Magnesium and COVID-19 - Some Further Comments - A Commentary on Wallace TC. Combating COVID-19 and Building Immune Resilience: A Potential Role for Magnesium Nutrition? J Am Coll Nutr. 2020;1-9. doi:10.1080/07315724.2020.1785971. Cited in: PMID: 32649272.

The paper "Combating COVID-19 and Building Immune Resilience: A Potential Role for Magnesium Nutrition?" by TC Wallace, which was published in the Journal of the American College of Nutrition highlights the importance of adequate magnesium (Mg) supply in relation to COVID-19. Wallace notes that Mg deficiency is associated with low-grade chronic inflammation. Furthermore, hypokalemia and a lack of active Vitamin D are consequences of a Mg deficit. In this way, Mg deficiency may exacerbate the course of COVID-19. Therefore, in patients with Covid-19 permanent monitoring of the Mg status and, if necessary, supplementation should be carried out. The possible importance of Mg in COVID-19 was only recently discussed also by Iotti et al. and the German Society for Magnesium Research e.V. Considering the meaningful connections between Mg and COVID-19 there are relevant research topics that should be addressed: Does Mg deficiency increase the risk of infection with COVID-19 or the risk of a severe course of the disease? Is there an increased prevalence of Mg deficiency in COVID-19 patients? Could Mg supplementation alleviate the course of the disease in COVID-19 or reduce complications? Does pharmacological induction of hypermagnesemia via intravenous Mg provide clinical benefits for COVID-19 patients in the intensive care unit (for example with regard to lung function or thromboembolism)?

Human CNNM2 is not a Mg(2+) transporter per se.

CNNM2 is associated with the regulation of serum Mg concentration, and when mutated, with severe familial hypomagnesemia. The function and cellular localization of CNNM2 and its isomorphs (Iso) remain controversial. The objective of this work was to examine the following: (1) the transcription-responsiveness of CNNM2 to Mg starvation, (2) the cellular localization of Iso1 and Iso2, (3) the ability of Iso1 and Iso2 to transport Mg(2+), and (4) the complex-forming ability and spectra of potential interactors of Iso1 and Iso2. The five main findings are as follows. (1) Mg-starvation induces CNNM2 overexpression that is markedly higher in JVM-13 cells (lymphoblasts) compared with Jurkat cells (T-lymphocytes). (2) Iso1 and Iso2 localize throughout various subcellular compartments in transgenic HEK293 cells overexpressing Iso1 or Iso2. (3) Iso1 and Iso2 do not transport Mg(2+) in an electrogenic or electroneutral mode in transgenic HEK293 cells overexpressing Iso1 or Iso2. (4) Both Iso1 and Iso2 form complexes of a higher molecular order. (5) The spectrum of potential interactors of Iso1 is ten times smaller than that of Iso2. We conclude that sensitivity of CNNM2 expression to extracellular Mg(2+) depletion depends on cell type. Iso1 and Iso2 exhibit a dispersed pattern of cellular distribution; thus, they are not exclusively integral to the cytoplasmic membrane. Iso1 and Iso2 are not Mg(2+) transporters per se. Both isomorphs form protein complexes, and divergent spectra of potential interactors of Iso1 and Iso2 indicate that each isomorph has a distinctive function. CNNM2 is therefore the first ever identified Mg(2+) homeostatic factor without being a Mg(2+) transporter per se.

Insulin Modulates the Na+/Mg2+ Exchanger SLC41A1 and Influences Mg2+ Efflux from Intracellular Stores in Transgenic HEK293 Cells.

