Aim
Altered mitochondrial function across various tissues is a key determinant of spaceflight‐induced physical deconditioning. In comparison to tissue biopsies, blood cell bioenergetics holds promise ...as a systemic and more readily accessible biomarker, which was evaluated during head‐down tilt bed rest (HDTBR), an established ground‐based analog for spaceflight‐induced physiological changes in humans. More specifically, this study explored the effects of HDTBR and an exercise countermeasure on mitochondrial respiration in peripheral blood mononuclear cells (PBMCs).
Methods
We subjected 24 healthy participants to a strict 30‐day HDTBR protocol. The control group (n = 12) underwent HDTBR only, while the countermeasure group (n = 12) engaged in regular supine cycling exercise followed by veno‐occlusive thigh cuffs post‐exercise for 6 h. We assessed routine blood parameters 14 days before bed rest, the respiratory capacity of PBMCs via high‐resolution respirometry, and citrate synthase activity 2 days before and at day 30 of bed rest. We confirmed PBMC composition by flow cytometry.
Results
The change of the PBMC maximal oxidative phosphorylation capacity (OXPHOS) amounted to an 11% increase in the countermeasure group, while it decreased by 10% in the control group (p = 0.04). The limitation of OXPHOS increased in control only while other respiratory states were not affected by either intervention. Correlation analysis revealed positive associations between white blood cells, lymphocytes, and basophils with PBMC bioenergetics in both groups.
Conclusion
This study reveals that a regular exercise countermeasure has a positive impact on PBMC mitochondrial function, confirming the potential application of blood cell bioenergetics for human spaceflight.
Gravitropism and phototropism play a primary role in orienting root growth. Tropistic responses of roots mediated by gravity and light have been extensively investigated, and a complex mutual ...interaction occurs between these two tropisms. To date, most studies have been conducted in 1 g, microgravity, or simulated microgravity, whereas no studies investigated root phototropism in hypergravity. Therefore, we studied the effects of several gravity treatments with those of different light wavelengths on root growth orientation. Here, we report growth and curvature of Brassica oleracea roots under different g levels, from simulated microgravity up to 20 g, and unilateral illumination with different spectral treatments provided by light emitting diodes. Microgravity was simulated with a random positioning machine whereas hypergravity conditions were obtained using the Large Diameter Centrifuge at the laboratories of the European Space Agency in the Netherlands. Four light treatments (white light, blue light, red light, and dark) were used in this study. Overall, roots of seedlings grown in the dark were longer than those developed under unilateral light treatments, regardless of the gravity level. Unilateral blue light or white light stimulated a negative phototropism of roots under all g levels, and root curvature was not affected by either hypergravity or simulated microgravity compared to 1 g. Results also confirmed previous findings on the effect of light intensity on root curvature and highlighted the relevance of blue-light photon flux density in root phototropism. Roots illuminated with red light showed a weak curvature in simulated microgravity but not in hypergravity. Moreover, root curvature under red light was similar to dark-grown roots in all g levels, suggesting a possible involvement of surface-dependent phenomena in root skewing under either red light or dark conditions. Further studies can confirm phototropic responses of B. oleracea in the weightless environment of orbiting spacecraft. Nevertheless, according to our findings, directional lighting represents an effective stimulus to guide root growth in a wide range of gravity conditions.
•Blue or white light stimulated a negative phototropism in Brassica oleracea roots.•Hypergravity and simulated microgravity did not affect root phototropic responses to blue or white light.•Increasing blue-photon flux in the range of ≈ 10–80 μmol m−2 s−1 did not affect root curvature.•Roots under red light or dark conditions showed a weak curvature in simulated microgravity but not hypergravity.
