 of bed rest

English, K. L.↗
NASA NTRS2011

Inadequate Loading Stimulus on ISS Results in Bone and Muscle Loss

INTRODUCTION Exercise has been the primary countermeasure to combat musculoskeletal changes during International Space Station (ISS) missions. However, these countermeasures have not been successful in preventing loss of bone mineral density (BMD) or muscle volume in crew members. METHODS We examined lower extremity loading during typical days on-orbit and on Earth for four ISS crew members. In-shoe forces were monitored using force-measuring insoles placed inside the shoes. BMD (by DXA), muscle volumes (by MRI), and strength were measured before and after long-duration spaceflight (181 +/- 15 days). RESULTS The peak forces measured during ISS activity were significantly less than those measured in 1g for the same activities. Typical single-leg loads on-orbit during walking and running were 0.89 +/- 0.17 body weights (BW) and 1.28 +/- 0.18 BW compared to 1.18 +/- 0.11 BW and 2.36 +/- .22 BW in 1g, respectively [2]. Crew members were only loaded for an average of 43.17 +/- 14.96 min a day while performing exercise on-orbit even though 146.8 min were assigned for exercise each day. Areal BMD decreased in the femoral neck and total hip by 0.71 +/- 0.34% and 0.81 +/- 0.21% per month, respectively. Changes in muscle volume were observed in the lower extremity (-10 to -16% calf; -4 to -7% thigh) but there were no changes in the upper extremity (+0.4 to -0.8%). Decrements in isometric and isokinetic strength at the knee (range: -10.4 to -24.1%), ankle (range: -4 to -22.3%), and elbow (range: -7.5 to - 16.7%) were also observed. Knee extension endurance tests showed an overall decline in total work (-14%) but an increased resistance to fatigue post-flight. DISCUSSION AND CONCLUSIONS Our findings support the conclusion that the measured exercise durations and/or loading stimuli were insufficient to protect bone and muscle health.

Rice, A. J.↗
NASA NTRS2011

Optimizing Muscle Parameters in Musculoskeletal Modeling Using Monte Carlo Simulations

Astronauts assigned to long-duration missions experience bone and muscle atrophy in the lower limbs. The use of musculoskeletal simulation software has become a useful tool for modeling joint and muscle forces during human activity in reduced gravity as access to direct experimentation is limited. Knowledge of muscle and joint loads can better inform the design of exercise protocols and exercise countermeasure equipment. In this study, the LifeModeler(TM) (San Clemente, CA) biomechanics simulation software was used to model a squat exercise. The initial model using default parameters yielded physiologically reasonable hip-joint forces. However, no activation was predicted in some large muscles such as rectus femoris, which have been shown to be active in 1-g performance of the activity. Parametric testing was conducted using Monte Carlo methods and combinatorial reduction to find a muscle parameter set that more closely matched physiologically observed activation patterns during the squat exercise. Peak hip joint force using the default parameters was 2.96 times body weight (BW) and increased to 3.21 BW in an optimized, feature-selected test case. The rectus femoris was predicted to peak at 60.1% activation following muscle recruitment optimization, compared to 19.2% activation with default parameters. These results indicate the critical role that muscle parameters play in joint force estimation and the need for exploration of the solution space to achieve physiologically realistic muscle activation.

Hanson, Andrea↗
NASA NTRS2014

Contributions of Astronauts Aerobic Exercise Intensity and Time on Change in VO2peak during Spaceflight

