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Abstract

Background

Dietary Mg intake is associated with a decreased risk of developing heart failure, whereas low circulating Mg level is associated with increased cardiovascular mortality. We investigated whether Mg deficiency alone could cause cardiomyopathy.

Methods and Results

C57BL/6J mice were fed with a low Mg (low‐Mg, 15–30 mg/kg Mg) or a normal Mg (nl‐Mg, 600 mg/kg Mg) diet for 6 weeks. To test reversibility, half of the low‐Mg mice were fed then with nl‐Mg diet for another 6 weeks. Low‐Mg diet significantly decreased mouse serum Mg (0.38±0.03 versus 1.14±0.03 mmol/L for nl‐Mg; P<0.0001) with a reciprocal increase in serum Ca, K, and Na. Low‐Mg mice exhibited impaired cardiac relaxation (ratio between mitral peak early filling velocity E and longitudinal tissue velocity of the mitral anterior annulus e, 21.1±1.1 versus 15.4±0.4 for nl‐Mg; P=0.011). Cellular ATP was decreased significantly in low‐Mg hearts. The changes were accompanied by mitochondrial dysfunction with mitochondrial reactive oxygen species overproduction and membrane depolarization. cMyBPC (cardiac myosin‐binding protein C) was S‐glutathionylated in low‐Mg mouse hearts. All these changes were normalized with Mg repletion. In vivo (2‐(2,2,6,6‐tetramethylpiperidin‐1‐oxyl‐4‐ylamino)‐2‐oxoethyl)triphenylphosphonium chloride treatment during low‐Mg diet improved cardiac relaxation, increased ATP levels, and reduced S‐glutathionylated cMyBPC.

Conclusions

Mg deficiency caused a reversible diastolic cardiomyopathy associated with mitochondrial dysfunction and oxidative modification of cMyBPC. In deficiency states, Mg supplementation may represent a novel treatment for diastolic heart failure.

Nonstandard Abbreviations and Acronyms

cMyBPC
cardiac myosin‐binding protein C
E/e’
ratio between mitral peak early filling velocity E and longitudinal tissue velocity of the mitral anterior annulus e
low‐Mg
mice fed with low‐Mg diet
low→nl‐Mg
mice fed with low‐Mg diet for 6 weeks and then normal Mg diet for another 6 weeks
mitoTEMPO
(2‐(2,2,6,6‐tetramethylpiperidin‐1‐oxyl‐4‐ylamino)‐2‐oxoethyl)triphenylphosphonium chloride
nl‐Mg
control mice fed with normal Mg diet
ROS
reactive oxygen species

Clinical Perspective

What Is New?

Hypomagnesemia is common in diabetes mellitus, and is associated with worsening heart failure symptoms; Mg supplementation can improve these symptoms.
Herein, we show that severe hypomagnesemia caused a reversible diastolic cardiomyopathy.
The diastolic cardiomyopathy was associated with mitochondrial dysfunction and responded to mitochondrial antioxidant therapy.

What Are the Clinical Implications?

The causative relationship between hypomagnesemia and diastolic dysfunction may help explain previous epidemiological data linking heart failure and Mg.
Mg repletion may help treat diastolic heart failure by improving mitochondrial function and reducing oxidative stress.
In the United States, about 6.5 million people have heart failure, and the number is increasing yearly.1 Half of the heart failure is heart failure with preserved ejection fraction (EF), and diastolic dysfunction is thought to be essential to the pathology. Cardiac diastolic dysfunction is characterized by the reduced ability of the left ventricle to relax and fill with blood adequately. Because of poor understanding of the underlying pathophysiology, there are no specific treatments currently for diastolic dysfunction.2, 3, 4 Previously, our group has studied hypertensive and diabetic mouse models of isolated diastolic dysfunction and heart failure with preserved EF and confirmed that cardiac mitochondrial oxidative stress is central to diastolic dysfunction, the relaxation defect being caused by increased S‐glutathionylation of cMyBPC (cardiac myosin‐binding protein C).5, 6, 7
Hypomagnesemia is increasingly common. As the fourth most abundant mineral and the second most abundant intracellular divalent cation, Mg is an essential element for cell functions, such as ATP production and protein synthesis.8, 9 Mg has been reported to play critical roles in heart rhythm,10, 11, 12 muscle contraction,13, 14 blood pressure,15, 16 insulin/glucose metabolism,17, 18 and bone integrity.19, 20 Increased consumption of processed food, filtered/deionized drinking water, and crops grown in Mg‐deficient soil has led to a significant decline of Mg intake in developed countries.21, 22 Most of the North American population consumes 185 to 235 mg/d Mg, compared with 450 to 485 mg/d in ≈1900.23 Dietary Mg intake is inversely correlated with the occurrence of metabolic diseases,24, 25 such as diabetes mellitus (types 1, 2, and 3)26, 27, 28 and hypertension,29, 30 that are high risk factors for diastolic dysfunction. Moreover, chronic diseases and medication can further decrease Mg absorption levels and cause hypomagnesemia (serum Mg concentration <0.8 mmol/L).
Mg deficiency is commonly observed in heart failure.31, 32, 33 Low serum Mg is a predictor for cardiovascular and all‐cause mortality34 and is associated with unstable cardiac repolarization, contributing to sudden cardiac death.34, 35, 36 Mg supplementation has been shown to improve heart function and contribute to a decreased risk of developing heart failure.37, 38 On the basis of these facts and our previous observation that Mg supplementation could improve cardiac relaxation in diabetes mellitus, we speculated that these clinical observations might be explained, in part, if Mg deficiency caused diastolic dysfunction and if this pathology were reversible with Mg.

