RICERCA ITALIANA     

Magnesium Homeostasis in pathologies with primary and secondary defects of ion metabolism

Università degli Studi di Bologna

Abstract

Mechanisms which regulate magnesium homeostasis in different tissues, are still not completely understood. Most studies report data about the total serum magnesium concentration, while is well known the intracellular free fraction to be that functionally important. This research project will contribute to the knowledge of the regulatory mechanism of magnesium homeostasis by assessing its distribution in several tissues in humans, by measuring the intracellular free concentration in skeletal muscle, brain, blood cells, and the total and free concentration in plasma. We will use analytical methods specific for each cell type investigated: phosphorus magnetic resonance spectroscopy (31P MRS) to measure in vivo intracellular free magnesium concentration in skeletal muscle and brain, fluorimetry and cytofluorimetry to measure intracellular free magnesium concentration in blood cells, atomic absorption and Mg-selective electrode to measure in plasma total and free concentration respectively. It is well known that the intracellular Mg2+ content changes in many pathologies. These can be divided in two wide groups: a) pathologies with primary defect of ion metabolism, in which Mg transport is directly affected, as canalopathies; b) pathologies with secondary defect of ion metabolism involving alteration in hormonal regulation or absorption defects . This research project will study three pathologies representing an adequate in vivo experimental models for studying magnesium >>>

Principal Investigator

Bruno BARBIROLI Università degli Studi di BOLOGNA

Research Objectives

This research project will contribute to the knowledge of the regulatory mechanism of magnesium homeostasis by assessing its distribution in several tissues in humans, by measuring the intracellular free concentration in skeletal muscle, brain, blood cells, and the total and free concentration in plasma. We will use analytical methods specific for each cell type investigated: phosphorus magnetic resonance spectroscopy (31P MRS) to measure in vivo intracellular free magnesium concentration in skeletal muscle and brain, fluorimetry and cytofluorimetry to measure intracellular free magnesium concentration in blood cells, atomic absorption and Mg-selective electrode to measure in plasma total and free concentration respectively. We will examine three pathologies representing an adequate in vivo experimental models for studying magnesium homeostasis, for which there is also a clinical interest in the functional evaluation of magnesium deficit. We choose to examine 14 patients affected by LQT syndrome enrolled by the research unit of "Dipartimento di Scienze Biochimiche, Fisiologiche e della Nutrizione-Università di Messina", 23 affected by primary or secondary aldosteronism enrolled by the research unit of "Dipartimento di Biomedica e Scienze Chirurgiche -Università di Verona", 12 affected by chronic intestinal failure enrolled by the research unit of "Medicina Interna, Centro Regionale di Riferimento per Insufficienza Intestinale Cronica Benigna -Università di Bologna" and 50 >>>

First Results

At the end of the first phase of the project, a first set of results obtained by 31P MRS and by the other analytical techniques will be available, and the study of patients affected by primary aldosteronism will be completed. A database will be made containing data coming from the exams and analytical assays of the subjects examined which will allow to get preliminary information about magnesium tissue distribution. The assessment of the skeletal muscle intracellular free magnesium concentration obtained in different metabolic condition by 31P MRS together with the measure of the post exercise phosphocreatine kinetics, both in healthy subjects and patients, will give information on the influence of magnesium on muscle mitochondrial functionality. Useful indication for the functional characterisation of the examined samples and for flow cytometric protocols setting up will be provided by comparing the results obtained by flow cytometry and spectrofluorimetryThe database will be completed containing all data coming from all exams and analytical assays of all subjects which will allow to obtain a detailed figure of magnesium tissue distribution and information on the regulatory mechanism of this ion.
Furthermore, the evaluation of tissue distribution of magnesium in the different pathologies will give pivotal indications on the opportunity of magnesium supplementation as therapeutic support for patient treatment putting the basis for the project of adequate clinical >>>

Timescale

24 months

National and international background

Magnesium is one of the most abundant cations in the cells of soft tissues, its cellular concentration ranging, in most of them, between 14 and 20 mM (1). Magnesium is known to be involved in many cellular process, such as transport systems, receptor, signal transduction, enzyme activities, energetic metabolism, DNA and protein synthesis and membrane functionality (1,2). Its relatively high intra-cellular concentration accompanied to limited fluctuations have suggested that this ion could act as a long term regulator for enzymes and cellular function (1,2). Its concentration depends both on the positive gradient between the intra- and the extra-cellular compartment which regulates the influx, and on transport mechanisms regulating the efflux mainly represented by the exchanger Na+/Mg2+ (1). Recently, new transepithelial magnesium transporters TRPM6 and TRPM7 have been identified which seems to be involved in Mg2+ homeostasis (3,4). However, the mechanisms which regulate magnesium homeostasis in different tissues, are not yet completely understood. Studies report data about the total serum magnesium concentration, while there are growing evidence that the intracellular free fraction is that functionally important (5-8). Magnesium was defined as the "forgotten ion" as, despite of being the second intracellular ion, it is rarely considered in medical practice (9). Furthermore not many data regarding its role in cellular homeostasis and its regulation mechanisms are available >>>