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Activation of nuclear transcription factor-kappaB in mouse brain induced by a simulated microgravity environment
Microgravity induces inflammatory responses and modulates immune functions that may increase oxidative stress. Exposure to a microgravity environment induces adverse neurological effects; however, there is little research exploring the etiology of these effects resulting from exposure to such an environment. It is also known that spaceflight is associated with increase in oxidative stress; however, this phenomenon has not been reproduced in land-based simulated microgravity models. In this study, an attempt has been made to show the induction of reactive oxygen species (ROS) in mice brain, using ground-based microgravity simulator. Increased ROS was observed in brain stem and frontal cortex with concomitant decrease in glutathione, on exposing mice to simulated microgravity for 7 d. Oxidative stress-induced activation of nuclear factor-kappaB was observed in all the regions of the brain. Moreover, mitogen-activated protein kinase kinase was phosphorylated equally in all regions of the brain exposed to simulated microgravity. These results suggest that exposure of brain to simulated microgravity can induce expression of certain transcription factors, and these have been earlier argued to be oxidative stress dependent.
An Environmental Innovation: The Sewer Mouse
In the effort to clean up America's waters, there is a little-known complicating factor: because they leak, sewer systems in many American cities are causing rather than preventing pollution of rivers and lakes. Fixing the leaks is difficult because their locations are unknown. Maintenance crews can't tear up a whole city looking for cracks in the pipes; they must first determine which areas are most likely suspects. An aerospace spinoff is providing help in that regard. The problem starts with heavy rains. Rainwater naturally flows into the sewers from streets, but sewage systems are designed to accommodate it. However, they are not designed to handle the additional flow of "groundwater", rain absorbed by the earth which seeps into the sewers through leaks in pipes and sewer walls. After a storm, groundwater seepage can increase the waterflow to deluge proportions, with the result that sewage treatment plants are incapable of processing the swollen flow. When that happens the sluices must be opened, dumping raw sewage into rivers and lakes.
Molecular and Histopathological Changes in Mouse Intestinal Tissue After Proton Exposure
Whole body exposure to protons in mice causes significant apoptosis in the crypts of the small intestine. Increasing numbers of crypts contained more apoptotic lesions as the dose of exposure increased. 16 genes associated with apoptotic pathways were shown to have significantly altered expression as compared to control samples for at least one of the doses of proton exposure 1 gene, Trp53inp1, was significantly up-regulated across all three doses. Those animals exposed to 0.1 Gy of proton irradiation showed greater amounts of significant alterations in gene expression as compared to 1 Gy and 2 Gy exposures. The differences in gene expression changes of low and high dose proton irradiated mice may offer insight into the molecular mechanisms of the possible high sensitivity at low proton doses. RAIDD (CRADD) may be responsible for the hypersensitivity observed in the duodenum of mice exposed to low doses of protons. Caspase-1 may also play a role in the hypersensitivity seen following proton irradiation at a dose of 0.1 Gy. FOXO3A may be involved in the down-regulation of GILZ observed at high doses of proton exposure.
Radio-Adaptive Responses of Mouse Myocardiocytes
One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) Cs-137 gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Pro-apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value . 0.003) 4hr after H, but not after 4hr LH when compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive response that mitigates the reduction in genetic expression associated with single high-dose gamma radiation exposure. This radio-adaptive response may serve as a potential countermeasure to radiation-induced myocardial remodeling and preserve the cardiovascular health of astronauts; thus, reducing the risks of human space exploration.
Altered Innate and Lymphocytic Immune Responses in Mouse Splenocytes Post-Flight
Space flight is known to affect immune responses of astronauts and animals, decreasing lymphocytic responses to mitogenic stimuli, delayed typed hypersensitivity reactions, and T-cell activation. Despite changes in immune suppression, there are no reports of consistent adverse clinical events post flight. To further investigate the spectrum of affected immune responses, murine splenocytes were stimulated immediately post-shuttle flight (14 days on STS-135) with T-cell stimulators or toll-like receptor agonists. Comparisons were made to ground control splenocytes from age-matched mice. Cell phenotypes were assessed, as well as activation markers and associated cytokine production. The CD4+ population decreased with no concurrent decrease in CD8+ cells from shuttle mice post flight compared to ground controls. Regarding antigen presenting cell populations, the number of CD11c+ cells were slightly elevated post flight, compared to ground controls, with increased MHC Class I expression (I-A(sup b)) and no change in Class II expression (H-2K(sup b)). CD86+ populations were also significantly diminished. However, the decreased markers did not correlate with activity. Stimulation of splenocytes post flight showed significant increase in bead uptake, increased Class I expression, increased TNF-alpha and IL-6 production in response to TLR-2 (zymosan) and TLR-4 (LPS) agonists. While most activated (ConA or anti-CD3/anti-CD28) CD4+ cells showed markedly diminished responses (reduced IL-2 production), non-specific T cell responses to superantigen (SEA/SEB) increased post flight as determined by expression of early activation markers. Production of additional cytokines was also dysregulated postflight. Overall, persistent immune changes during space flight could represent unique clinical risks for exploration class missions. The consequences of pathogenic encounter remain an important concern that should be addressed.