Methods

Any supporting data not available within the article are available from the corresponding author on reasonable request. Full description of methods is in Data S1.

Reagents

Chemicals and reagents were purchased from Sigma‐Aldrich (St. Louis, MO), except as stated otherwise.

Study Approval

Animal care and interventions were undertaken in accordance with the National Institutes of Health Guide for the Care and Use of Experimental Animals, and the animal protocol (IACUC‐2003‐37940A) was approved by the Institutional Animal Care and Use Committees of the University of Minnesota.

Animal Groups

C57BL/6J mice were purchased from Jackson Laboratory (Bar Harbor, ME). Mice were randomly assigned to different groups at 10 weeks of age: (1) nl‐Mg: control mice fed with a normal Mg diet (TD.94253, containing 600 mg/kg Mg; Envigo Teklad Diets, Madison, WI) for 6 weeks; (2) low‐Mg: mice fed with a low‐Mg diet (TD.93106, containing ≈15–30 mg/kg Mg; Envigo Teklad Diets) for 6 weeks; (3) low→nl‐Mg: mice fed with the low‐Mg diet for 6 weeks and then given the normal Mg diet for another 6 weeks. Distilled and deionized H2O was given to all the mice to control any possible Mg intake from drinking water. In different experiments, different animal numbers (3–17 mice) were used for each group. The exact numbers are shown in figures or figure legends and Table in parentheses. The low‐Mg diet was chosen on the basis of a previous study by Rude et al, showing that this diet caused significant hypomagnesemia.20 Six of the low‐Mg mice were also treated with (2‐(2,2,6,6‐tetramethylpiperidin‐1‐oxyl‐4‐ylamino)‐2‐oxoethyl)triphenylphosphonium chloride (mitoTEMPO, IP injection, 1 mg/kg per day) for 2 weeks after 6‐week low‐Mg diet. Under general anesthesia with 2% isoflurane, the mouse heart was excised as the final step, and the heart was used for ventricular myocyte isolation, ATP tests, and protein lysates.
Table 1. Characteristics and Parameters of Mg Deficiency–Induced Changes in Low‐Mg Mouse Hearts and Cells: Reintroduction of Mg Normalized the Impairments Caused by Mg Deficiency
Parameternl‐MgLow‐MgLow→nl‐Mg
Cardiac function
EF, %52.0±1.7 (13)42.3±1.4 (21)*52.1±1.4 (18)
E/e’15.4±0.4 (5)21.1±1.1 (17)15.3±0.7 (12)
Volume, diastolic, µL66.0±3.2 (11)45.5±4.8 (12)*63.3±4.1 (6)§
LV mass Cor, mg94.6±3.0 (5)84.6±3.6 (6)91.2±3.5 (10)
LVPW, diastolic, mm0.77±0.05 (9)0.77±0.03 (6)0.81±0.02 (10)
LVPW, systolic, mm1.02±0.04 (9)0.95±0.03 (6)1.10±0.04 (10)
LVAW, diastolic, mm0.86±0.03 (5)0.77±0.04 (6)0.87±0.04 (10)
LVAW, systolic, mm1.12±0.06 (5)0.95±0.04 (6)1.21±0.06 (10)
QTc, ms46.0±1.2 (8)55.1±0.8 (6)*49.4±1.7 (8)§
Serum chemistry
Mg, mmol/L1.14±0.03 (13)0.38±0.03 (12)*1.10±0.04 (13)
Ca, mmol/L2.29±0.02 (13)2.73±0.10 (12)*2.36±0.03 (13)
K, mmol/L4.37±0.14 (13)4.87±0.12 (12)4.11±0.12 (12)
Na, mmol/L144.3±3.7 (7)152.8±0.9 (8)146.4±2.3 (8)§