In nematode Caenorhabditis elegans, an intestinal signaling cascade in canonical Wnt/β-catenin signaling pathway, including β-catenin transcriptional factor BAR-1, has been identified to be involved ...in the control of response to simulated microgravity. However, the downstream target(s) of BAR-1 in regulating the response to simulated microgravity are still unclear. In this study, we found that BAR-1 and its direct target of Wnt effector POP-1 functioned upstream of a Meis TALE-class transcription factor UNC-62 to regulate the response to simulated microgravity. Moreover, UNC-62 regulated the response to simulated microgravity by suppressing the function of FOXO transcriptional factor DAF-16 and its target (mitochondrial Mn-SOD/SOD-3) in insulin signaling pathway. Therefore, canonical Wnt/β-catenin signaling mediates a protective intestinal response to simulated microgravity by inducing a nucleus-mitochondria communication. Our results provide an important molecular basis for intestinal Wnt/β-catenin signaling in response to simulated microgravity in organisms.
•We examined molecular basis of Wnt/β-catenin BAR-1 in response to microgravity stress.•Both BAR-1 and Wnt effector POP-1 were required the response to microgravity stress.•UNC-62-DAF-16 acted downstream of BAR-1 and POP-1 to regulate microgravity stress.•BAR-1-POP-1-UNC-62-DAF-16 activated the activity of SOD-3, a mitochondrial Mn-SOD.
Due to short life cycle, nematode Caenorhabditis elegans is a suitable animal model for assessing the effect of long-term simulated microgravity treatment on organisms. We here investigated the ...effect of simulated microgravity treatment for 24-h on development and functional state of intestinal barrier in nematodes. Simulated microgravity treatment not only caused a broadened intestinal lumen, but also enhanced intestinal permeability. Intestinal overexpression of SOD-2, a mitochondrial Mn-SOD protein, prevented the damage on functional state of intestinal barrier by simulated microgravity and induced a resistance to toxicity of simulated microgravity, suggesting the crucial role of oxidative stress in inducing the damage on functional state of intestinal barrier in simulated microgravity treated nematodes. For the molecular basis of damage on functional state of intestinal barrier, we observed significant decrease in expressions of some genes (acs-22, erm-1, and hmp-2) required for maintenance of functional state of intestinal barrier in simulated microgravity treated nematodes. Our results highlight the potential of long-term simulated microgravity treatment in inducing intestinal damage in animals.
•Simulated microgravity treatment for 24-h resulted in the intestinal damage.•Simulated microgravity affected functional state of intestinal barrier.•Oxidative stress plays crucial role in inducing intestinal damage by simulated microgravity.•Simulated microgravity dysregulated genes required for intestinal barrier maintenance.•Our data highlights potential of long-term microgravity in inducing the intestinal damage.
Spaceflight exposure, like prolonged skeletal unloading, is known to result in significant bone loss, but the molecular mechanisms responsible are still partly unknown. This impairment, ...characterizing both conditions, suggests the possibility of identifying common signalling pathways and developing innovative treatment strategies to counteract the bone loss typical of astronauts and osteoporotic patients. In this context, primary cell cultures of human osteoblasts derived from healthy subjects and osteoporotic patients were exposed to random positioning machine (RPM) to reproduce the absence of gravity and to exacerbate the pathological condition, respectively. The duration of exposure to RPM was 3 or 6 days, with the aim of determining whether a single administration of recombinant irisin (r-irisin) could prevent cell death and mineralizing capacity loss. In detail, cellular responses were assessed both in terms of death/survival, by MTS assay, analysis of oxidative stress and caspase activity, as well as the expression of survival and cell death proteins, and in terms of mineralizing capacity, by investigating the pentraxin 3 (PTX3) expression. Our results suggest that the effects of a single dose of r-irisin are maintained for a limited time, as demonstrated by complete protection after 3 days of RPM exposure and only partial protection when RPM exposure was for a longer time. Therefore, the use of r-irisin could be a valid strategy to counteract the bone mass loss induced by weightlessness and osteoporosis. Further studies are needed to determine an optimal treatment strategy based on the use of r-irisin that is fully protective even over very long periods of exposure and/or to identify further approaches to be used in a complementary manner.