BACKGROUND: Magnesium deficiency is a common complication of diabetes with an unclear molecular background. OBJECTIVE: We investigated the effect of the insulin (INS)-signaling pathway (ISP) on the regulation of Mg(2+) efflux (Mg(2+)E) conducted by solute carrier family 41, member A1 (SLC41A1; activated by protein kinase A) in transgenic human embryonic kidney (HEK) 293 cells. METHODS: HEK293 cells overexpressing SLC41A1 were loaded with the Mg(2+) fluorescent indicator mag-fura-2 and Mg(2+). Measurements of Mg(2+)E were conducted in Mg(2+)-free buffer by using fast-filter fluorescence spectrometry. We examined the effects of INS, inhibitors of ISP or p38 mitogen-activated protein kinase (p38 MAPK), an activator of adenylate cyclase (ADC), and their combinations on SLC41A1-attributed Mg(2+)E. RESULTS: The application of 400 µU/mL INS inhibited SLC41A1-mediated Mg(2+)E by up to 50.6% compared with INS-untreated cells (P < 0.001). Moreover, INS evoked the early onset of Mg(2+) release from intracellular stores. The application of 0.1 µM wortmannin or 10 µM zardaverine (both ISP inhibitors) restored SLC41A1 Mg(2+)E capacity in the presence of INS to the same levels in INS-untreated cells. The simultaneous application of 10 µM forskolin, an ADC activator, and INS resulted in a reduction of Mg(2+)E of up to 59% compared with untreated cells (P < 0.001), which was comparable to that in cells treated with INS alone. Inhibition of p38 MAPK with 10 µM SB 202190 (SB) in the absence of INS resulted in a decrease (P < 0.001) of SLC41A1-dependent Mg(2+)E (by up to 49%) compared with Mg(2+)E measured in untreated cells. Simultaneous exposure of cells to SB and INS had a stronger inhibitory effect on SLC41A1 activity than INS alone (P < 0.05). CONCLUSIONS: INS affects intracellular Mg(2+) concentration in transgenic HEK293 cells by regulating SLC41A1 activity (via ISP) and by influencing the compartmentalization and cellular distribution of Mg(2+). In addition, p38 MAPK activates SLC41A1 independently of INS action.

Magnesium supplementation to prevent high blood pressure in pregnancy: a randomised placebo control trial.

PURPOSE: To assess if hypertension during the last part of pregnancy could be prevented by magnesium supplementation. METHODS: Pregnant primagravida women from a local antenatal care unit were given an oral supply of 300 mg magnesium as citrate or placebo from pregnancy week 25 in a randomised double-blind setup. Blood pressure was recorded during pregnancy as well as pregnancy outcome. RESULTS: In the magnesium-supplemented group, the average diastolic blood pressure at week 37 was significantly lower than in the placebo group (72/1.4 mean/SEM vs 77/1.4, p = 0.031). The number of women with an increase in diastolic blood pressure of ≥15 mmHg was significantly lower in the magnesium group compared with the women who received placebo (p = 0.011). There was an inverse relation between the urinary excretion of magnesium during pregnancy and the diastolic blood pressure (p = 0.005). CONCLUSIONS: Magnesium supplementation prevented an increase in diastolic blood pressure during the last weeks of pregnancy. The relation between diastolic blood pressure and urinary excretion of magnesium suggests that magnesium is involved in the regulation of blood pressure and that the increase in diastolic blood pressure in pregnancy could be due to a lack of magnesium.

Human gene SLC41A1 encodes for the Na+/Mg²+ exchanger.

