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Introduction: Spaceflight is associated with substantial and variable musculoskeletal (MSK) adaptations. Characterisation of muscle and joint loading profiles can provide key information to better align exercise prescription to astronaut MSK adaptations upon return-to-Earth. A case-study is presented of single-leg hopping in hypogravity to demonstrate the additional benefit computational MSK modelling has when estimating lower-limb MSK loading. Methods: A single male participant performed single-leg vertical hopping whilst attached to a body weight support system to replicate five gravity conditions (0.17, 0.25, 0.37, 0.50, 1 g). Experimental joint kinematics, joint kinetics and ground reaction forces were tracked in a data-tracking direct collocation simulation framework. Ground reaction forces, sagittal plane hip, knee and ankle net joint moments, quadriceps muscle forces (Rectus Femoris and three Vasti muscles), and hip, knee and ankle joint reaction forces were extracted for analysis. Estimated quadriceps muscle forces were input into a muscle adaptation model to predict a meaningful increase in muscle cross-sectional area, defined in (DeFreitas et al., 2011). Results: Two distinct strategies were observed to cope with the increase in ground reaction forces as gravity increased. Hypogravity was associated with an ankle dominant strategy with increased range of motion and net plantarflexor moment that was not seen at the hip or knee, and the Rectus Femoris being the primary contributor to quadriceps muscle force. At 1 g, all three joints had increased range of motion and net extensor moments relative to 0.50 g, with the Vasti muscles becoming the main muscles contributing to quadriceps muscle force. Additionally, hip joint reaction force did not increase substantially as gravity increased, whereas the other two joints increased monotonically with gravity. The predicted volume of exercise needed to counteract muscle adaptations decreased substantially with gravity. Despite the ankle dominant strategy in hypogravity, the loading on the knee muscles and joint also increased, demonstrating this provided more information about MSK loading. Discussion: This approach, supplemented with muscle-adaptation models, can be used to compare MSK loading between exercises to enhance astronaut exercise prescription. [ABSTRACT FROM AUTHOR]