There is considerable variability among astronauts with respect to changes in maximal aerobic capacity (VO2peak) during International Space Station (ISS) missions, ranging from a 5% increase to 30% decline. Individual differences may be due to in-flight aerobic exercise time and intensity. PURPOSE: To evaluate the effects of in-flight aerobic exercise time and intensity on change in VO2peak during ISS missions. METHODS: Astronauts (N=11) performed peak cycle tests approx 60 days before flight (L-60), on flight day (FD) approx 14, and every approx 30 days thereafter. Metabolic gas analysis and heart rate (HR) were measured continuously during the test using the portable pulmonary function system. HR and duration of each in-flight cycle ergometer and treadmill (TM) session were recorded and averaged in time segments corresponding to each peak test. Mixed effects linear regression with exercise mode (TM or cycle) as a categorical variable was used to assess the contributions of exercise intensity (%time >70% peak HR or %time >90% peak HR) and time (min/wk), adjusted for body weight, on %change in VO2peak during the mission, and incorporating the repeated-measures experimental design. RESULTS: 110 observations were included in the model (4-6 peak cycle tests per astronaut, 2 exercise devices). VO2peak was reduced from preflight throughout the mission (FD14: 13+/-13% and FD 105: 8+/-10%). Exercise intensity (%peak HR: FD14=66+/-14; FD105=75+/-8) and time (min/wk: FD14=82+/-46; FD105=158+/-40) increased during flight. The models showed main effects for exercise time and intensity with no interactions between time, intensity, and device (70% peak HR: time [z-score=2.39; P=0.017], intensity [z-score=3.51; P=0.000]; 90% peak HR: time [zscore= 3.31; P=0.001], intensity [z-score=2.24; P=0.025]). CONCLUSION: Exercise time and intensity independently contribute to %change in VO2peak during ISS missions, indicating that there are minimal values for exercise time and intensity required to maintain VO2peak. As the FD105 average exercise intensity and time did not prevent a decline in VO2peak from preflight, astronauts' exercise prescriptions should target at least 160 min of weekly aerobic exercise at an average above 75% peak HR with increased time at intensities above 90% of peak HR starting early in the mission.

Downs, Meghan E.↗
NASA NTRS2015

Effects of Unpredictable Variable Prenatal Stress (UVPS) on Bdnf DNA Methylation and Telomere Length in the Adult Rat Brain

In utero exposure to stress can shape neurobiological and behavioral outcomes in offspring, producing vulnerability to psychopathology later in life. Animal models of prenatal stress likewise have demonstrated long-­‐term alterations in brain function and behavioral deficits in offspring. For example, using a rodent model of unpredictable variable prenatal stress (UVPS), in which dams are exposed to unpredictable, variable stress across pregnancy, we have found increased body weight and anxiety-­‐like behavior in adult male, but not female, offspring. DNA methylation (addition of methyl groups to cytosines which normally represses gene transcription) and changes in telomere length (TTAGGG repeats on the ends of chromosomes) are two molecular modifications that result from stress and could be responsible for the long-­‐term effects of UVPS. Here, we measured methylation of brain-­‐derived neurotrophic factor (bdnf), a gene important in development and plasticity, and telomere length in the brains of adult offspring from the UVPS model. Results indicate that prenatally stressed adult males have greater methylation in the medial prefrontal cortex (mPFC) compared to non-­‐stressed controls, while females have greater methylation in the ventral hippocampus compared to controls. Further, prenatally stressed males had shorter telomeres than controls in the mPFC. These findings demonstrate the ability of UVPS to produce epigenetic alterations and changes in telomere length across behaviorally-­‐relevant brain regions, which may have linkages to the phenotypic outcomes.

epigenetic developmental programming↗
NASA NTRS2015

NASA's Rodent Research Project: Validation of Flight Hardware, Operations and Science Capabilities for Conducting Long Duration Experiments in Space

