Impairment of Glucose Uptake Induced by Elevated Intracellular Ca<sup>2+</sup> in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice
Malignant hyperthermia (MH) is a genetic disorder triggered by depolarizing muscle relaxants or halogenated inhalational anesthetics in genetically predisposed individuals who have a chronic elevated intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i&l...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-11-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/13/22/1888 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Malignant hyperthermia (MH) is a genetic disorder triggered by depolarizing muscle relaxants or halogenated inhalational anesthetics in genetically predisposed individuals who have a chronic elevated intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) in their muscle cells. We have reported that the muscle dysregulation of [Ca<sup>2+</sup>]<sub>i</sub> impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca<sup>2+</sup>]<sub>i</sub> and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice. The [Ca<sup>2+</sup>]<sub>i</sub> was recorded using a Ca<sup>2+</sup>-selective microelectrode, and the glucose uptake was assessed utilizing the fluorescent glucose analog 2-NBDG. The MH-R163C hippocampal neurons exhibited elevated [Ca<sup>2+</sup>]<sub>i</sub> and impaired insulin-dependent glucose uptake compared with the WT neurons. Additionally, exposure to isoflurane exacerbated these deficiencies in the MH-R163C neurons, while the WT neurons remained unaffected. Lowering [Ca<sup>2+</sup>]<sub>i</sub> using a Ca<sup>2+</sup>-free solution, SAR7334, or dantrolene increased the glucose uptake in the MH-R163C neurons without significantly affecting the WT neurons. However, further reduction of the [Ca<sup>2+</sup>]<sub>i</sub> below the physiological level using BAPTA decreased the insulin-dependent glucose uptake in both genotypes. Furthermore, the homogenates of the MH-R163C hippocampal neurons showed an altered protein expression of the PI3K/Akt signaling pathway and GLUT4 compared with the WT mice. Our study demonstrated that the chronic elevation of [Ca<sup>2+</sup>]<sub>i</sub> was sufficient to compromise the insulin-dependent glucose uptake in the MH-R163C hippocampal neurons. Moreover, reducing the [Ca<sup>2+</sup>]<sub>i</sub> within a specific range (100–130 nM) could reverse insulin resistance, a hallmark of type 2 diabetes mellitus (T2D). |
|---|---|
| ISSN: | 2073-4409 |