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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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11 records
All sourcesNASA NTRSDOE OSTI
NASA NTRS2015

Oxidative Stress and Autophagy Responses of Osteocytes Exposed to Spaceflight-like Radiation.

Weightlessness and radiation, two of the unique elements of the space environment, causes a profound decrement in bone mass that mimics aging. This bone loss is thought to result from increased activity of bone-resorbing osteoclasts and functional changes in bone-forming osteoblasts, cells that give rise to mature osteocytes. Our current understanding of the signaling factors and mechanisms underlying bone loss is incomplete. However, it is known that oxidative stress, characterized by the excess production of free radicals, is elevated during radiation exposure. The goals of this study is to examine the response of osteocytes to spaceflight-like radiation and to identify signaling processes that may be targeted to mitigate bone loss in scenarios of space exploration, earth-based radiotherapy and accidental radiation exposure. We hypothesize that (1) oxidative stress, as induced by radiation, decreases osteocyte survival and increases pro-osteoclastogenic signals and that (2) autophagy is one of the key cellular defenses against oxidative stress. Autophagy is the process by which cellular components including organelles and proteins are broken down and recycled. To test our hypothesis, we exposed the osteocyte-like cell line, MLO-Y4, to 0.5, 1, and 2 Gy of simulated space radiation (Iron-56 radiation at 600 MeV/n) and assessed cell numbers, cell growth-associated molecules as well as markers of autophagy and oxidative stress at various time points post-irradiation. We observed a reduction in cell numbers in the groups exposed to 1 and 2 Gy of Iron-56 radiation. Collectively, flow cytometry and gene expression analysis revealed that radiation caused a shift in cell cycle distribution consistent with growth arrest. Compared to sham-treatment, 2 Gy of Iron-56 increased FoxO3, SOD1, and RANKL gene expression yet unexpectedly decreased LC3B-II protein levels at 4 and 24 hours post-IR. Taken together, these findings suggest that simulated space radiation invoke antioxidant, pro-osteoclastogenic, and growth arrest responses in osteocytes. The implications of reduced autophagy flux at the time points examined remain to be elucidated.

Biological Sciences↗
NASA NTRS2017

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..

Autophagy↗
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 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. We aimed to 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 tamoxifen-inducible Cre. 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. qPCR revealed increased expression of pro-osteoclastogenic cytokines in bone and marrow respectively in male iKOs compared to controls. Microcomputed tomography 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. Histology showed that compared to male controls, male iKOs had 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 pro-osteoclastogenic signals and regulating chondrocyte proliferation and differentiation.

Atg12↗
NASA NTRSDate not supplied

Gene expression changes in peripheral blood mononuclear cells of ISS crewmembers suggest impacts of spaceflight on cell death

In space, living organisms are exposed to numerous stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures. This study is part of the Functional Immune Project, intended to determine alterations in crewmembers` immunobiology before, during, and after spaceflight. For this project, blood samples were collected from International Space Station (ISS) crewmembers at the following time points: i) at two pre-flight time points of 180 days (L180) and 45 days (L45) before launch. ii) During flight, blood was drawn at approximately the midpoint (mid-flight, MF) of the mission, and shortly before egress from the ISS (late-flight, LF). iii) Post-flight blood samples were collected within 24 hrs (R0), 30 days (R30) and 90 days (R90) after landing. For each crewmember, blood was also drawn from a matching test subject on the ground at the corresponding time point. For both the ISS crewmembers and the ground control subjects, total RNA was isolated from peripheral blood mononuclear cells (PBMC) and mRNA was analysed using next generation RNA-sequencing (NGS). Differentially expressed genes were determined by performing contrast analysis. Using the data from all of the time points from the ground control subjects as a control, a number of dysregulated genes were identified in astronauts at MF, LF and R0, including downregulations of several cell cycle related genes including CDKN1A and VEGFA at MF and LF. Pathway analysis of these differentially expressed genes indicated that, in space, pathways associated with autophagy and senescence were affected. Our analysis also indicated that the genes related to metabolisms were downregulated in the microgravity environment. Taken together, our data suggests that PBMC in the ISS crewmembers may be starved, resulting in autophagy and delayed senescence in space. Such findings are in agreement with delayed cell death in PBMC under simulated microgravity conditions on the ground and offer an explanation for telomere lengthening that has been reported among the ISS astronauts in flight.