Cellular parameters
Mg, F/F06.57±0.08 (13)2.90±0.02 (12)*6.46±0.09 (13)
Diastolic Ca, F/F01.28±0.03 (42)1.19±0.04 (42)1.25±0.09 (59)
ATP, µmol/g heart tissue2.7±0.2 (7)1.2±0.2 (9)*3.2±0.2 (8)
Mitochondrial ROS, ΔMFI232.4±17.3 (29)432.2±24.8 (67)*207.1±6.3 (118)
Mitochondrial Δψm, JC‐1 red/green ΔMFI0.76±0.04 (49)0.37±0.01 (79)*0.61±0.03 (70)
John Wiley & Sons, Ltd
Data represent the mean±SEM values. Numbers in parentheses indicate the mouse or cell numbers tested for each group. The 2‐tailed Student t test and 1‐way ANOVA with Bonferroni post hoc tests for multiple group comparisons were used. E/e’ indicates ratio between mitral peak early filling velocity E/longitudinal tissue velocity of the mitral anterior annulus e’; EF, ejection fraction; F/F0, ratio of cell fluorescent intensity F/background intensity F0; Low‐Mg, mice fed with low‐Mg diet; Low→nl‐Mg, mice fed with low‐Mg diet for 6 weeks and then normal Mg diet for another 6 weeks; LV Mass Cor, left ventricular mass corrected; LVAW, left ventricular anterior wall thickness; LVPW, left ventricular posterior wall thickness; nl‐Mg, control mice fed with normal Mg diet; QTc, corrected intervals between the Q and T waves of the ECG; ROS, reactive oxygen species; Δψm, mitochondrial membrane potential; and ΔMFI, difference of mean fluorescent intensity between cells and background in the same images.
*
P<0.01 vs nl‐Mg.
P<0.01 vs low‐Mg.
P<0.05 vs nl‐Mg.
§
P<0.05 vs low‐Mg.

Echocardiographic Assessment

Noninvasive echocardiography was performed with a Vevo 2100 ultrasound system (VisualSonics, Toronto, Canada), as we have done previously.5 The ratio between mitral peak early filling velocity E/longitudinal tissue velocity of the mitral anterior annulus e’ (E/e’) was used to evaluate the diastolic function. Cardiac EF was used to evaluate the systolic function.

ECG Recording

One minute of ECG signals from limb lead II were averaged for the measurement of corrected intervals between the Q and T waves of the ECG using the Mitchell formula.39

Telemetry

Cardiac rhythm was monitored using telemetry devices. Briefly, mice were implanted with ETA‐F10 transmitter (Data Science International, St. Paul, MN), as done previously.40

Serum Ion Levels and Urine Mg levels

Ions were measured with the Beckman Coulter AU480 Chemistry analyzer (Veterinary Medical Center, Clinical Pathology Lab, University of Minnesota, St. Paul, MN) within 24 hours of sample collection.

Cellular ATP Measurements

ATP was measured with the EnzyLight ATP Assay Kit (BioAssay Systems, Hayward, CA) by following the manufacturer’s instructions with ≈20 to 30 mg frozen ventricles.

Isolation of Ventricular Cardiomyocytes

Ventricular cardiomyocytes were isolated, as described before,5, 41, 42 and suspended in standard Tyrode solution for experiments.

