BACKGROUND: While canonical anabolic and proteolytic pathways have been well examined in the context of skeletal muscle proteostasis, the roles of endoplasmic reticulum stress (ERS) and the induced unfolded protein response (UPR) are underappreciated. Thus, we aimed to determine whether aging and/or disuse atrophy in rats altered skeletal muscle ERS/UPR markers. METHODS AND RESULTS: Soleus (SOL) and plantaris (PLT) muscles of 3-month-old (mo), 6 mo, 12 mo, 18 mo, and 24 mo rats (9-10 per group, 48 in total) were analyzed for UPR proteins with further analysis performed on the protein CHOP. The gastrocnemius muscles of 4 mo rats that had undergone hindlimb immobilization (HLI, n = 12) or sham casting (CTL, n = 12) were analyzed for similar targets as well as more extensive CHOP-related targets. CHOP protein was greater in the PLT and SOL of 18 and 24 mo rats versus other age groups (P <
0.05). Moreover, negative correlations existed between CHOP expression and normalized PLT (R=-0.702, P <
0.001) and SOL (R=-0.658, P <
0.001) muscle weights in all rats analyzed at different ages. CHOP protein expression was also greater in the gastrocnemius of HLI versus CTL rats (P <
0.001), and a negative correlation existed between CHOP protein expression and normalized muscle weights in these rats (R=-0.814, P <
0.001). Nuclear CHOP protein levels (P <
0.010) and genes transcriptionally regulated by CHOP were also greater in HLI versus CTL rats (P <
0.001) implicating transcriptional activity of CHOP is elevated during disuse atrophy. CONCLUSIONS: CHOP is operative during aging- and disuse-induced skeletal muscle atrophy in rodents, and more research is needed to determine if CHOP is a key mechanistic driver of these processes.