Various cellular insults such as radiation, nutrient deprivation, hypoxia, and stress to the endoplasmic reticulum induce integrated stress responses (ISR), which activate phosphorylation of eukaryotic initiation factor 2 - subunitα (eIF2α). This activation of eIF2α phosphorylation decreases translational efficiency of a majority of proteins for preventing stress-driven apoptosis. In the present study, we addressed a pair of questions: Does mechanical loading or unloading activate phosphorylation of eIF2α? If yes, is GCN2 (general control repressed 2) responsible for its phosphorylation? To answer those questions, we employed C57BL/6 wildtype and GCN2 knockout mice and applied ankle loading and hindlimb suspension. The Western blotting results using loaded and unloaded tibia samples revealed that loading reduced the level of eIF2α phosphorylation regardless of the presence of GCN2 gene, while unloading elevated its phosphorylation. These results suggest that unloading is a unique form of integrated stress source, while appropriate loading can be its suppressor.