Induction of a Radio-Adaptive Response by Low-dose Gamma Irradiation in Mouse Cardiomyocytes
One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) 137Cs gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value < or = 0.003) 4hr after H, but not after 4hr LH compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive response that mitigates the reduction in genetic expression associated with single high-dose gamma radiation exposure. This radio-adaptive response may serve as a potential countermeasure to radiation-induced myocardial remodeling and preserve the cardiovascular health of astronauts; thus, reducing the risks of human space exploration.
Spaceflight Effects and Molecular Responses in the Mouse Eye: Observations after NASA Shuttle Mission STS-133
Background: Human space exploration implies a combination of stressors including microgravityinduced cephalad fluid shift and radiation exposure. Ocular changes in astronauts leading to visual impairment are of occupational health relevance. The effect of this complex environment on ocular morphology and function is poorly understood. Material and Methods: Mice were assigned to a Flight (FLT) group flown on shuttle mission STS133, Animal Enclosure Module (AEM), or vivarium (VIV) ground controls. Eyes were collected at 1, 5 and 7 days after landing, and were fixed for histological sectioning. The contralateral eye was used for gene expression profiling by qRT-PCR. Routine histology and immunohistochemistry using 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3, glial fibrillary acidic protein (GFAP) and beta-amyloid were used to study the eyes. Results and Conclusions: 8-OHdG and caspase-3 immunoreactivity was increased in the retina in FLT samples at return from flight (R+1) compared to ground controls, and decreased at day 7 (R+7), suggesting an increase in oxidative stress and cell apoptosis. FLT mice showed evidence of retinal pigment epithelium (RPE) apoptosis possibly secondary to oxidative damage. Although attenuation of RPE has been related to retinal choroidal folds in astronauts, it is yet to be determined whether or not increased RPE apoptosis may contribute to the formation of choroidal folds or may increase the risk for other retinal pathologies, such as AMD. beta-amyloid was seen in the nerve fibers at the post-laminar region of the optic nerve in the flight samples (R+7). Deposition of beta-amyloid has a strong correlation with mechanical trauma. The coexpression of GFAP in astrocytes and oligodentrocytes in these same areas supports the possible mechanical origin probably secondary to intracranial pressure that is transmitted into the nerve, as a result of an increase in venous pressure associated to microgravity-induced cephalic fluid shift. However, there is the need to further investigate the nature of the changes through additional experimental work. Gene expression of oxidative and cellular stress response genes was unregulated in the retina of FLT samples upon landing followed by lower levels by R+7. These results suggest that reversible molecular damage occurs in the retina of mice exposed to spaceflight and that protective cellular and molecular pathways are induced in the retina in response to these changes.
Spaceflight Effects and Molecular Responses in the Mouse Eye: Observations After Shuttle Mission STS-133
Microgravity-induced cephalad fluid shift and radiation exposure are some of the stressors seen in space exploration. Ocular changes leading to visual impairment in astronauts are of occupational health relevance. Therefore, we analyzed the effects of space flight in the eyes of mice. Six mice were assigned to Flight (FLT), Animal enclosure Module (AEM), or vivarium (VIV) group, respectively. Mice were sacrificed at 1, 5 or 7 days after landing from space. One eye was used for histological and immunohistoche-mistry analysis and the other eye for gene expression profiling. 8-OHdG and caspase-3 immunoreactivity were increased in the retina in FLT samples at return(R+1) compared to AEM/VIV groups, and decreased at day 7 (R+7). beta-amyloid was seen in the nerve fibers at the post-laminar region of the optic nerve in the flight samples (R+7). In addition, oxidative and cellular stress response genes were upregulated in the retina of FLT samples upon landing, and decreased by R+7. According to the results, a reversible molecular damage may occur in the retina of mice exposed to spaceflight followed by protective cellular response.