Magnesium (Mg(2+)), the second most abundant divalent intracellular cation, is involved in the vast majority of intracellular processes, including the synthesis of nucleic acids, proteins, and energy metabolism. The concentration of intracellular free Mg(2+) ([Mg(2+)](i)) in mammalian cells is therefore tightly regulated to its optimum, mainly by an exchange of intracellular Mg(2+) for extracellular Na(+). Despite the importance of this process for cellular Mg(2+) homeostasis, the gene(s) encoding for the functional Na(+)/Mg(2+) exchanger is (are) still unknown. Here, using the fluorescent probe mag-fura 2 to measure [Mg(2+)](i) changes, we examine Mg(2+) extrusion from hSLC41A1-overexpressing human embryonic kidney (HEK)-293 cells. A three- to fourfold elevation of [Mg(2+)](i) was accompanied by a five- to ninefold increase of Mg(2+) efflux. The latter was strictly dependent on extracellular Na(+) and reduced by 91% after complete replacement of Na(+) with N-methyl-d-glucamine. Imipramine and quinidine, known unspecific Na(+)/Mg(2+) exchanger inhibitors, led to a strong 88% to 100% inhibition of hSLC41A1-related Mg(2+) extrusion. In addition, our data show regulation of the transport activity via phosphorylation by cAMP-dependent protein kinase A. As these are the typical characteristics of a Na(+)/Mg(2+) exchanger, we conclude that the human SLC41A1 gene encodes for the Na(+)/Mg(2+) exchanger, the predominant Mg(2+) efflux system. Based on this finding, the analysis of Na(+)/Mg(2+) exchanger regulation and its involvement in the pathogenesis of diseases such as Parkinson's disease and hypertension at the molecular level should now be possible.

Serum magnesium: time for a standardized and evidence-based reference range.

Magnesium deficiency can have serious health consequences. Low magnesium intake or low serum levels are risk factors for e.g. type 2 diabetes and cardiovascular diseases. Despite its scientifically recognized importance, too little attention is paid to magnesium in clinical practice. This may be due to the fact that there is no uniform and evidence-based reference range for serum magnesium as is the case for other electrolytes such as sodium and potassium. The serum magnesium concentration is also of a limited informative value, as it is maintained for a long time by releasing magnesium from body pools. A low serum magnesium is a definite sign of magnesium deficiency; however, values within the reference range do not rule out deficiencies. Nevertheless, serum magnesium should become part of routine diagnostics in order to be able to better detect deficiency states. For serum magnesium, a reference range of 0.75 to 0.95 mmol/L (1.82 to 2.31 mg/dL) can often be found. However, according to the current data situation, serum magnesium values of less than 0.85 mmol/L are associated with increased health risks. Therefore, the lower limit of the reference range should be raised to 0.85 mmol/L (2.07 mg/dL).

Magnesium citrate supplementation decreased blood pressure and HbA1c in normomagnesemic subjects with metabolic syndrome: a 12-week, placebo-controlled, double-blinded pilot trial.

Magnesium (Mg) supplementation was shown to improve metabolic syndrome (MetS) parameters in hypomagnesemic patients. The current study evaluated the role of Mg in normomagnesemic individuals with MetS. Patients were randomly assigned to 400 mg Mg as Mg citrate or placebo daily for 12 weeks. Blood pressure (BP), HbA1c, plasma concentrations of glucose, Mg and Ca, blood-ionized Mg, serum concentrations of cholesterol, triglycerides, vitamin D, creatinine, interleukin-6, and C-reactive protein were measured at baseline and after 12 weeks. Data were obtained from n = 13 in the Mg supplemented and n = 11 in the placebo group. Mg supplementation led to a significant increase in plasma Mg concentration (0.78 ± 0.07 mmol/L to 0.83 ± 0.07 mmol/L) and a decrease in systolic and diastolic BP (baseline: 145 ± 10/85 ± 3 mmHg; 12 weeks: 121 ± 5/79 ± 3 mmHg). HbA1c decreased significantly in the Mg group (6.43 ± 0.64% to 6.15 ± 0.55%), and the difference in change between placebo and Mg group was significant. Serum vitamin D levels significantly increased only in the Mg group. In normomagnesemic individuals with MetS, oral Mg citrate supplementation reduced HbA1c and BP.

[Magnesium: Relevance for general practitioners - a position paper of the Society for Magnesium Research e. V.] / Magnesium: Bedeutung für die hausärztliche Praxis ­ Positionspapier der Gesellschaft für Magnesium-Forschung e. V.

