Chronic Elevation of Skeletal Muscle [Ca] Impairs Glucose Uptake. An and Study.

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 concentration at rest [(Ca)] compromises glucose homeostasis in malignant hyperthermia muscle cells. To further investigate how chronic elevated muscle [Ca] modifies insulin-mediated glucose homeostasis, we measured [Ca] and glucose uptake and in intact polarized muscle cells from glucose-intolerant -p.R163C and db/db mice. Glucose-intolerant -p.R163C and db/db mice have significantly elevated muscle [Ca] 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 [Ca] and increased muscle glucose uptake compared to untreated -p.R163C and db/db mice. Furthermore, -p.R163C and db/db mice had abnormal basal insulin levels and response to glucose-stimulated insulin secretion. experiments conducted on single muscle fibers, dantrolene improved insulin-mediated glucose uptake in -p.R163C and db/db muscle fibers without affecting WT muscle fibers. In muscle cells with chronic elevated [Ca], 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] decreases insulin-stimulated glucose uptake and consequently causes hyperglycemia; ii) Reduced muscle [Ca] by dantrolene improves muscle glucose uptake and subsequent hyperglycemia; iii) The mechanism by which chronic high levels of [Ca] interfere with insulin action appears to involve the expression of GLUT4 and its subcellular fractionation.