Spaceflight and the Mouse Eye: Results from Experiments on Shuttle Missions STS-133 and STS-135
Vision alterations associated with globe flattening, chorodial folds and papilledema, shown in some crew members returning from long duration missions. Hypothesis: Ocular neuroanatomical changes observed in the VIIP syndrome are accompanied by retinal changes at the molecular and cellular level that may affect retinal health and physiology. Objective: Investigate evidence of ocular (retinal) changes associated with spaceflight: (1) histological markers of cellular death and damage (2) molecular markers of oxidative stress (3) gene expression markers of stress
JSC ASTRONAUT Mice Dissection Training Mouse Urinary Protein Exposure Evaluation
No abstract available
Analysis of Adult Female Mouse (Mus musculus) Group Behavior on the International Space Station (ISS)
As interest in long duration effects of space habitation increases, understanding the behavior of model organisms living within the habitats engineered to fly them is vital for designing, validating, and interpreting future spaceflight studies. A handful of papers have previously reported behavior of mice and rats in the weightless environment of space. The Rodent Research Hardware and Operations Validation (Rodent Research-1; RR1) utilized the Rodent Habitat (RH) developed at NASA Ames Research Center to fly mice on the ISS (International Space Station). Ten adult (16-week-old) female C57BL/6 mice were launched on September 21st, 2014 in an unmanned Dragon Capsule, and spent 37 days in microgravity. Here we report group behavioral phenotypes of the RR1 Flight (FLT) and environment-matched Ground Control (GC) mice in the Rodent Habitat (RH) during this long-duration flight. Video was recorded for 33 days on the ISS, permitting daily assessments of overall health and well-being of the mice, and providing a valuable repository for detailed behavioral analysis. We previously reported that, as compared to GC mice, RR1 FLT mice exhibited the same range of behaviors, including eating, drinking, exploration, self- and allo-grooming, and social interactions at similar or greater levels of occurrence. Overall activity was greater in FLT as compared to GC mice, with spontaneous ambulatory behavior, including organized 'circling' or 'race-tracking' behavior that emerged within the first few days of flight following a common developmental sequence, and comprised the primary dark cycle activity persisting throughout the remainder of the experiment. Participation by individual mice increased dramatically over the course of the flight. Here we present a detailed analysis of 'race-tracking' behavior in which we quantified: (1) Complete lap rotations by individual mice; (2) Numbers of collisions between circling mice; (3) Lap directionality; and (4) Recruitment of mice into a group phenotype. This analysis contributes to the first NASA long-duration study of rodent behavior, providing evidence for the emergence of a distinctive, organized group behavior unique to the weightless space environment.
Change in Mouse Bone Turnover in Response to Microgravity on RR-1
Mechanical unloading during spaceflight is known to adversely affect mammalian physiology. Our previous studies using the Animal Enclosure Module on short duration Shuttle missions enabled us to identify a deficit in stem cell based-tissue regeneration as being a significant concern for long-duration spaceflight. Specifically, we found that mechanical unloading in microgravity resulted in inhibition of differentiation of mesenchymal and hematopoietic stem cells in the bone marrow compartment. Also, we observed overexpression of a cell cycle arrest molecule, CDKN1ap21, in osteoprecursor cells on the bone surface, chondroprogenitors in the articular cartilage, and in myofibers attached to bone tissue. Specifically in bone tissue during both short (15-day) and long (30-day) microgravity experiments, we observed significant loss of bone tissue and structure in both the pelvis and the femur. After 15-days of microgravity on STS-131, pelvic ischium displayed a 6.23 decrease in bone fraction (p0.005) and 11.91 decrease in bone thickness (p0.002). Furthermore, during long-duration spaceflight we observed onset of an accelerated aging-like phenotype and osteoarthritic disease state indicating that stem cells within the bone tissue fail to repair and regenerate tissues in a normal manner, leading to drastic tissue alterations in response to microgravity. The Rodent Research Hardware System provides the capability to investigate these effects during long-duration experiments on the International Space Station. During the Rodent Research-1 mission 10 16-week-old female C57Bl6J mice were exposed to 37-days of microgravity. All flight animals were euthanized and frozen on orbit for future dissection. Ground (n10) and vivarium controls (n10) were housed and processed to match the flight animal timeline. During this study we collected pelvis, femur, and tibia from all animal groups to test the hypothesis that stem cell-based tissue regeneration is significantly altered after 37-days of spaceflight. To do this, we will analyze differences in bone morphometric parameters using MicroCT. The pelvis, femur, and tibia are key in supporting and distributing weight under normal conditions. Therefore, we expect to see altered remodeling in flight animals in response to microgravity with respect to ground controls. In combination with histomorphometry, these results will help elucidate the complex mechanisms underlying bone tissue maintenance and stem cell regeneration.