Magnesium deficiency is to be expected in the population and particularly among risk groups. Magnesium deficiency can cause numerous symptoms, is per se pathological and thus requires treatment. Diagnostics is based on clinical symptoms in conjunction with anamnestic criteria and laboratory parameters. Insufficient magnesium supply is associated with an increased risk for many diseases, e. g. metabolic syndrome, type 2 diabetes and cardiovascular diseases. Magnesium deficiency often appears as comorbidity and may exacerbate diseases. Physicians should pay more attention to magnesium in order to avoid deficits as a cause for multiple symptoms and risk factor for diseases. Optimisation of magnesium status may make an important contribution to the prevention of diseases. Oral magnesium therapy is safe and cost effective.

Exercise Training, Intermittent Fasting and Alkaline Supplementation as an Effective Strategy for Body Weight Loss: A 12-Week Placebo-Controlled Double-Blind Intervention with Overweight Subjects.

BACKGROUND: Intermittent fasting (IF) combined with exercise has been suggested to enhance weight loss. However, both procedures might negatively influence acid-base status. The aim of this study was to determine the combined effects of IF, exercise training and alkaline supplementation in overweight subjects on body composition and running performance. METHODS: 80 overweight subjects of age 45.5 ± 7.8 years were assigned to IF or non-intermittent fasting (nIF). Furthermore, subjects were randomly assigned to take either an alkaline supplement (IF-v, nIF-v) or a placebo (IF-p, nIF-p) twice a day. All subjects performed a personalized endurance exercise program (3-4 times/week for 12 weeks). Body weight, body composition, running performance and acid-base parameters were determined before (pre) and after the 12-week program (post). RESULTS: 68 participants completed the study. There was a significant effect on body weight loss, body fat loss, visceral fat loss and running performance enhancement in all groups (p < 0.01) for pre and post measurements. Body weight decreased in all groups (IF-p: -5.80 ± 0.77 kg and nIF-p: -3.40 ± 0.58 kg; IF-v: -8.28 ± 0.75 kg and nIF-v: -5.59 ± 0.87 kg). In both dietary strategies, weight loss was significantly further enhanced by alkaline supplementation. The increase in running velocity was significantly higher in IF combined with alkaline supplementation (IF-v 1.73 ± 0.23 km/h and IF-p 0.97 ± 0.20 km/h). In addition, alkaline supplementation increased plasma HCO3- concentration and urinary pH. CONCLUSION: Exercise training in combination with IF and alkaline supplementation is an effective strategy to reduce body weight and improve running performance in a 12-week intervention.

Acid-base conditions regulate calcium and magnesium homeostasis.

BACKGROUND: Previous experimental studies demonstrate that the acid-base balance influences mineral homeostasis by regulating the absorption of calcium and magnesium in the kidneys. No intervention studies are available on population samples. AIMS: To study the urinary excretion of calcium and magnesium before and after an intervention with the aim of decreasing the acid load. METHODS: Healthy subjects aged 50-75 years were recruited by advertising. Urinary calcium, magnesium and urea as well as blood pressure were measured before and after the intervention. This comprised taking tablets containing potassium hydrogen carbonate or potassium chloride (placebo) during 7-10 days. RESULTS: There were significant relationships between the urinary excretion of urea and magnesium and calcium before the intervention. Comparing before and after intervention, the change in urinary excretion of urea was related to a change in urinary excretion of calcium and magnesium. There was a significant decrease in systolic as well as diastolic blood pressure both after administration of potassium hydrogen carbonate and citrate. CONCLUSION: The results confirm previous studies showing a relation between acid conditions in the body and the excretion of calcium and add new data on magnesium. A blood pressure decrease after potassium has been found in previous studies. This suggests an alternative for the treatment of moderately increased levels of blood pressure that should be further explored.

Assessment of bioavailability of Mg from Mg citrate and Mg oxide by measuring urinary excretion in Mg-saturated subjects.

