{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T18:20:58Z","timestamp":1774376458142,"version":"3.50.1"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T00:00:00Z","timestamp":1650844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Skeletal muscle is the primary site of insulin-mediated glucose uptake through the body and, therefore, an essential contributor to glucose homeostasis maintenance. We have recently provided evidence that chronic elevated intracellular Ca<jats:sup>2+<\/jats:sup> concentration at rest [(Ca<jats:sup>2+<\/jats:sup>)<jats:sub>i<\/jats:sub>] compromises glucose homeostasis in malignant hyperthermia muscle cells. To further investigate how chronic elevated muscle [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> modifies insulin-mediated glucose homeostasis, we measured [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and glucose uptake <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> in intact polarized muscle cells from glucose-intolerant <jats:italic>RYR1<\/jats:italic>-p.R163C and db\/db mice. Glucose-intolerant <jats:italic>RYR1<\/jats:italic>-p.R163C and db\/db mice have significantly elevated muscle [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and reduced muscle glucose uptake compared to WT muscle cells. Dantrolene treatment (1.5\u00a0mg\/kg IP injection for 2\u00a0weeks) caused a significant reduction in fasting blood glucose levels and muscle [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and increased muscle glucose uptake compared to untreated <jats:italic>RYR1<\/jats:italic>-p.R163C and db\/db mice. Furthermore, <jats:italic>RYR1<\/jats:italic>-p.R163C and db\/db mice had abnormal basal insulin levels and response to glucose-stimulated insulin secretion. <jats:italic>In vitro<\/jats:italic> experiments conducted on single muscle fibers, dantrolene improved insulin-mediated glucose uptake in <jats:italic>RYR1<\/jats:italic>-p.R163C and db\/db muscle fibers without affecting WT muscle fibers. In muscle cells with chronic elevated [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, GLUT4 expression was significantly lower, and the subcellular fraction (plasma membrane\/cytoplasmic) was abnormal compared to WT. The results of this study suggest that i) Chronic elevated muscle [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> decreases insulin-stimulated glucose uptake and consequently causes hyperglycemia; ii) Reduced muscle [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> by dantrolene improves muscle glucose uptake and subsequent hyperglycemia; iii) The mechanism by which chronic high levels of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> interfere with insulin action appears to involve the expression of GLUT4 and its subcellular fractionation.<\/jats:p>","DOI":"10.3389\/fphys.2022.872624","type":"journal-article","created":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T13:22:57Z","timestamp":1650892977000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Chronic Elevation of Skeletal Muscle [Ca2+]i Impairs Glucose Uptake. 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