Research using rodents is an essential tool for advancing biomedical research on Earth and in space. Rodent Research (RR)-1 was conducted to validate flight hardware, operations, and science capabilities that were developed at the NASA Ames Research Center. Twenty C57BL/6J adult female mice were launched on Sept 21, 2014 in a Dragon Capsule (SpaceX-4), then transferred to the ISS for a total time of 21-22 days (10 commercial mice) or 37 (10 validation mice). Tissues collected on-orbit were either rapidly frozen or preserved in RNA later at less than or equal to -80 C (n=2/group) until their return to Earth. Remaining carcasses were rapidly frozen for dissection post-flight. The three controls groups at Kennedy Space Center consisted of: Basal mice euthanized at the time of launch, Vivarium controls, housed in standard cages, and Ground Controls (GC), housed in flight hardware within an environmental chamber. FLT mice appeared more physically active on-orbit than GC, and behavior analysis are in progress. Upon return to Earth, there were no differences in body weights between FLT and GC at the end of the 37 days in space. RNA was of high quality (RIN greater than 8.5). Liver enzyme activity levels of FLT mice and all control mice were similar in magnitude to those of the samples that were optimally processed in the laboratory. Liver samples collected from the intact frozen FLT carcasses had RNA RIN of 7.27 +/- 0.52, which was lower than that of the samples processed on-orbit, but similar to those obtained from the control group intact carcasses. Nonetheless, the RNA samples from the intact carcasses were acceptable for the most demanding transcriptomic analyses. Adrenal glands, thymus and spleen (organs associated with stress response) showed no significant difference in weights between FLT and GC. Enzymatic activity was also not significantly different. Over 3,000 tissues collected from the four groups of mice have become available for the Biospecimen Sharing Program. Together, these validation flight findings demonstrate the capability to support long-duration RR on the ISS to achieve both basic science and biomedical objectives.

rodents↗
NASA NTRS2015

NASA's Rodent Research Project: Validation of Capabilities for Conducting Long Duration Experiments in Space

Research using rodents is an essential tool for advancing biomedical research on Earth and in space. Prior rodent experiments on the Shuttle were limited by the short flight duration. The International Space Station (ISS) provides a new platform for conducting rodent experiments under long duration conditions. Rodent Research (RR)-1 was conducted to validate flight hardware, operations, and science capabilities that were developed at the NASA Ames Research Center. Twenty C57BL6J adult female mice were launched on Sept 21, 2014 in a Dragon Capsule (SpaceX-4), then transferred to the ISS for a total time of 21-22 days (10 commercial mice) or 37 days (10 validation mice). Tissues collected on-orbit were either rapidly frozen or preserved in RNAlater at -80C (n2group) until their return to Earth. Remaining carcasses on-orbit were rapidly frozen for dissection post-flight. The three controls groups at Kennedy Space Center consisted of: Basal mice euthanized at the time of launch, Vivarium controls housed in standard cages, and Ground Controls (GC) housed in flight hardware within an environmental chamber. Upon return to Earth, there were no differences in body weights between Flight (FLT) and GC at the end of the 37 days in space. Liver enzyme activity levels of FLT mice and all control mice were similar in magnitude to those of the samples that were processed under optimal conditions in the laboratory. Liver samples dissected on-orbit yielded high quality RNA (RIN8.99+-0.59, n7). Liver samples dissected post-flight from the intact, frozen FLT carcasses yielded RIN of 7.27 +- 0.52 (n6). Additionally, wet weights of various tissues were measured. Adrenal glands and spleen showed no significant differences in FLT compared to GC although thymus and livers weights were significantly greater in FLT compared to GC. Over 3,000 tissue aliquots collected post-flight from the four groups of mice were deposited into the Ames Life Science Data Archives for future Biospecimen Sharing Program. Together, the RR validation flight successfully demonstrates the capability to support long-duration experimentation on the ISS to achieve both basic science and biomedical objectives.

spaceflight↗
NASA NTRS2016

Rodent Habitat on ISS: Advances in Capability for Determining Spaceflight Effects on Mammalian Physiology

