Suppression of endoplasmic reticulum stress prevents disuse muscle atrophy in a mouse model of microgravity

Background: Hind-limb unloaded (HLU) mouse model exhibits skeletal muscle atrophy and weakness mimicking the conditions such as prolonged spaceflight. However, the molecular mechanisms and interventions of muscle loss during muscle unloading remain elusive. Dysfunction of protein folding by ednoplasmic reticulum (ER), a condition called ER stress, is implicated in diseases of various cell types, but its contribution to skeletal muscle detriment remains elusive. In this study, we investigated the contribution of ER stress to muscle atrophy.Methods: Sixteen-week-old c57BL/6j male mice were grouped into ground-based controls and HLU group, which was subsequently injected with injected saline (HLU-sal.) or pan-ER stress inhibitor 4-PBA (100mg/kg/d; HLU4PBA) via intraperitoneal injections for three weeks.Results: Three weeks of HLU resulted in reduction in muscle mass and strength, which were restored with 4PBA injections. We also report myofibers atrophy, myonuclear apoptosis, and aterations in the expressions of genes associated with ER stress, apoptosis, and calcium dysregulation. These findings were reversed by 4-PBA treatment.Conclusion: Altogether, our results indicate that ER stress contributes to muscle atrophy in HLU conditions. We suggest that blocking ER stress may be an effective pharmacological therapy to prevent muscle weakness and atrophy during prolonged muscle unloading.