Aging and Spaceflight: Catalase targeted to mitochondria alters skeletal structure and responses to musculoskeletal disuse

Abstract

Accumulation of oxidative damage from excess reactive oxygen species (ROS) contributes to aging and also may mediate adverse tissue responses to the space environment. We aim to explore the importance of cellular redox defense for physiological adaptation and tissue degeneration during spaceflight or prolonged bedrest on Earth. To begin to test this, transgenic mice (male, 16 weeks of age) with human catalase targeted to mitochondria (mCAT), and wildtype (WT) littermates were analysed for responsiveness to a combination of hindlimb unloading (to simulate weightlessness) and a single dose of ionizing radiation (137Cs, 0.83 Gy/min, 2Gy); mCAT mice are known to display improved longevity and reduced age‐related diseases compared to WT mice (Schriner et al. 2005, Dai et al. 2010). After 2 weeks, bones were recovered for analysis of cell behavior (osteoblast and osteoclast differentiation ex vivo from bone marrow cells), oxidative lipid damage (malondialdehyde, 4‐hydroxynonenol) and structure (3D microcomputed tomography). mCAT mice expressed the catalase transgene in skeletal tissues, and in cultured marrow‐derived osteoblasts and pre‐osteoclasts. Treatment with unloading and radiation led to increased lipid oxidative damage markers in bones from WT mice but not mCAT mice, showing that transgene expression effectively mitigated oxidative damage. Ex vivo osteoblast colony growth rate was 95% greater in mCAT mice than WT, and correlated with catalase activity levels (P<0.005, r=0.6679), though terminal differentiation of osteoblasts (mineralization) and osteoclasts (resorption pit formation) remained unaffected. Microarchitectural analysis of high turnover, cancellous tissue revealed diminished size of mCAT bones compared to WT (−16% bone volume/total volume mCAT/WT), and no genotype‐dependent difference in cancellous bone loss caused by treatment. Similarly, slow‐turnover, cortical bones were smaller in control mCAT mice (−7% cortical area), although treatment of mCAT mice showed an unexpected and rapid stimulation of radial expansion (+8% cortical area, +22% moment of inertia, mCAT:Treated/Control), which was not observed in WT mice. Thus, quenching of mitochondrial ROS by over‐expression of catalase appeared to stimulate growth but not differentiation of osteoprogenitors ex vivo; nonetheless, the smaller size of mCAT bones showed that mitochondrial ROS signaling was important for the acquisition of adult bone structure. Further, we conclude that transgene expression led to changes in cortical structure following treatment that are similar to those that occur during aging, indicative of a role for mitochondrial ROS in coordinating skeletal remodeling in response to challenge.Support or Funding InformationGrant funding from NASA Space Biology program (NNH14ZTT001N) and the National Space Biomedical Research Institute through NCC 9–58, Project MA02501. A.S. Schreurs was supported by a NASA Space Biology Postdoctoral Program Fellowship award.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.