Maria Moreno-Villanueva↗
NASA NTRSDate not supplied

Gene Expression Changes in Peripheral Blood Mononuclear Cells of ISS Crewmembers Suggest Impacts of Spaceflight on Cell Death

In space, living organisms are exposed to numerous stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures. This study is part of the Functional Immune Project, intended to determine alterations in crewmembers` immunobiology before, during, and after spaceflight. For this project, blood samples were collected from International Space Station (ISS) crewmembers at the following time points: i) at two pre-flight time points of 180 days (L180) and 45 days (L45) before launch. ii) During flight, blood was drawn at approximately the midpoint (mid-flight, MF) of the mission, and shortly before egress from the ISS (late-flight, LF). iii) Post-flight blood samples were collected within 24 hrs (R0), 30 days (R30) and 90 days (R90) after landing. For each crewmember, blood was also drawn from a matching test subject on the ground at the corresponding time point. For both the ISS crewmembers and the ground control subjects, total RNA was isolated from peripheral blood mononuclear cells (PBMC) and mRNA was analysed using next generation RNA-sequencing (NGS). Differentially expressed genes were determined by performing contrast analysis. Using the data from all of the time points from the ground control subjects as a control, a number of dysregulated genes were identified in astronauts at MF, LF and R0, including downregulations of several cell cycle related genes including CDKN1A and VEGFA at MF and LF. Pathway analysis of these differentially expressed genes indicated that, in space, pathways associated with autophagy and senescence were affected. Our analysis also indicated that the genes related to metabolisms were downregulated in the microgravity environment. Taken together, we hypothesize that PBMC in the ISS crewmembers may be starved, resulting in autophagy and delayed senescence in space. Such findings are in agreement with delayed cell death in PBMC under simulated microgravity conditions on the ground and offer an explanation for telomere lengthening that has been reported among the ISS astronauts in flight

Maria Moreno-Villanueva↗
NASA NTRS2024

iGCE and MitoFlyght Spaceflight Missions: Unraveling Oxidative Stress Responses in Space

Thriving In DEep Space (TIDES) initiative aims to comprehensively understand how hostile environments such as the Moon and Mars affect human physiology. Here we present two NASA-selected spaceflight experiments under the TIDES portfolio, iGCE (Integrated Gravity Continuum Experiment) and MitoFlyght (Mitochondrial Investigation of Oxidative Stress in Flies). We hypothesize that exposure to spaceflight conditions induces oxidative stress responses that negatively impact physiology. The iGCE mission employs two well-established spaceflight models, Drosophila melanogaster and C.elegans, using Redwire’s Multi-use Variable-g Platform (MVP) hardware to assess changes in cardiac, muscle, and nervous systems across five different gravities: Hypergravity (2g), Earth (1g), Mars (0.37g), Moon (0.16g), and microgravity (ug). This mission focuses on uncovering alterations in protein homeostasis, autophagy, and mitochondrial function conserved across species. In the MitoFlyght mission to the ISS, Drosophila will be housed in the Vented Fly Box (VFB). This mission evaluates the oxidative stress response and autophagic pathway in muscle, heart, and nervous system. Additionally, we will (a) use the genetic mutant, Tor7/P to test whether increased autophagy is beneficial or a maladaptive response to the spaceflight stressors, and (b) utilize fly lines with tissue-specific expression (neuronal, muscle, and cardiac) of an antioxidant gene, SOD2 (superoxide dismutase) as a potential countermeasure. Data from these missions will be compared with previous LEO-based datasets to identify shared signatures. Furthermore, cross-species analysis of the transcriptomic data from other invertebrate and vertebrate spaceflight studies will help determine evolutionarily conserved pathways perturbed by space stressors. Overall, both these missions aim to provide crucial insights into the mechanisms underlying oxidative stress responses, synaptic changes, and heart and muscle deficits, facilitating the identification of diagnostic and therapeutic targets to mitigate the adverse health effects of long-duration space habitation. Ultimately, this research will enhance our ability to thrive in deep space and inform future missions.