Transgenic Mouse Model for Reducing Oxidative Damage in Bone
Bone loss can occur due to many challenges such age, radiation, microgravity, and Reactive Oxygen Species (ROS) play a critical role in bone resorption by osteoclasts (Bartell et al. 2014). We hypothesize that suppression of excess ROS in skeletal cells, both osteoblasts and osteoclasts, regulates skeletal growth and remodeling. To test our hypothesis, we used transgenic mCAT mice which overexpress the human anti-oxidant catalase gene targeted to the mitochondria, the main site for endogenous ROS production. mCAT mice have a longer life-span than wildtype controls and have been used to study various age-related disorders. To stimulate remodeling, 16 week old mCAT mice or wildtype mice were exposed to treatment (hindlimb-unloading and total body-irradiation) or sham treatment conditions (control). Tissues were harvested 2 weeks later for skeletal analysis (microcomputed tomography), biochemical analysis (gene expression and oxidative damage measurements), and ex vivo bone marrow derived cell culture (osteoblastogenesis and osteoclastogenesis). mCAT mice expressed the transgene and displayed elevated catalase activity in skeletal tissue and marrow-derived osteoblasts and osteoclasts grown ex vivo. In addition, when challenged with treatment, bone tissues from wildtype mice showed elevated levels of malondialdehyde (MDA), indicating oxidative damage) whereas mCAT mice did not. Correlation analysis revealed that increased catalase activity significantly correlated with decreased MDA levels and that increased oxidative damage correlated with decreased percent bone volume (BVTV). In addition, ex-vivo cultured osteoblast colony growth correlated with catalase activity in the osteoblasts. Thus, we showed that these transgenic mice can be used as a model to study the relationship between markers of oxidative damage and skeletal properties. mCAT mice displayed reduced BVTV and trabecular number relative to wildtype mice, as well as increased structural model index in the cancellous tibia. Treatment caused bone loss in wildtype mice, as expected. Treatment also caused deficits in microarchitecture of mCAT mice, although less severe than wildtype mice in some parameters (percent bone volume, structural model index and cortical area). In conclusion, our results indicate that endogenous ROS signaling in both osteoblast and osteoclast lineage cells contributes to skeletal growth and remodeling, and quenching oxidative damage could play a role in bone loss prevention.
Changes in Mouse Bone Turnover in Response to Microgravity
Mechanical unloading during spaceflight is known to adversely affect mammalian physiology. Our previous studies using the Animal Enclosure Module on short duration Shuttle missions enabled us to identify a deficit in stem cell based-tissue regeneration as being a significant concern for long-duration spaceflight. Specifically, we found that mechanical unloading in microgravity resulted in inhibition of differentiation of mesenchymal and hematopoietic stem cells in the bone marrow compartment. Also, we observed overexpression of a cell cycle arrest molecule, CDKN1a/p21, in osteoprecursor cells on the bone surface, chondroprogenitors in the articular cartilage, and in myofibers attached to bone tissue. Specifically in bone tissue during both short (15-day) and long (30-day) microgravity experiments, we observed significant loss of bone tissue and structure in both the pelvis and the femur. After 15-days of microgravity on STS-131, pelvic ischium displayed a 6.23% decrease in bone fraction (p=0.005) and 11.91% decrease in bone thickness (p=0.002). Furthermore, during long-duration spaceflight we observed onset of an accelerated aging-like phenotype and osteoarthritic disease state indicating that stem cells within the bone tissue fail to repair and regenerate tissues in a normal manner, leading to drastic tissue alterations in response to microgravity. The Rodent Research Hardware System provides the capability to investigate these effects during long-duration experiments on the International Space Station. During the Rodent Research-1 mission 10 16-week-old female C57Bl/6J mice were exposed to 37-days of microgravity. All flight animals were euthanized and frozen on orbit for future dissection. Ground (n=10) and vivarium controls (n=10) were housed and processed to match the flight animal timeline. During this study we collected pelvis, femur, and tibia from all animal groups to test the hypothesis that stem cell-based tissue regeneration is significantly altered after 37-days of spaceflight. To do this, we will analyze differences in bone morphometric parameters using MicroCT. The pelvis, femur, and tibia are key in supporting and distributing weight under normal conditions. Therefore, we expect to see altered remodeling in flight animals in response to microgravity with respect to ground controls. In combination with histomorphometry, these results will help elucidate the complex mechanisms underlying bone tissue maintenance and stem cell regeneration.