Rodent research is a valuable essential tool for advancing biomedical discoveries in life sciences on Earth and in space. The National Research Counsel's Decadal survey (1) emphasized the importance of expanding NASAs life sciences research to perform long duration, rodent experiments on the International Space Station (ISS). To accomplish this objective, new flight hardware, operations, and science capabilities were developed at NASA ARC to support commercial and government-sponsored research. The flight phases of two separate spaceflight missions (Rodent Research-1 and Rodent Research-2) have been completed and new capabilities are in development. The first flight experiments carrying 20 mice were launched on Sept 21, 2014 in an unmanned Dragon Capsule, SpaceX4; Rodent Research-1 was dedicated to achieving both NASA validation and CASIS science objectives, while Rodent Reesearch-2 extended the period on orbit to 60 days. Groundbased control groups (housed in flight hardware or standard cages) were maintained in environmental chambers at Kennedy Space Center. Crewmembers previously trained in animal handling transferred mice from the Transporter into Habitats under simultaneous veterinary supervision by video streaming and were deemed healthy. Health and behavior of all mice on the ISS was monitored by video feed on a daily basis, and post-flight quantitative analyses of behavior were performed. The 10 mice from RR-1 Validation (16wk old, female C57Bl6/J) ambulated freely and actively throughout the Habitat, relying heavily on their forelimbs for locomotion. The first on-orbit dissections of mice were performed successfully, and high quality RNA (RIN values>9) and liver enzyme activities were obtained, validating the quality of sample recovery. Post-flight sample analysis revealed that body weights of FLT animals did not differ from ground controls (GC) housed in the same hardware, or vivarium controls (VIV) housed in standard cages. Organ weights analyzed post-flight showed that there were no differences between FLT and GC groups in adrenal gland and spleen weights, whereas FLT thymus and liver weights exceeded those of GC. Minimal differences between the control groups (GC and VIV) were observed. In addition, Over 3,000 aliquots collected post-flight from the four groups of mice were deposited into the Ames Life Science Data Archives for the Biospecimen Sharing Program and Genelab project. New capabilities recently developed include DEXA scanning, grip strength tests and male mice. In conclusion, new capability for long duration rodent habitation of group-housed rodents was developed and includes in-flight sample collection, thus avoiding the complication of reentry. Results obtained to date reveal the possibility of striking differences between the effects of short duration vs. long duration spaceflight. This Rodent Research system enables achievement of both basic science and translational research objectives to advance human exploration of space.

Bone Loss↗
NASA NTRS2016

Low Force Penetration of Icy Regolith

A percussive cone penetrometer measures the strength of granular material by using percussion to deliver mechanical energy into the material. A percussive cone penetrometer was used in this study to penetrate a regolith ice mixture by breaking up ice and decompacting the regolith. As compared to a static cone penetrometer, percussion allows low reaction forces to push a penetrometer probe tip more easily into dry regolith in a low gravity environment from a planetary surface rover or a landed spacecraft. A percussive cone penetrates icy regolith at ice concentrations that a static cone cannot penetrate. In this study, the percussive penetrator was able to penetrate material under 65 N of down-force which could not be penetrated using a static cone under full body weight. This paper discusses using a percussive cone penetrometer to discern changes in the concentration of water-ice in a mixture of lunar regolith simulant and ice to a depth of one meter. The rate of penetration was found to be a function of the ice content and was not significantly affected by the down-force. The test results demonstrate that this method may be ideal for a small platform in a reduced gravity environment. However, there are some cases where the system may not be able to penetrate the icy regolith, and there is some risk of the probe tip becoming stuck so that it cannot be retracted. It is also shown that a percussive cone penetrometer could be used to prospect for water ice in regolith at concentrations as high as 8 by weight.

surface stabilization↗
NASA NTRS2016

Atg12 Maintains Skeletal Integrity by Modulating Pro-Osteoclastogenic Signals and Chondrocyte Differentiation

