Uryash Arkady, Mijares Alfredo, Lopez Carlos E, Adams Jose A, Lopez Jose R
Division of Neonatology, Mount Sinai Medical Center, Miami Beach, FL, United States.
Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela.
Front Physiol. 2022 Apr 25;13:872624. doi: 10.3389/fphys.2022.872624. eCollection 2022.
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.
骨骼肌是胰岛素介导的全身葡萄糖摄取的主要部位，因此是维持葡萄糖稳态的重要贡献者。我们最近提供的证据表明，静息时细胞内钙浓度长期升高[（Ca）]会损害恶性高热肌肉细胞中的葡萄糖稳态。为了进一步研究慢性升高的肌肉[Ca]如何改变胰岛素介导的葡萄糖稳态，我们测量了葡萄糖不耐受的-p.R163C和db/db小鼠完整极化肌肉细胞中的[Ca]和葡萄糖摄取。与野生型（WT）肌肉细胞相比，葡萄糖不耐受的-p.R163C和db/db小鼠的肌肉[Ca]显著升高，肌肉葡萄糖摄取减少。与未治疗的-p.R163C和db/db小鼠相比，丹曲林治疗（腹腔注射1.5mg/kg，持续2周）导致空腹血糖水平和肌肉[Ca]显著降低，并增加了肌肉葡萄糖摄取。此外，-p.R163C和db/db小鼠的基础胰岛素水平以及对葡萄糖刺激的胰岛素分泌反应异常。在单根肌纤维上进行的实验表明，丹曲林改善了-p.R163C和db/db肌纤维中胰岛素介导的葡萄糖摄取，而不影响WT肌纤维。在[Ca]长期升高的肌肉细胞中，葡萄糖转运蛋白4（GLUT4）的表达显著降低，与WT相比，亚细胞部分（质膜/细胞质）异常。本研究结果表明：i）慢性升高的肌肉[Ca]会降低胰岛素刺激的葡萄糖摄取，从而导致高血糖；ii）丹曲林降低肌肉[Ca]可改善肌肉葡萄糖摄取及随后的高血糖；iii）慢性高水平[Ca]干扰胰岛素作用的机制似乎涉及GLUT4的表达及其亚细胞分级。