BACKGROUND: Low magnesium (Mg) levels are linked to many diseases. Studies suggest that organic salts of Mg are more readily bioavailable than its oxide or inorganic salts used for supplements production. Unfortunately, the plethora of variables in the previous study designs complicates the making of any clear and reliable conclusions. METHODS: 14 healthy males were supplemented for five days with 400 mg Mg to saturate Mg pools before intake of the test products. Bioavailability of 400 mg Mg from Mg citrate (MgC) and Mg oxide (MgO) after single-dose administration was assessed by measuring renal Mg excretion in 24-h urine and blood plasma [Mg] at time points 0, 2, 4, 8, and 24 h. RESULTS: Single-dose MgC supplementation led to a significant (P < 0.05) increase in 24 h urinary Mg excretion, but this was not significant following MgO. Plasma [Mg] was also significantly higher for MgC than for MgO at 4 h (P < 0.05) and 8 h (P < 0.05). Compared with baseline levels, MgC supplementation showed a significant increase in plasma [Mg] at all time points, in contrast to MgO. CONCLUSIONS: MgC shows higher bioavailability compared with MgO. Furthermore, urinary Mg excretion should be determined as the primary endpoint of Mg bioavailability studies.

Myth or Reality-Transdermal Magnesium?

In the following review, we evaluated the current literature and evidence-based data on transdermal magnesium application and show that the propagation of transdermal magnesium is scientifically unsupported. The importance of magnesium and the positive effects of magnesium supplementation are extensively documented in magnesium deficiency, e.g., cardiovascular disease and diabetes mellitus. The effectiveness of oral magnesium supplementation for the treatment of magnesium deficiency has been studied in detail. However, the proven and well-documented oral magnesium supplementation has become questioned in the recent years through intensive marketing for its transdermal application (e.g., magnesium-containing sprays, magnesium flakes, and magnesium salt baths). In both, specialist and lay press as well as on the internet, there are increasing numbers of articles claiming the effectiveness and superiority of transdermal magnesium over an oral application. It is claimed that the transdermal absorption of magnesium in comparison to oral application is more effective due to better absorption and fewer side effects as it bypasses the gastrointestinal tract.

Magnesium: Nutrition and Homoeostasis.

The essential mineral magnesium is involved in numerous physiological processes. Recommended dietary intake is often not met and a low magnesium status increases the risk for various diseases. Magnesium status is regulated by several magnesium transport systems either in cellular or paracellular pathways. Numerous drugs either interfere with magnesium absorption in the intestines or the reabsorption from primary urine in the kidney. Low magnesium status has been identified as a significant risk factor for several diseases, including type-2 diabetes, cardiovascular diseases, arrhythmias, as well as general muscular and neurological problems. Therefore, an adequate magnesium supply would be of special benefit to our overall health.

Coenzyme Q10 affects expression of genes involved in cell signalling, metabolism and transport in human CaCo-2 cells.

Coenzyme Q10 is an essential cofactor in the electron transport chain and serves as an important antioxidant in both mitochondria and lipid membranes. CoQ10 is also an obligatory cofactor for the function of uncoupling proteins. Furthermore, dietary supplementation affecting CoQ10 levels has been shown in a number of organisms to cause multiple phenotypic effects. However, the molecular mechanisms to explain pleiotrophic effects of CoQ10 are not clear yet and it is likely that CoQ10 targets the expression of multiple genes. We therefore utilized gene expression profiling based on human oligonucleotide sequences to examine the expression in the human intestinal cell line CaCo-2 in relation to CoQ10 treatment. CoQ10 caused an increased expression of 694 genes at threshold-factor of 2.0 or more. Only one gene was down-regulated 1.5-2-fold. Real-time RT-PCR confirmed the differential expression for seven selected target genes. The identified genes encode proteins involved in cell signalling (n = 79), intermediary metabolism (n = 58), transport (n = 47), transcription control (n = 32), disease mutation (n = 24), phosphorylation (n = 19), embryonal development (n = 13) and binding (n = 9). In conclusion, these findings indicate a prominent role of CoQ10 as a potent gene regulator. The presently identified comprehensive list of genes regulated by CoQ10 may be used for further studies to identify the molecular mechanism of CoQ10 on gene expression.

