Mg2+ Supplementation Mitigates Metabolic Deficits Associated With TRPM7 Disruption

Boulassel, Severin; Schreier, Pascale C. F.; Melyshi, Anna M.; Berger, Johanna; Reinach, Peter S.; Jacob, Katharina; Boekhoff, Ingrid; Breit, Andreas ; Müller, Timo D. ; Zierler, Susanna; Gudermann, Thomas und Khajavi, Noushafarin (2025): Mg2+ Supplementation Mitigates Metabolic Deficits Associated With TRPM7 Disruption. In: Journal of Cellular Physiology, Vol. 240, No. 4, e70042

Abstract

Transient receptor potential channel subfamily M member 7 (TRPM7) regulates cellular and systemic Mg2+ homeostasis through its channel domain and induces protein phosphorylation via its kinase domain. We recently found that mice with selective deletion of Trpm7 in β-cells develop glucose intolerance and declines in insulin secretion, primarily due to the impaired enzymatic activity of this protein. Accumulating evidence suggests that Mg2+ supplementation effectively mitigates the detrimental effects of TRPM7 disruption in various cell types. However, the impact of Mg2+ supplementation on metabolic impairments caused by TRPM7 inactivation remains unclear. In the present study, we found that Mg2+ supplementation significantly ameliorates glucose intolerance observed in high-fat-fed TRPM7 kinase-deficient mice (Trpm7R/R). However, our ex vivo analysis of islets isolated from Trpm7R/R mice revealed that Mg2+ supplementation does not enhance glucose-induced insulin secretion. Instead, the improvement appears to be partially driven by enhanced insulin sensitivity and increased β-cell proliferation. The pharmacological analysis in MIN6 cells showed that inhibiting TRPM7 with either NS8593 or VER155008 disrupts β-cell proliferation. These effects mimicked the phenotype seen in Trpm7R/R mice. We attribute this impairment to diminished ERK1/2 signaling, which suppressed PDX1 expression, while Mg2+ supplementation in vitro partially restored ERK1/2 phosphorylation levels. Collectively, Mg2+ supplementation enhances glucose metabolism in Trpm7R/R mice and mitigates the ERK1/2 signaling disruptions and proliferation arrest induced by TRPM7 inactivation in vitro. These findings provide compelling evidence that Mg2+ supplementation can reverse the adverse metabolic and cellular phenotypes associated with the loss of TRPM7 function.

• Item Type: Journal article
• Faculties: Medicine > Walther Straub Institute of Pharmacology and toxicology
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0021-9541
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 239283807
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 239283807
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 424957847