Cytosol Mg Levels

The cytosol level of free Mg was measured using a specific Mg probe, Mag‐fluo‐4 AM (10 µmol/L; Thermo Fisher Scientific, Eugene, OR) by fluorescence microscopy (Zeiss Axio Inverted Observer.Z1; Zeiss, Thornwood, NY), as described previously.5

Mitochondrial Reactive Oxygen Species and Mitochondrial Membrane Potential

Mitochondrial reactive oxygen species (ROS) and mitochondrial membrane potential were measured by confocal imaging with isolated cardiomyocytes, as described before.5, 41, 42, 43

Cellular Ca Changes

The mechanical properties of cardiomyocytes were assessed using an IonOptix system (IonOptix LLC, Milton, MA), and cellular Ca2+ levels and transients were monitored by Indo‐1 fluorescence (2 µmol/L; Thermo Fisher Scientific), as done previously.5, 6, 7

Western Blotting for Protein Levels

Heart ventricles were collected and processed for Western blotting. The mouse cMyBPC antibody was purchased from Santa Cruz Biotechnology (sc‐137180; Dallas, TX), and the anti‐glutathione antibody was purchased from Virogen (101‐A100; Watertown, MA). GAPDH and β‐actin (Abcam, ab9484 and ab8277, Cambridge, MA) were used as loading controls.

Statistical Analysis

Data are presented as mean±SEM. For the dot plots, the lines indicated the mean values, and the error bars indicated SEM values. GraphPad Prism 5 (GraphPad Software Inc, San Diego, CA) was used for statistical analysis. The 2‐tailed Student t test and 1‐way ANOVA with Bonferroni post hoc tests for multiple group comparisons were used where appropriate. Figure S1 used the Kaplan‐Meier plot for the survival analysis of mice with the nl‐Mg and low‐Mg diet, and the log‐rank (Mantel‐Cox) test was applied for comparison between the 2 groups. The 2‐tailed paired Student t test was used when the same animals were tested before and after the mitoTEMPO treatment. P<0.05 was considered statistically significant.

Results

Changes of Serum and Urine Mg Under Low‐Mg Diet and Mg Repletion

After 6 weeks of low‐Mg diet, 31 of 48 male (64.6%) and 0 of 40 (0.0%) female mice survived. The Kaplan‐Meier survival curve of the mice on the normal and low‐Mg diet is shown in Figure S2. The log‐rank (Mantel‐Cox) test gave a P<0.0001. It is unknown if a shorter treatment time would have been equally deleterious. On the basis of observation and ECG telemetry, the mice died of seizures, a known complication of hypomagnesemia.44 We monitored the serum and urine Mg levels during the low‐Mg diet and after Mg repletion (for 2 weeks). As shown in Figure 1A, significantly decreased serum Mg was observed after 1 week of low‐Mg diet and reached a nadir after 2 weeks. The urine Mg levels reached a nadir after 1 week of low‐Mg diet (Figure 1B). The full recovery of serum and urine Mg levels after Mg repletion with the nl‐Mg diet took 1 and 2 weeks, respectively. Similar fast recovery of Mg levels has been observed in humans.45
image
Figure 1. The time courses of Mg changes in mouse serum and urine under different diets.
The Mg levels in mouse serum (A) and urine (B) were decreased during 6 weeks of the low‐Mg diet and recovered within 2 weeks of the normal Mg diet. A total of 3 to 13 mice were tested for each time point.

Mg Deficiency–Induced Cardiomyopathies

Echocardiography showed that low‐Mg mice had impaired relaxation with decreased ratio between the early and late diastole tissue velocity of the mitral valve anterior annulus e’ and a’ (as shown in Figure 2A) and increased E/e’ (Figure 2B and Table). In addition, decreased contractile function was observed in low‐Mg mice (EF, 42.3±1.4% versus 52.0±1.7% of nl‐Mg mice; P=0.0001; Table). ECGs showed prolongation of the corrected intervals between the Q and T waves of the ECG (Figure 2C). The low→nl‐Mg mice showed fully recovered heart function (Table). This implied that the Mg deficiency–induced cardiomyopathy was reversible by Mg repletion.
image
Figure 2. Mg deficiency impaired the cardiac functions with decreased ratio between the early and late diastole tissue velocity of the mitral valve anterior annulus e’ and a’ (e’/a’) ratio (A), increased ratio between mitral peak early filling velocity E/longitudinal tissue velocity of the mitral anterior annulus e’ (E/e’) (B), and prolonged corrected intervals between the Q and T waves of the ECG (QTc interval) (C).
Mg repletion in mice fed with low‐Mg diet for 6 weeks and then normal Mg diet for another 6 weeks (low→nl‐Mg) normalized these changes. A, Representative images of tissue Doppler echocardiography showed decreased e’/a’ ratio in low‐Mg mice compared with normal Mg (nl‐Mg) and low→nl‐Mg mice. The mean and SEM (error bars; see Table) and the exact numbers of mice tested are shown in parentheses in each figure. The 2‐tailed Student t test and 1‐way ANOVA with Bonferroni post hoc tests for multiple group comparisons were used. *P<0.05 vs nl‐Mg; #P<0.05 vs low‐Mg.

