* Sonette Steczina, Candice G. T. Tahimic, Megan Pendleton, Ons M’Saad, Moniece Lowe, Joshua S. Alwood, Bernard P. Halloran, Ruth K. Globus & Ann-Sofie Schreurs
Scientific Reports 10, Article number: 6484 (2020) Published: 16 April 2020
“Spaceflight is a unique environment that includes at least two factors which can negatively impact skeletal health: microgravity and ionizing radiation. We have previously shown that a diet supplemented with dried plum powder (DP) prevented radiation-induced bone loss in mice. In this study, we investigated the capacity of the DP diet to prevent bone loss in mice following exposure to simulated spaceflight, combining microgravity (by hindlimb unloading) and radiation exposure. The DP diet was effective at preventing most decrements in bone micro-architectural and mechanical properties due to hindlimb unloading alone and simulated spaceflight. Furthermore, we show that the DP diet can protect osteoprogenitors from impairments resulting from simulated microgravity. Based on our findings, a dietary supplementation with DP could be an effective countermeasure against the skeletal deficits observed in astronauts during spaceflight.
“Alterations in the gravity vector and exposure to ionizing radiation can disrupt skeletal homeostasis in mice1,2,3. There are multiple stressors associated with spaceflight, including microgravity and radiation which are known to cause bone loss4,5,6. Decrements in bone mineral density (BMD) have been observed in astronauts from the Mir missions as well as missions to the International Space Station (ISS)7,8,9. While much research has focused on the detrimental effects of microgravity on skeletal tissue, less is known about the impact of spaceflight radiation. Crewed missions have, to this point, primarily remained within low-Earth orbit (LEO). While sources of ionizing space radiation within LEO include galactic cosmic radiation and charged particles from unpredictable solar particle events (SPE)10,11, the presence of the Earth’s magnetosphere reduces exposure to ionizing space radiation. Missions beyond LEO pose the greatest risk of radiation exposure and is of significant concern for crew health12,13,14. Spaceflight-relevant radiation includes a mix of low-linear energy transfer (LET) species such as protons and helium ions as well as high-LET species such as iron15,16. Beyond LEO, for example, astronauts may be exposed to up to 0.7 Sv of ionizing radiation12,15,17 during a multi-year mission to the Moon or Mars14,15,18.
“On Earth, bone homeostasis is effectively maintained by the controlled remodeling activity of bone-forming osteoblasts and bone-resorbing osteoclasts. However, exposure to low-LET radiation (137Cs or X-ray, 1–2 Gy) leads to a transient increase in the number of osteoclasts, accompanied by an increase in trabecular separation (Tb.Sp) and decrease in trabecular thickness (Tb.Th), overall leading to a reduction in bone volume fraction (BV/TV)19,20,21,22. Together, this early increase in bone resorption and decrease in bone formation due to radiation exposure can result in a state of osteopenia, potentially leading to an increased risk of bone fracture16,23,24. A possible mechanism of action responsible for these changes in bone homeostasis is the generation of reactive oxygen species (ROS) due to radiation exposure2,25. Furthermore, reduction of antioxidant defense mechanisms26,27 and activation of pro-inflammatory cytokines16,28 have been associated with altered redox-balance due to radiation exposure. Together, these critical changes in cellular signaling lead to compromised bone strength and increased fracture risk25,29. Due to the involvement of redox-signaling in radiation-induced bone loss, antioxidants have been considered as candidate countermeasures to mitigate spaceflight-induced bone loss30. Proposed mechanisms by which antioxidants exert protective effects include the quenching of ROS via an increase in antioxidant activity and decreasing pro-inflammatory signaling cascades29.
“Dried plum, Prunus domestica L., has been shown to have beneficial effects against bone loss31 (reviewed in Wallace et al. 2017). Dried plum’s positive effects on bone health markers have been investigated in multiple models of osteopenia, in both human clinical trials32,33,34,35,36 and rodent studies37,38. While the mechanism of action of dried plum is still unknown, it has been hypothesized that the high antioxidant capacity and high polyphenolic content of this fruit scavenges free-radicals as well as promotes bone formation and inhibits bone resorption39,40,41,42. Our lab has reported that mice fed a diet composed of Dried Plum (DP) prevented cancellous bone loss caused by ionizing radiation (IR), both low-LET such as gamma (137Cs) and a mixture of both low-LET and high-LET (sequential beam of proton, 1H and iron, 56Fe). The proposed mechanism for DP’s protective effect is via the prevention of radiation-induced increases in markers of bone resorption, inflammation and oxidative stress43.
“Since the spaceflight environment includes exposure to both IR and microgravity, we sought to extend our hypothesis that DP could be a countermeasure for both radiation- and microgravity-induced bone loss. The current literature indicates that simulated microgravity and IR each have detrimental effects on cancellous bone structure, although there is no consensus on whether simulated microgravity and IR cause additive or synergistic effects when combined20,44,45. Thus, more studies are needed to determine whether combining simulated microgravity and IR leads to cumulative effects compared to simulated microgravity and IR alone. Hindlimb unloading (HU) is widely used to simulate the effects of the microgravity environment in rodents46. This model allows for a simulation of the cephalad fluid shift47 and removal of load-bearing forces typically experienced by the hindlimbs, which can lead to increased numbers of bone-resorbing osteoclasts and decreased numbers of bone-forming osteoblasts48. Together, these events result in bone loss as well as reduced bone mechanical properties in rodents49,50,51,52. In addition, exposure to microgravity in mice adversely affects osteoprogenitors53,54. The bone marrow niche contains osteoblast progenitors cells4 and it has been shown that exposure to microgravity alters the cells proliferation capacity and impairs their ability to produce extracellular matrix, in turn inhibiting the maturation of the bone matrix. Thus, the ability to maintain bone homeostasis is diminished16,54,55,56.
“To address these knowledge gaps related to spaceflight-induced bone loss and candidate countermeasures, we sought to evaluate the potentially distinct effects of microgravity and ionizing radiation when applied independently, or in combination. For this study, we utilized the HU model and exposure to total body irradiation (137Cs gamma radiation, at 2 Gy dose) as analogs of weightlessness and radiation exposure, respectively. A relatively high dose of radiation (2 Gy) was chosen as a positive control dose to ensure bone loss in rodents and to allow for testing of DP as a countermeasure, as previously described43. We sought to determine whether DP diet prevents simulated microgravity-induced bone loss alone, and in combination with radiation, as compared to respective control diet controls. We also assessed the ability of DP to mitigate simulated weightlessness- and/or radiation-induced changes to the axial skeleton57, specifically the lumbar 4 (L4) vertebrae. We analyzed both cancellous and cortical bone microarchitecture as well as mechanical properties of skeletal tissue. Additionally, we determined whether the DP diet had the capacity to protect osteoprogenitors after exposure to simulated microgravity, an essential part in the healthy maintenance of skeletal tissue…”
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