Janani Iyer↗
NASA NTRSDate not supplied

Transcriptomic Analysis of ISS Crewmembers’ Peripheral Blood Mononuclear Cells Reveals Homeostatic Regulations in Space

The impact of spaceflight on the immune system has been investigated for decades. Studies conducted in cell models, animals and humans suggest that the spaceflight environment affects the innate and acquired immune systems, as the ability to recognize antigens, defend against foreign invaders, and orchestrate repair is significantly hindered. However, the molecular mechanisms behind spaceflight-induced immune dysregulations are still unclear. In this study, blood from eleven (11) International Space Station (ISS) crewmembers was collected before, during and after long duration space missions, as well as from 11 matched ground control subjects. Transcriptomic analysis was performed in isolated peripheral blood mononuclear cells (PBMCs) using the RNA-sequencing technique. In comparison to the blood samples collected from the crewmembers pre-flight, a total of ~1000 genes were found to be upregulated and ~1000 genes downregulated in PBMC collected between 4 and 6 months after they were in space. The most significantly DEGs (differentially expressed genes) include activation of RUBCNL which is an autophagy enhancer and inhibition of GRASP which regulates cell trafficking. Genes involved in cell adhesion, cell cycle progression and other functions were also dysregulated. Pathway analysis of the DEGs indicates mitochondria dysfunction, particularly reduced ATP production in the electron transport chain. Other pathways impacted by spaceflight include glycolysis, autophagy and inflammatory response. Our results suggest that, in space, blood cells may have also experienced energy depletion and reduced metabolism. Consequently, the cells may become autophagic, which is a known homeostatic mechanism for blood cells to become quiescent, but to stay alive. Further analysis of the data shows recovery of the crewmembers after mission and potential differential responses between genders to the space environment. Our data potentially explains some of the physiological changes that have been observed in space such as mitochondria dysfunction, inhibition of T cell activation and telomere lengthening. Comparison of our results with other transcriptomics studies of ISS crewmembers’ blood cells will also be presented.

Maria Moreno Villanueva↗
NASA NTRS2016

A "Bony" Proposition: Pathways Mediating Responses to Simulated Weightlessness and Radiation

There is evidence that weightlessness and radiation, two elements of the spaceflight environment, can lead to detrimental changes in human musculoskeletal tissue, including bone loss and muscle atrophy. This bone loss is thought to be brought about by the increased activity of bone-resorbing osteoclasts and functional changes in bone-forming osteoblasts, cells that give rise to mature osteocytes. My current area of research focuses on understanding the mechanistic basis for the responses of bone to the spaceflight environment using earth-based animal and cellular models. The overarching goal is to identify molecular targets to prevent bone loss in space exploration and earth-based scenarios of radiotherapy, accidental radiation exposure and reduced mobility. In this talk, I will highlight two signaling pathways that potentially play a role in the response of bone to spaceflight-like conditions. Firstly, I will discuss the role of insulin-like growth factor 1 (IGF1) signaling as it pertains to the recovery of bone from simulated weightlessness (rodent hindlimb unloading model). Secondly, I will share recent findings from our study that aims to understand the emerging role of autophagy in maintaining the balance between bone formation and resorption (bone homeostasis) as well as normal skeletal structure.

autophagy↗
NASA NTRS1986

Regulation of Ca(2+)-dependent protein turnover in skeletal muscle by thyroxine

Dantrolene, an agent that inhibits Ca(2+) mobilization, improved protein balance in skeletal muscle, as thyroid status was increased, by altering rates of protein synthesis and degradation. Thyroxine (T4) caused increases in protein degradation that were blocked by leupeptin, a proteinase inhibitor previously shown to inhibit Ca(2+)-dependent nonlysosomal proteolysis in these muscles. In addition, T4 abolished sensitivity to the lysosomotropic agent methylamine and the autophagy inhibitor 3-methyladenine, suggesting that T4 inhibits autophagic/lysosomal proteolysis.

Zeman, Richard J.↗
NASA NTRS1987

Hypogravity-induced atrophy of rat soleus and extensor digitorum longus muscles

Prolonged exposure of humans to hypogravity causes weakening of their skeletal muscles. This problem was studied in rats exposed to hypogravity for 7 days aboard Spacelab 3. Hindlimb muscles were harvested 12-16 hours postflight for histochemical, biochemical, and ultrastructural analyses. The majority of the soleus and extensor digitorum longus fibers exhibited simple cell shrinkage. However, approximately 1% of the fibers in flight soleus muscles appeared necrotic. Flight muscle fibers showed increased glycogen, lower subsarcolemmal staining for mitochondrial enzymes, and fewer subsarcolemmal mitochondria. During atrophy, myofibrils were eroded by multiple focal losses of myofilaments; lysosomal autophagy was not evident. Tripeptidylaminopeptidase and calcium-activated protease activities of flight soleus fibers were significantly increased, implying a role in myofibril breakdown. Simple fiber atrophy appears to account for muscle weakening during spaceflight, but fiber necrosis is also a contributing factor.

manned↗