Magnesium: nutrition and metabolism.

Magnesium is an essential mineral that is needed for a broad variety of physiological functions. The usual daily magnesium uptake with a western diet is sufficient to avoid deficiency but seems not to be high enough to establish high normal serum magnesium concentrations that are protective against various diseases. Changes in magnesium homeostasis mainly concern the extracellular space, as the intracellular magnesium concentration is well regulated and conserved. The extracellular magnesium concentration is primarily regulated by the kidney, the mechanisms of this regulation have been elucidated recently. Due to the growing knowledge about the regulation of extra- and intracellular magnesium concentrations and the effects of changed extracellular magnesium levels the use of magnesium in therapy gains more widespread attention.

Magnesium and hearing.

The last several decades have revealed clinical and experimental data regarding the importance of magnesium (Mg) in hearing. Increased susceptibility to noise damage, ototoxicity, and auditory hyperexcitability are linked to states of Mg deficiency. Evidence for these processes has come slowly and direct effects have remained elusive because plasma Mg levels do not always correlate with its deficiency. Despite the major progress in the understanding of cochlear mechanical and auditory nerve function, the neurochemical and pharmacologic role of Mg is not clear. The putative mechanism suggests that Mg deficiency may contribute to a metabolic cellular cascade of events. Mg deficiency leads to an increased permeability of the calcium channel in the hair cells with a consequent over influx of calcium, an increased release of glutamate via exocytosis, and over stimulation of NMDA receptors on the auditory nerve. This paper provides a current overview of relevant Mg metabolism and deficiency and its influence on hearing.

Blood pressure in pregnancy and magnesium sensitive genes.

OBJECTIVES: High blood pressure during the last part of pregnancy is a risk indicator of pre-eclampsia and eclampsia which augment infant and maternal morbidity and mortality. Magnesium deficiency has been related to the risk of hypertension. A study was performed to assess the relation between pregnancy induced hypertension, excretion of urinary magnesium and expression of magnesium sensitive genes (MgSG). METHODS: A cohort of healthy, nulliparous women with singleton pregnancies was recruited. Blood pressure was recorded throughout pregnancy. Urinary magnesium excretion and expression of MgSGs in leukocytes were determined. RESULTS: The expression of the gene TRPM6 was higher among pregnant women compared to non-pregnant controls at week 12. All other genes had lower expressions in pregnant women. At week 37 the expressions of all genes were lower than at week 12. The expressions of SLC41A1, SLC41A3, and TRPM7 were related to the systolic and diastolic blood pressures. Furthermore, the expression of TRPM6 was related to the urinary excretion of magnesium and the change in diastolic blood pressure weeks 12-37 was inversely related to the change in magnesium excretion. CONCLUSIONS: Systolic and diastolic blood pressure and the excretion of magnesium during pregnancy were related to the expression of different MgSGs. The results suggest that magnesium is involved in the regulation of blood pressure during pregnancy.

SLC41A1 is the only magnesium responsive gene significantly overexpressed in placentas of preeclamptic women.

OBJECTIVE: To examine expression profile of magnesium responsive genes (MRGs) in placentas of normoevolutive and preeclamptic women. METHODS: The expression profiles of MRGs were determined in placentas of normoevolutive (N=26) and preeclamptic (N=25) women by RT-qPCR. RESULTS: Among all tested MRGs (9) only SLC41A1 (encoding for Na(+)/Mg(2+) exchanger) was significantly overexpressed in ~54.2% of preeclamptic (n=24) and in ~9.5% of normoevolutive (n=21) specimens. On average, SLC41A1 was overexpressed sixfold in the preeclamptic group. Presence of SLC41A1 in placentas was confirmed by Western blot analysis. CONCLUSION. SLC41A1 is significantly overexpressed in nearly 55% of preeclamptic placentas. This may indicate a direct contribution of changed Mg homeostasis in the development of preeclampsia.