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- Title
Chronic Elevation of Skeletal Muscle [Ca<sup>2+</sup>]<sub>i</sub> Impairs Glucose Uptake. An in Vivo and in Vitro Study.
- Authors
Uryash, Arkady; Mijares, Alfredo; Lopez, Carlos E.; Adams, Jose A.; Lopez, Jose R.
- Abstract
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 Ca2+ concentration at rest [(Ca2+)i] compromises glucose homeostasis in malignant hyperthermia muscle cells. To further investigate how chronic elevated muscle [Ca2+]i modifies insulin-mediated glucose homeostasis, we measured [Ca2+]i and glucose uptake in vivo and in vitro in intact polarized muscle cells from glucose-intolerant RYR1 -p.R163C and db/db mice. Glucose-intolerant RYR1 -p.R163C and db/db mice have significantly elevated muscle [Ca2+]i and reduced muscle glucose uptake compared to WT muscle cells. Dantrolene treatment (1.5 mg/kg IP injection for 2 weeks) caused a significant reduction in fasting blood glucose levels and muscle [Ca2+]i and increased muscle glucose uptake compared to untreated RYR1 -p.R163C and db/db mice. Furthermore, RYR1 -p.R163C and db/db mice had abnormal basal insulin levels and response to glucose-stimulated insulin secretion. In vitro experiments conducted on single muscle fibers, dantrolene improved insulin-mediated glucose uptake in RYR1 -p.R163C and db/db muscle fibers without affecting WT muscle fibers. In muscle cells with chronic elevated [Ca2+]i, 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 [Ca2+]i decreases insulin-stimulated glucose uptake and consequently causes hyperglycemia; ii) Reduced muscle [Ca2+]i by dantrolene improves muscle glucose uptake and subsequent hyperglycemia; iii) The mechanism by which chronic high levels of [Ca2+]i interfere with insulin action appears to involve the expression of GLUT4 and its subcellular fractionation.
- Subjects
SKELETAL muscle; GLUCOSE; BLOOD sugar; SUBCELLULAR fractionation; MUSCLE cells
- Publication
Frontiers in Physiology, 2022, Vol 13, p1
- ISSN
1664-042X
- Publication type
Article
- DOI
10.3389/fphys.2022.872624