Mouse Behavior on ISS: The Emergence of a Distinctive, Organized Group Circling Behavior Unique to Spaceflight
As interest in long duration effects of space habitation increases, understanding the behavior of model organisms living within the habitats engineered to fly them is vital for designing, validating, and interpreting future spaceflight studies. Only a handful of papers have previously reported behavior of mice and rats in the weightless environment of space (Andreev-Andrievskiy, et al., 2013; Cancedda et al., 2012; Ronca et al., 2008). The Rodent Research Hardware and Operations Validation Mission (Rodent Research-1; RR1) utilized the Rodent Habitat (RH) developed at NASA Ames Research Center to fly mice on the ISS. Ten adult (16-week-old) female C57BL6J mice were launched on September 21st, 2014 in an unmanned Dragon Capsule, and spent 37 days in flight. Here we report group behavioral phenotypes of the RR1 Flight (FLT) and environment-matched Ground Control (GC) mice in the RH during this long duration flight. Video was recorded for 34 days on the ISS, permitting daily assessments of overall health and well being of the mice, and providing a valuable repository for detailed behavioral analysis. As compared to GC mice, RR1 FLT mice exhibited the same range of behaviors, including eating, drinking, exploration, self- and allogrooming, and social interactions at similar or greater levels of occurrence. Overall activity was greater in FLT as compared to GC mice, with spontaneous ambulatory behavior, including organized circling or race-tracking behavior that emerged within the first few days of flight following a common developmental sequence, comprising the primary dark cycle activity of FLT mice. Circling participation by individual mice persisted throughout the mission. Analysis of group behavior over mission days revealed recruitment of mice into the group phenotype, coupled with decreasing numbers of collisions between circling mice. This analysis provides insights into the behavior of mice in microgravity, and clear evidence for the emergence of a distinctive, organized group behavior unique to the weightless space environment. Supported by the NASA Rodent Research Project, Space Biology Program, and Space Life Sciences Training Program.
Mouse Behavior on ISS: The Emergence of Distinctive, Organized Group Circling Behavior Unique to Spaceflight
As interest in long duration effects of space habitation increases, understanding the behavior of model organisms living within the habitats engineered to fly them is vital for designing, validating, and interpreting future spaceflight studies. Only a handful of papers have previously reported behavior of mice and rats in the weightless environment of space (Andreev-Andrievskiy, et al., 2013; Cancedda et al., 2012; Ronca et al., 2008). The Rodent Research Hardware and Operations Validation Mission (Rodent Research-1; RR1) utilized the Rodent Habitat (RH) developed at NASA Ames Research Center to fly mice on the ISS. Ten adult (16-week-old) female C57BL6J mice were launched on September 21st, 2014 in an unmanned Dragon Capsule, and spent 37 days in flight. Here we report group behavioral phenotypes of the RR1 Flight (FLT) and environment-matched Ground Control (GC) mice in the RH during this long duration flight. Video was recorded for 34 days on the ISS, permitting daily assessments of overall health and well being of the mice, and providing a valuable repository for detailed behavioral analysis. As compared to GC mice, RR1 FLT mice exhibited the same range of behaviors, including eating, drinking, exploration, self- and allogrooming,and social interactions at similar or greater levels of occurrence. Overallactivity was greater in FLT as compared to GC mice, with spontaneous ambulatory behavior, including organized circling or race-tracking behavior that emerged within thefirst few days of flight following a common developmental sequence, comprising theprimary dark cycle activity of FLT mice. Circling participation by individual micepersisted throughout the mission. Analysis of group behavior over mission days revealed recruitment of mice into the group phenotype, coupled with decreasing numbers of collisions between circling mice. This analysis provides insights into the behavior of mice in microgravity, and clear evidence for the emergence of a distinctive,organized group behavior unique to the weightless space environment.
Spaceflight Activates Autophagy Programs and the Proteasome in Mouse Liver
Increased oxidative stress is an unavoidable consequence of exposure to the space environment. Our previous studies showed that mice exposed to space for 13.5 days had decreased glutathione levels, suggesting impairments in oxidative defense. Here we performed unbiased, unsupervised and integrated multi-'omic analysis of metabolomic and transcriptomic datasets from mice flown aboard the Space Shuttle Atlantis. Enrichment analyses of metabolite and gene sets showed significant changes in osmolyte concentrations and pathways related to glycerophospholipid and sphingolipid metabolism, likely consequences of relative dehydration of the spaceflight mice. However, we also found increased enrichment of aminoacyl-tRNA biosynthesis and purine metabolic pathways, concomitant with enrichment of genes associated with autophagy and the ubiquitin-proteasome. When taken together with a down-regulation in NRF2-mediated signaling, our analyses suggest that decreased hepatic oxidative defense may lead to aberrant tRNA post-translational processing, induction of degradation programs and senescence-associated mitochondrial dysfunction in response to the spaceflight environment..