Bone is a dynamic tissue that is constantly remodeling. However, for individuals requiring bed rest or astronauts exposed to microgravity in space, a lack of normal loaded activities leads to disuse osteoporosis. We examined whether knee loading increases bone mineral density (BMD) of both control and tail-suspended hindlimbs. We also examined whether the phosphorylation levels of Akt in phosphoinositide 3-kinase (PI3K) signaling and eukaryotic initiation factor 2α (eIF2α) in an integrated stress response (ISR) is altered in the loaded femur and tibia. Knee loading was applied to the right hindlimb using a custom-made piezoelectric mechanical loader. The BMD of control and tail-suspended hindlimbs was determined by PIXImus imaging, and Western blot analysis was performed to determine the phosphorylation levels of Akt and eIF2α. The results revealed that knee loading significantly increased the BMD in the loaded limb of tail-suspended mice. Compared to non-loaded limbs in the hindlimb-suspended mice, loaded limbs demonstrated a 6.6% increase in BMD. In the control group, the loaded limb showed a 7.4% increase in BMD over the non-loaded limb. Furthermore, knee loading activated PI3K signaling through the induction of Akt phosphorylation and reduced ISR by the suppression of eIF2α phosphorylation. The present study thus supports knee loading as a potential loading method of preventing the detrimental effects of disuse due to unloading.
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