Weightlessness and radiation, two unique elements of space, profoundly decreases bone mass. This bone loss is attributed to increased activity of bone-resorbing osteoclasts and functional changes in bone-forming osteoblasts, cells that give rise to mature osteocytes. Our long-term goal is to identify signaling pathways that may be targeted to mitigate bone loss in scenarios of space exploration, radiotherapy and accidental radiation exposure. We have previously shown that exposure of MLO-Y4 osteocyte-like cells to simulated space radiation (56Fe) increased the expression of the pro-osteoclastogenic gene rankl and decreased protein levels of LC3B-II, a key player in autophagy. In this current study, we aimed to further elucidate the role of autophagy in maintaining structural integrity of the skeleton. We hypothesize that loss of autophagy in bone leads to an imbalance in pro-osteoclastogenic and pro-osteogenic signals, resulting in net bone loss. To test our hypothesis we performed global postnatal deletion of Atg12 using tamoxifeninducible Cre recombinase under the control of the CAG promoter. Six-week-old CAGCreERT2/ FloxAtg12 animals were treated daily with Tamoxifen or Vehicle (Control, oil only) for five days and euthanasia performed two weeks after the onset of treatment. Percent change in body weights (prior to treatment and at euthanasia) was not significantly different between treatment groups within the same gender. Compared to Vehicle (Control) groups, Tamoxifen (Atg12 iKO) groups showed decreased LC3B-I to II conversion and increased p62 protein levels, consistent with loss of autophagy. Quantitative PCR revealed increased expression of proosteoclastogenic cytokines mcp1 and rankl in bone and marrow respectively in male iKOs compared to male controls. Expression levels of these genes were not significantly altered in the Atg12 iKO females compared to females controls. Microcomputed tomography of tibiae revealed decreased cortical bone volume, cortical thickness and periosteal perimeter consistent with bone loss; and a longer primary spongiosa in male Atg12 iKOs display compared to male controls. These decrements were less pronounced in the female Atg12 iKOs. Cancellous bone structure was not significantly different between iKOs and controls in both genders. Histological analysis also revealed that compared to male controls, male iKOs showed a profound increase in chondrocyte column length of the growth plate with hyper-expansion of both proliferating and hypertrophic zones. Taken together, these findings indicate that autophagy plays an important role in the maintenance of bone structural integrity by mediating the production of proosteoclastogenic signals and regulating chondrocyte proliferation and differentiation.

autophagy↗
NASA NTRS2017

Group Housing During Hindlimb Unloading to Simulate Weightlessness

The rodent hindlimb unloading (HU) model was developed in the 1980s to faciliate the study of mechanisms, responses, and treatments for the adverse effects of spaceflight. A number of variations on unloading systems and cage designs have been developed, although most entail individually housing the HU animals. In this study, we performed hindlimb unloading under group housing conditions. Our preliminary results indicate that HU animals that were group housed for 30 days, displayed musculoskeletal decrements associated with disuse, and further, body weights did not differ compared to age-matched controls. In conclusion, group housing of HU mice provides a novel means to simulate weightlessness under conditions that more closely resemble living conditions of Rodent Research Project ISS flight hardware habitats, and minimizes the social stress of isolation, which is consistent with current animal welfare standards (Guide for the Care and Use of Laboratory Animals: Eighth Edition, National Research Council).

group housing↗
NASA NTRS2017

Zoledronate Prevents Simulated Weightlessness-Induced Bone Loss in the Cancellous Compartment While Blunting the Efficacy of a Mechanical Loading Countermeasure

