{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T20:10:55Z","timestamp":1790021455504,"version":"4.0.1"},"reference-count":42,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2021,8,1]]},"abstract":"<jats:p> Prolonged endoplasmic reticulum (ER) stress can mediate inflammatory myopathies and insulin signaling pathways. The double-stranded RNA (dsRNA)-activated protein kinase R (PKR) has been implicated in skeletal muscle dysfunction. However, pathological roles of PKR in ER stress in muscle are not fully understood. The current study aimed to investigate the effect of imoxin (IMX), a selective PKR inhibitor, on tunicamycin (TN)-induced promotion of ER stress and suppression of insulin signaling in C2C12 myotubes. Cells were pretreated with 5 \u00b5M IMX for 1\u2009h and exposed to 0.5\u2009\u00b5g\/mL TN for 23\u2009h. A subset of cells was stimulated with 100\u2009nM insulin for the last 15\u2009min. mRNA expression and protein levels involved in ER stress were measured by RT-PCR and Western blotting, respectively. TN significantly augmented PKR phosphorylation by 231%, which was prevented by IMX. In addition, IMX reduced mRNA and protein levels of ER stress-related markers, including CCAAT-enhancer-binding protein homologous protein (CHOP, mRNA: 95% decrease; protein: 98% decrease), activating transcription factor 4 (ATF4, mRNA: 69% decrease; protein: 99% decrease), cleavage of ATF6, and spliced X-box-binding protein 1 (XBP-1s, mRNA: 88% decrease; protein: 79% decrease), which were induced by TN. Furthermore, IMX ameliorated TN-induced suppression of phospho-insulin receptor \u03b2 (317% increase) and Akt phosphorylation (by 36% at Ser473 and 30% at Thr308) in myotubes, while augmenting insulin-stimulated AS160 phosphorylation and glucose uptake (by \u223c30%). These findings suggest that IMX may protect against TN-induced skeletal muscle ER stress and insulin resistance, which are potentially mediated by PKR. <\/jats:p>","DOI":"10.1152\/ajpcell.00544.2020","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T18:38:45Z","timestamp":1622659125000},"page":"C221-C229","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Imoxin inhibits tunicamycin-induced endoplasmic reticulum stress and restores insulin signaling in C2C12 myotubes"],"prefix":"10.1152","volume":"321","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1532-613X","authenticated-orcid":true,"given":"Hyeyoon","family":"Eo","sequence":"first","affiliation":[{"name":"Department of Kinesiology, Iowa State University, Ames, Iowa,"},{"name":"Interdepartmental Graduate Program in Nutritional Sciences, Iowa State University, Ames, 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