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Study Title:

Dietary Magnesium Supplementation Ameliorates Anemia in a Mouse Model of β-Thalassemia

Study Abstract

To ascertain the quantitative effect on the disease β-thalassemia of a low-magnesium (Mg) diet compared with a high-Mg diet and a standard-Mg diet, we studied the effect these diets had over a 4-week period on β-thalassemic (β thal) mice compared with normal C57BL/6 mice used as controls. The low-Mg diet consisted of 6 ± 2 mg Mg/kg body weight/d, the high-Mg diet 1,000 ± 20 mg Mg/kg body weight/d, and the standard-Mg diet 400 ± 20 mg Mg/kg body weight/d. β thal mice that were fed the low-Mg diet became more anemic, had reduced serum and erythrocyte Mg, and had decreased erythrocyte K. Their K-Cl cotransport increased, followed by commensurate cell dehydration. The high-Mg group showed a significant improvement of the anemia, increased serum and erythrocyte Mg, increased erythrocyte Mg, increased erythrocyte K, reduced K-Cl cotransport, and diminished cell dehydration. C57BL/6 control mice that received the low-Mg diet experienced anemia with erythrocyte dehydration, whereas the high-Mg diet had little effect on the hematologic parameters. β thal and C57BL/6 control mice that were fed a standard diet showed no changes. These results indicate that dietary Mg supplementation corrects hypomagnesemia and improves anemia in murine β thal and should be assessed in human β-thalassemia.

MAGNESIUM (Mg) is the second most abundant intracellular metal after potassium (K), and plays an essential role in the activity of many enzymes involved in cellular metabolism.1 Cell Mg is an important modulator in cell volume regulation and affects the activity of various membrane cation transport pathways such as the sodium (Na)/K pump, Na-K-chloride (Cl) cotransport, calcium (Ca) and K channels, and K-Cl cotransport. The physical properties of the erythrocyte membrane are also markedly affected by changes in cell Mg content.1 ,2

Mg deficiency spontaneously occurs in farm animals and in humans; it has been extensively studied in rats, where it is easily produced by dietary Mg restriction.3 ,4 With a Mg-deficient diet, rats develop hemolytic anemia characterized by changes in erythrocyte morphology and reduction in erythrocyte survival.3 ,4 The mechanism(s) by which Mg deficiency produces anemia remains poorly understood.

The anemia of human β-thalassemia is determined by a combination of different factors such as ineffective erythropoiesis, destruction of erythrocytes containing α chain inclusions, and reduced hemoglobin (Hb) content with hypochromic, microcytic erythrocytes.5 ,6 Although the molecular defects responsible for decreasing β-globin chain synthesis have been characterized in great detail, the pathophysiologic consequences of membrane damage imposed by the excess of α chains and the determinants of the reduced erythrocyte survival are less well characterized.5-9

Abnormalities of Mg metabolism have been described in β-thalassemia, and low serum Mg has been reported in children affected by the homozygous form of the disease.10 ,11 Subjects with heterozygous β-thalassemia and β-thalassemia intermedia showed an abnormally low erythrocyte Mg content when compared with normal controls and patients with hypochromic sideropenic anemia.11 ,12 There is no clear explanation for the abnormalities in Mg metabolism observed in β-thalassemia. There have also been no systematic studies on the possible role played by Mg deficiency in the anemia of β-thalassemia.

Mice homozygous for deletion of the β major gene (β thal) have clinical and biologic features similar to those observed in human β-thalassemia intermedia. This spontaneous murine model for β-thalassemia reproduces several erythrocyte abnormalities characteristic of the human disease.13-20 The anemia of this mouse model has been shown to improve following treatment with either hydroxyurea14 or recombinant human erythropoietin (rHuEPO),13 which also improve some hematologic parameters of human β-thalassemia intermedia. Additionally, clotrimazole may have a benefit when combined with either hydroxyurea or rHuEPO.20 Different mouse models for β-thalassemia obtained from deletion of both the b1 and b2 adult globin genes have been recently reported.21 ,22

We therefore hypothesized that regulation of dietary Mg intake would affect the course of some hematologic parameters in β thal mice. These results could point the way to experimentation with dietary Mg in human β-thalassemia.

The objective of this study was to evaluate the extent to which diets containing different amounts of Mg might affect the anemia of β thal mice. We show that Mg dietary supplementation leads to increased hematocrit (Hct), Hb, and cell K content and reduces mean corpuscular Hb content (MCHC) and K-Cl cotransport activity in β thal mouse erythrocytes.

Study Information

Lucia De Franceschi, Carlo Brugnara and Yves Beuzard
Dietary Magnesium Supplementation Ameliorates Anemia in a Mouse Model of β-Thalassemia
Blood.
1997 January