Overview
Simulated Space Radiation and Weightlessness: Vascular-Bone Coupling Mechanisms to Preserve Skeletal Health
Principal Investigator:
Ruth Globus, Ph.D.
Organization:
NASA Ames Research Center
Technical Summary
Long term spaceflight leads to extensive changes in the musculoskeletal system attributable to unloading in microgravity, although with future exploration outside the protection of Earth's magnetosphere space radiation also may have adverse, long-term effects. Acute, whole body irradiation at high doses can cause significant depletion of stem/progenitor cell pools throughout the body as well as inflammation associated with prompt tissue degradation. To date, little is known about the combined effects of weightlessness and space radiation on the musculoskeletal system and its associated vasculature. Radiation can increase cancellous osteoclasts, leading to rapid bone loss, which can be mitigated in the short term by treatment with a potent anti-oxidant (α-lipoic acid). Furthermore, simulated weightlessness in adult mice exacerbates the adverse effects of space-relevant radiation on cancellous tissue, mechanical properties and osteoprogenitors, as well as long-term responses during recovery from disuse. If weightlessness undermines the capacity to mount radio-protective mechanisms, then potentially irreversible oxidative injury and persistent skeletal damage to stem and progenitor populations may ensue. Deficits in vascular-perfusion coupling also can lead to profound bone loss and may contribute to spaceflight-induced osteopenia. Together, these findings support a two-pronged approach for countermeasure development; one focusing on preventing acute bone loss and another on protecting cell populations needed for skeletal remodeling in the long term.
The researchers long-term goals are twofold; define the mechanisms and risk of bone loss in the spaceflight environment and facilitate the development of effective countermeasures if needed.
Hypothesis
Prolonged musculoskeletal disuse and radiation together cause cumulative, adverse changes in the structure and function of bone and its vasculature resulting from oxidative stress, and prevent recovery from unloading by damaging the stem and progenitor cells needed for subsequent recovery.
The rationale for this research is that a better understanding of the mechanisms and long-term risks posed by exposure to weightlessness and space radiation will improve the development and application of countermeasures for future exploration-class missions.
Key Findings
Progress has been made on multiple fronts during the first year of the grant. The researchers have confirmed structural and cellular phenotypes with previous results. Work remains to study the cellular and molecular mechanisms in more detail and to investigate how antioxidants can effectively modulate skeletal radioresponses. The following provides a summary of key findings:
Bone Structure and Vascular Reactivity Acute Effects
• Radiation-induced bone loss results above a cumulative dose of 100 cGy from low- or high-LET ion constituents.
• Vasodilation responses to acetylcholine were diminished in gastrocnemius muscle feed arteries in hindlimb unloaded and irradiated mice relative to that in control animals. The combined effects of hindlimb unloading and irradiation did not further depress endothelium-dependent vasodilation.
Simulated Spaceflight Effects on Osteoblast Cell Cultures
• These results suggest that osteoprogenitor growth from marrow progenitors may be impaired above a threshold dose of heavy-ions between 20 and 50 cGy.
These experiments inform the radiation doses and duration of hindlimb unloading to be utilized in future work, as part of Milestone 1, 2 and 3 of the grant proposal, and to establish treatment schedules to modulate bone structure and vascular reactivity.
In the coming year, the researchers plan to test antioxidant countermeasures to radiation-induced bone loss and to protect osteoprogenitors. Pilot studies will be conducted at ARC and NSRL/BNL to establish the efficacy of different antioxidant compounds and additional experiments will be conducted to investigate if simulated space-irradiation affects vascular reactivity, responses to unloading, and oxidative mechanisms.