Caenorhabditis elegans is an important in vivo assay system for toxicological studies. Herein, we investigated the role of oxidative stress and the underlying molecular mechanism for induced adverse ...effects of simulated microgravity. In nematodes, simulated microgravity treatment induced a significant induction of oxidative stress. Genes (mev-1, gas-1, and isp-1) encoding a molecular machinery for the control of oxidative stress were found to be dysregulated in simulated microgravity treated nematodes. Meanwhile, genes (sod-2, sod-3, sod-4, sod-5, aak-2, skn-1, and gst-4) encoding certain antioxidant defense systems were increased in simulated microgravity treated nematodes. Mutation of mev-1, gas-1, sod-2, sod-3, aak-2, skn-1, or gst-4 enhanced susceptibility to oxidative stress induced by simulated microgravity, whereas mutation of isp-1 induced a resistance to oxidative stress induced by simulated microgravity. Mutation of sod-2, sod-3, or aak-2 further suppressed the recovery effect of simulated microgravity toxicity in nematodes after simulated microgravity treatment for 1h. Moreover, administration of ascorbate could inhibit the adverse effects including the induction of oxidative stress in simulated microgravity treated nematodes. Mutation of any of the genes encoding metallothioneins or the genes of hsp-16.1, hsp-16.2 and hsp-16.48 encoding heat-shock proteins did not affect the induction of oxidative stress in simulated microgravity treated nematodes. Our results provide a molecular basis for the induction of oxidative stress in simulated microgravity treated organisms.
Simulated microgravity induced an induction of oxidative stress by dysregulating the ROS and antioxidant-related genes. Meanwhile, simulated microgravity activated the antioxidation defense system to be against its adverse effects in nematodes. Display omitted
•Simulated microgravity induced induction of oxidative stress in nematodes.•Molecular machinery for oxidative stress was dysregulated by simulated microgravity.•Antioxidation defense system was dysregulated by simulated microgravity.•Mutation of certain genes enhanced susceptibility to simulated microgravity.•sod-2 or sod-3 mutation suppressed recovery of simulated microgravity toxicity.
Many of the activities associated with spaceflight require individuals to coordinate actions between the limbs (e.g., controlling a rover, landing a spacecraft). However, research investigating the ...influence of gravity on bimanual coordination has been limited. The current experiment was designed to determine an individual's ability to adapt to altered-gravity when performing a complex bimanual force coordination task, and to identify constraints that influence coordination dynamics in altered-gravity. A tilt table was used to simulate gravity on Earth 90° head-up tilt (HUT) and microgravity 6° head-down tilt (HDT). Right limb dominant participants (
= 12) were required to produce 1:1 in-phase and 1:2 multi-frequency force patterns. Lissajous information was provided to guide performance. Participants performed 14, 20 s trials at 90° HUT (Earth). Following a 30-min rest period, participants performed, for each coordination pattern, two retention trials (Earth) followed by two transfer trials in simulated microgravity (6° HDT). Results indicated that participants were able to transfer their training performance during the Earth condition to the microgravity condition with no additional training. No differences between gravity conditions for measures associated with timing (interpeak interval ratio, phase angle slope ratio) were observed. However, despite the effective timing of the force pulses, there were differences in measures associated with force production (peak force, STD of peak force mean force). The results of this study suggest that Lissajous displays may help counteract manual control decrements observed during microgravity. Future work should continue to explore constraints that can facilitate or interfere with bimanual control performance in altered-gravity environments.