Astronauts using high-force resistance training while weightless show a high-turnover remodeling state within the skeletal system, with resorption and formation biomarkers being elevated. One countermeasure for the skeletal health of astronauts includes an antiresorptive of the bisphosphonate (BP) drug class. We asked, does the combination of an anti-resorptive and high-force exercise during weightlessness have negative effects on bone remodeling and strength? In this study, we developed an integrated model to mimic the mechanical strain of exercise via cyclical loading (CL) in mice treated with the BP Zoledronate (ZOL) combined with hind limb unloading (HU) to simulate weightlessness. We hypothesized that ZOL prevents structural degradation from simulated weightlessness and that CL and ZOL interact to render CL less effective. Thirty-two C57BL/6 mice (male, 16 weeks old, n=8/group) were exposed to 3 weeks of either HU or normal ambulation (NA). Cohorts of mice received one subcutaneous injection of ZOL (45μg/kg), or saline vehicle (VEH), prior to the start of HU. The right tibia was axially compressed in vivo 60x/day to 9N (+1200μstrain on the periosteal surface) and repeated 3x/week during HU. Left tibiae served as a within subject, non-compressed control. Ex vivo μCT was performed on all subjects to determine cancellous and cortical architectural parameters. Static and dynamic histomorphometry were carried out for the left and right tibiae to determine osteoclast- and osteoblast relevant surfaces. Further, micro damage was assessed in select groups by basic-fuchsin staining to test whether CL had an effect. For all assays, a multivariate (2x2x2) ANCOVA model was used to account for body weight changes. Additionally, for the tibiae, we incorporated a random effect for the subject (hence, a mixed model) to account for observations of both left and right tibiae within each subject. P < 0.05 was considered significant. In the cancellous compartment of the proximal tibial metaphysis, we observed a main effect from each independent variable, as determined by structural and histomorphometric assays. Specifically, as expected, ZOL showed an increase in the cancellous bone volume to total volume fraction (BV/TV, +32%) and trabecular number (+18%) compared to the VEH. As expected, ZOL decreased osteoclast surface (OC/BS) by -45% compared to VEH. Surprisingly, ZOL reduced mineralizing surface (MS/BS) and bone formation rate (BFR), indicators of osteoblast activity, by -40% and -54%, respectively, compared to VEH. Altogether, ZOL-treated mice displayed a low turnover state of remodeling in the metaphysis. In the context of skeletal aging, we speculate that ZOL prevented age-related cancellous strut loss during the experiment. As a main effect, as expected, HU decreased BV/TV by - 31% via reductions in both trabecular thickness (-11%) and number (-22%) compared to NA controls. Additionally, HU decreased MS/BS by -38% and bone formation rate (BFR) by -50% compared to NA controls. Altogether, these data are consistent with structural degradation resulting from imbalanced remodeling that favors resorption. As a main effect, CL increased BV/TV by +15% via increased trabecular thickness (+12%) compared to the noncompressed limb. As expected, CL increased MS/BS (+20%) and BFR (+24%), indicating osteoblast mineralization contributed to bone gains. These data show that CL provided an anabolic stimulus to the cancellous tissue. We observed unique interactions in ZOL*CL and HU*CL. First, ZOL prevented CL-induced increases in BV/TV and trabecular number, as compared to VEH. In the context of skeletal aging, these data suggest no added benefit from CL in the ZOL-treated mice. Interestingly, no microdamage was observed in mice that were unloaded and treated with ZOL (independent of CL). Secondly, HU prevented CL-induced increases in BFR, as compared to NA controls. These data suggest that either exercise is less effective or the kinetics of formation are slower during simulated weightlessness. Osteoclast surface was unchanged by either treatment. Thus, in contrast to exercising astronauts, these data do not suggest a high-turnover state in the metaphysis. To assess mechanical properties as a function of HU or ZOL, we tested the left femur in three-point bending ex vivo. As expected, HU decreased stiffness (-30%) compared to NA, and ZOL increased stiffness compared to VEH (+28%). Interestingly, HU increased the post-yield displacement, related to collagenous tensile loading, compared to NA (+20%). ZOL increased yield force (+11%) and ultimate force (+17%), which seems to explain the significant effect of ZOL increasing total energy (work-to-fracture, +15%), while not affecting the post yield displacement. Taken together, ZOL did not have detrimental affect on mechanical properties. Our integrated model simulates the combination of weightlessness, exercise-induced mechanical strain, and anti-resorptive treatment that astronauts experience during space missions. We conclude that Zoledronate was an effective countermeasure against weightlessness-induced bone loss, though zoledronate, as well as weightlessness, rendered exercise-related mechanical loading less effective.

bone↗
NASA NTRSDate not supplied

Human placenta-derived stromal cells mitigate select immune responses to simulated weightlessness

