Overexpression of Catalase in Mitochondria Mitigates the Inflammatory Effects of Simulated Microgravity and Social Isolation in Mouse Hippocampus

Abstract

Space flight missions are becoming longer and more common and evidence points to the physiological toll the missions have on the human body. Aging, sedentary lifestyle, and spaceflight have similar degenerative effects on almost every part of our body; both exposure to the space environment and aging result in cardiovascular deconditioning, bone loss, muscle atrophy, brain changes, and immune response impairment. We hypothesize that exposure to the space environment generates excessive Reactive Oxygen Species (ROS), which results in neuroinflammation and aging‐like degenerative symptoms in the brain. We used the hindlimb unloading (HU) model to mimic microgravity with either paired or single housed animals (social isolation). Responses to 30d of HU were compared in wildtype or transgenic MCAT mice, in which mitochondrial ROS is quenched by over‐expression of human catalase. Expression of 4‐Hydroxynonenal (4HNE) and Park7 (redox‐sensitive chaperone and sensor of oxidative stress) were measured by ELISA, a protein array quantified from the hippocampal cytokines and 8‐hydroxy‐2’‐deoxyguanosine in serum was measured by ELISA to assess oxidative DNA damage. Preliminary analysis of cage behavior patterns from video collected at the end of the study showed that MCAT HU mice (socially housed) were more active and conducted more exploratory activities compared to NL. Our biochemical results showed simulated microgravity and/or social isolation caused changes in levels of cytokines related to immune responses. Two‐way ANOVA revealed significant interaction effects of HU and genotype in expression levels of five cytokines (out of 35) in socially‐housed animals. Elevation of these generally pro‐inflammatory cytokines by HU in WT mice was mitigated in MCAT mice, suggesting a role for mitochondrial ROS signaling in inflammatory CNS responses to microgravity. Interestingly, some of these cytokines in the hippocampus displayed strong correlations to the 4HNE levels. We also found substantive cytokine responses to social isolation in the hippocampus; housing and genotype interaction effects were significant (by 2‐Factor ANOVA) for 15 cytokines, most of which were mitigated in MCAT mice.Taken together, our results showed that both simulated microgravity and social isolation influenced cytokine levels in the hippocampus and MCAT mice were at least partially protected from these changes. These findings implicate a potentially important role for mitochondrial ROS in CNS responses to the challenges posed by long duration spaceflight.Support or Funding InformationThis work is supported by a NASA Space Biology Grant to RKG (NNH14ZTT001N). LG was supported by a Space Biology NASA Postdoctoral Fellowship AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.