The human cardiovascular system has evolved to accommodate the gravity of Earth. Microgravity during spaceflight has been shown to induce vascular remodeling, leading to a decline in vascular ...function. The underlying mechanisms are not yet fully understood. Our previous study demonstrated that miR‐214 plays a critical role in angiotensin II‐induced vascular remodeling by reducing the levels of Smad7 and increasing the phosphorylation of Smad3. However, its role in vascular remodeling evoked by microgravity is not yet known. This study aimed to determine the contribution of miR‐214 to the regulation of microgravity‐induced vascular remodeling. The results of our study revealed that miR‐214 expression was increased in the forebody arteries of both mice and monkeys after simulated microgravity treatment. In vitro, rotation‐simulated microgravity‐induced VSMC migration, hypertrophy, fibrosis, and inflammation were repressed by miR‐214 knockout (KO) in VSMCs. Additionally, miR‐214 KO increased the level of Smad7 and decreased the phosphorylation of Smad3, leading to a decrease in downstream gene expression. Furthermore, miR‐214 cKO protected against simulated microgravity induced the decline in aorta function and the increase in stiffness. Histological analysis showed that miR‐214 cKO inhibited the increases in vascular medial thickness that occurred after simulated microgravity treatment. Altogether, these results demonstrate that miR‐214 has potential as a therapeutic target for the treatment of vascular remodeling caused by simulated microgravity.
Youyou Li et al. demonstrate that microgravity elevates miR‐214 levels in VSMCs to downregulate Smad7 expression, thereby disinhibiting Smad2/3 signaling, which causes upregulation of collagen I and TNF‐α in VSMCs, which likely contributes to the development of vascular stiffness, hypertrophy, fibrosis, and inflammation in microgravity‐induced orthostatic intolerance.
Human space travel and exploration are of interest to both the industrial and scientific community. However, there are many adverse effects of spaceflight on human physiology. In particular, there is ...a lack of understanding of the extent to which microgravity affects the immune system. T cells, key players of the adaptive immune system and long-term immunity, are present not only in blood circulation but also reside within the tissue. As of yet, studies investigating the effects of microgravity on T cells are limited to peripheral blood or traditional 2D cell culture that recapitulates circulating blood. To better mimic interstitial tissue, 3D cell culture has been well established for physiologically and pathologically relevant models. In this work, we utilize 2D cell culture and 3D collagen matrices to gain an understanding of how simulated microgravity, using a random positioning machine, affects both circulating and tissue-resident T cells. T cells were studied in both resting and activated stages. We found that 3D cell culture attenuates the effects of simulated microgravity on the T cells transcriptome and nuclear irregularities compared to 2D cell culture. Interestingly, simulated microgravity appears to have less effect on activated T cells compared to those in the resting stage. Overall, our work provides novel insights into the effects of simulated microgravity on circulating and tissue-resident T cells which could provide benefits for the health of space travellers.
Skin and its cell components continuously subject to extrinsic and intrinsic mechanical forces and are mechanical sensitive. Disturbed mechanical homeostasis may lead to changes in skin functions. ...Gravity is the integral mechanical force on the earth, however, how gravity contributes to the maintenance of skin function and how microgravity in space affects the wound healing are poorly understood. Here, using microgravity analogs, we show that simulated microgravity (SMG) inhibits the healing of cutaneous wound and the accumulation of dermal fibroblasts in the wound bed. In vitro, SMG inhibits the migration of human foreskin fibroblast cells (HFF‐1), and decreases the F‐actin polymerization and YAP (yes‐associated protein) activity. The SMG‐inhibited migration can be recovered by activating YAP or F‐actin polymerization using lysophosphatidic acid (LPA) or jasplakinolide (Jasp), suggesting the involvement of F‐actin/YAP signaling pathway in this process. In SMG rats, LPA treatment improves the cutaneous healing with increased dermal fibroblasts in the wound bed. Together, our results demonstrate that SMG attenuates the cutaneous wound healing by inhibiting dermal fibroblast migration, and propose the crucial role of F‐actin/YAP mechano‐transduction in the maintenance of skin homeostasis under normal gravity, and YAP as a possible therapeutic target for the skin care of astronauts in space.
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