BACKGROUND: Aging dampens the ability of skeletal muscle to respond to stimuli and is a key driver in dysregulated proteostasis. Such dysfunction can lead to an accumulation of truncated, improperly translated, or otherwise misfolded proteins. The accumulation of these proteins can result in endoplasmic reticulum stress (ERS) and trigger the unfolded protein response (UPR). The chief function of the UPR is to blunt global translation while enhancing the production of chaperones and foldases. While ERS responses have been examined in certain age contexts, the expression of ERS related proteins have not been examined across the lifespan. Therefore, the purpose of this study was to examine the basal expression of ERS and UPR effector proteins across the lifespan in a cohort of rats. METHODS: Fischer 344 rats were sacrificed at 3, 6, 12, 18, and 24 months (mo) of age, whereafter plantaris and soleus muscles were collected for analysis. ERS and UPR effector proteins were examined via western blotting, and all data were normalized to 3 mo and expressed as fold change. Data were checked for normality via Shapiro-Wilk tests and one-way ANOVAs were performed with Tukey post-hoc tests. RESULTS: The ER chaperone binding immunoglobulin protein (BiP) was significantly different across the lifespan in both plantaris and soleus (P<0.001) with 24 mo rats being lower than 3 mo in plantaris and soleus (P<0.001). The translation inhibitor eukaryotic initiation factor 2 alpha (eIF2α) was different across the lifespan (phospho/pan) in both muscles (P<0.001) and was upregulated in the plantaris as compared to 3 mo (P=0.006). The apoptosis signaling protein and downstream UPR effector C/EBP homologous protein (CHOP) was differentially expressed across the lifespan in plantaris and soleus (P<0.001). CHOP was upregulated ~2.79 and 3.08-fold at 18 and 24 mo respectively in the soleus (P<0.001), and 2.62 and 2.44-fold at 18 and 24 mo respectively in the plantaris. Finally, principal effector Activating Transcription Factor 6 (ATF6) was differentially expressed across the lifespan (cleaved/pan) in the plantaris and the soleus (P≤0.024). ATF6 was upregulated 1.23-fold at 18 mo in the soleus (P=0.035) and 1.34-fold at 18 mo in the plantaris (P=0.026). CONCLUSIONS: Effectors of the UPR are upregulated across the lifespan. Given the global maladaptation of aging, this represents a potential avenue for further research and therapeutics.

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