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Summary: Human expansion in space is hampered by the physiological risks of spaceflight. The muscle and the liver are among the most affected tissues during spaceflight and their relationships in response to space exposure have never been studied. We compared the transcriptome response of liver and quadriceps from mice on NASA RR1 mission, after 37 days of exposure to spaceflight using GSEA, ORA, and sparse partial least square-differential analysis. We found that lipid metabolism is the most affected biological process between the two organs. A specific gene cluster expression pattern in the liver strongly correlated with glucose sparing and an energy-saving response affecting high energy demand process gene expression such as DNA repair, autophagy, and translation in the muscle. Our results show that impaired lipid metabolism gene expression in the liver and muscle atrophy gene expression are two paired events during spaceflight, for which dietary changes represent a possible countermeasure.