Space flight presents unique risks to human health. Microgravity and social isolation are important space flight stressors which have vast impact on multiple systems such as the musculoskeletal, immune and central nervous system (CNS). To explore candidate countermeasures against tissue decrements caused by spaceflight, we performed a pilot study with PLacental-eXpanded stromal (PLX) cells. PLX cells secrete factors that modulate the immune system, but do not trigger host immune responses, enabling treatment in subjects that have intact immune systems. These cells had previous success in treating critical limb ischemia and acute radiation syndrome in murine models. In this study, 4-month-old female mice underwent 30 days of hindlimb unloading (HU) in single housing conditions to simulate long-term weightlessness and isolation. HU and normally ambulating controls were administered with PLX cells or sham-injected with Plasmalyte. We hypothesized that administration of PLX cells will mitigate some of the effects caused by prolonged HU. We found that treatment with PLX cells was well tolerated as indicated by body weights, circulating corticosterone levels and immune organ response to injection of the cells. HU led to the expected decreases in soleus muscle weights and bone loss. We did not observe any protective properties of the PLX cells in the musculoskeletal system but found that the cell treatment partially protected from a subset of HU-induced immune and CNS changes. In the hippocampus, protein levels of 9 of 44 cytokines were downregulated by HU. PLX administration mitigated changes in expression of 8 of these cytokines, including IL-2, IL-6 and MCP-1. To our knowledge, this is the first report on the protective effects of PLX-PAD against HU-induced changes in the cytokine milieu of the CNS. Our findings warrant further studies, which includes testing in actual spaceflight.

Microgravity↗
NASA NTRSDate not supplied

Countermeasures for Mitigation of Sensorimotor Decrements Following Head-Down Bed Rest

BACKGROUND Decrements in functional performance of tasks requiring postural and locomotor control remain common among crewmembers returning to Earth after6months on the International Space Station (ISS). These impairments will presumably be exacerbated after longer exploration-class missions with fewer exercise hardware options. Our recent studies suggest that an in-flight proprioceptive countermeasure may keep the proprioceptive system tuned to respond to upright balance challenges in a gravitational environment. Before testing a proprioceptive countermeasure in-flight, we must conduct an initial proof-of-concept study to determine its potential efficacy in a controlled unloading analog setting. OBJECTIVES We will determine if proprioceptive training during 60 days of 6° head down bed rest (HDBR) mitigates declines in functional task performance. We consider it critical to characterize the interaction between proprioceptive training and exercise. Thus, we will compare 3groupsof subjects(N=12 each): a proprioceptive training group, an exercise plus proprioceptive training group, and a control group(i.e. no training or exercise).The primary outcome measure will be the well-established and operationally relevant seat egress and walk test (also referred to as the functional mobility test)performed before and after HDBR. Other functional tests will also represent high priority exploration mission tasks that require high demand for dynamic control of postural stability. Additional measures will be used to identify the key physiological factors contributing to countermeasure benefits. COUNTERMEASURE METHODS We will use a ground version of our countermeasure to test the efficacy of proprioceptive training while maintaining HDBR constraints. Subjects will remain in the horizontal supine position on a sled that moves freely on air-bearings, similar to a puck on an air hockey table. Subjects will be loaded axially up to one full body weight via lateral cable pulleys towards their feet on an instrumented tilt board using a harness and weights system. Visual feedback of board tilt will be used to guide subjects while they make active tilts. Exercise and proprioceptive training prescriptions will represent those expected to be implemented during exploration spaceflight missions(e.g.20-minute proprioceptive training sessions3 times per week). RELEVANCE The deliverable from this project will be a proof-of-concept countermeasure design that has been fully assessed for efficacy in a spaceflight analog. The findings and lessons learned from this study will be translated for validation of this countermeasure on the ISS. An effective countermeasure will be added to the suite of operationally implemented in-flight sensorimotor countermeasures.

T R Macaulay↗