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This situation of unloading and reloading influences human physiology, and readaptation to full weight\u2010bearing may significantly impact astronauts' health. On Earth, similar situations can be observed in patients who are bedridden or suffer from sport\u2010related injuries. However, our knowledge of male physiology far exceeds our knowledge of female's, which creates an important gap that needs to be addressed to understand the sex\u2010based differences regarding musculoskeletal adaptation to unloading and reloading, necessary to preserve health of both sexes. Using a ground\u2010based model of total unloading for 14\u2009days and reloading at full weight\u2010bearing for 7\u2009days rats, we aimed to compare the musculoskeletal adaptations between males and females. Our results reveal the existence of significant differences. Indeed, males experienced bone loss both during the unloading and the reloading period while females did not. During simulated microgravity, males and females showed comparable muscle deconditioning with a significant decline in rear paw grip strength. However, after 7\u2009days of recovery, muscle strength improved. 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