Serum and Cellular Ion Changes in Mg Deficiency

Compared with nl‐Mg mice, serum Mg levels were significantly decreased in low‐Mg mice (Table and Figure 3A), accompanied by increased serum Ca, K, and Na levels (Figure 3B through D). After 6‐week low‐Mg diet, the serum Mg level decreased to 0.38±0.03 mmol/L, compared with 1.14±0.03 mmol/L of nl‐Mg mice. This serum Mg level corresponds to severe hypomagnesemia in humans, which is <0.5 mmol/L, and has been associated with use of proton pump inhibitors and chemotherapeutic regimens.46, 47, 48 A correlation between serum Mg and E/e’ is shown in Figure S2. The linear regression fitting gave the following results: r2=0.3870, P=0.0077, and the slope=−7.0±2.3 per mmol/L serum Mg. The cellular Mg was also decreased in low‐Mg mice (P<0.0001 versus nl‐Mg; Table and Figure 3E). These parameters were fully restored to normal in low→nl‐Mg mice. As we have observed before with diastolic dysfunction, the cellular diastolic Ca level was not affected by low‐Mg diet (Figure 3F).5 The Ca transient peak time (the time from the start of Ca transient to the peak) and decay time (the time from peak to 10% of the baseline) were unaltered in low‐Mg myocytes (Figure S3). Consistent with the systolic dysfunction (decreased EF), the cellular Ca transient amplitude was decreased, together with reduced sarcoplasmic reticulum Ca load and fractional release in low‐Mg myocytes (Figure S3).
image
Figure 3. Serum ion levels and the cellular Mg level were altered by Mg deficiency.
The serum chemistry (A through D: serum Mg, Ca, Na, and K) and cellular Mg (E) levels were altered by Mg deficiency in low‐Mg mice and normalized by Mg repletion in mice fed with low‐Mg diet for 6 weeks and then normal Mg diet for another 6 weeks (low→nl‐Mg). F, The cellular diastolic Ca levels were unaltered under these conditions. The mean and SEM (error bars; see Table) and the exact numbers of mice or cardiomyocytes tested are shown in parentheses in each figure. The 2‐tailed Student t test and 1‐way ANOVA with Bonferroni post hoc tests for multiple group comparisons were used. *P<0.05 vs normal Mg (nl‐Mg); #P<0.05 vs low‐Mg. F/F0 indicates ratio of cell fluorescent intensity F/background intensity F0.

Cellular ATP and Mitochondrial Function

As shown in Figure 4 and Table, the cellular ATP level was significantly decreased in low‐Mg mouse hearts (1.2±0.2 versus 2.7±0.2 µmol/g heart tissue of nl‐Mg; P=0.0002), indicating a dysregulated cellular energy metabolism. At the mitochondrial level, we observed significantly increased mitochondrial ROS and depolarized mitochondrial membrane potential in low‐Mg mouse cardiomyocytes. Cellular ATP and mitochondrial ROS were fully recovered in low→nl‐Mg myocytes, and mitochondrial membrane potential was partially repolarized. This change in mitochondrial ROS production was not secondary to antioxidant manganese superoxide dismutase or catalase, which were unaltered in low‐Mg hearts (1.07±0.14‐fold and 0.96±0.09‐fold of nl‐Mg, respectively; P>0.05 versus nl‐Mg; Figure S4).
image
Figure 4. The mitochondrial function was altered in low‐Mg hearts, as shown in decreased cellular ATP levels (A), increased mitochondrial reactive oxygen species production (B), and depolarized mitochondrial membrane potential (C).
All 3 parameters were normalized by Mg repletion in mice fed with low‐Mg diet for 6 weeks and then normal Mg diet for another 6 weeks (low→nl‐Mg). The mean and SEM (error bars; see Table) and the exact numbers of mice (A) or cardiomyocytes (B and C) tested are shown in parentheses in each figure. The 2‐tailed Student t test and 1‐way ANOVA with Bonferroni post hoc tests for multiple group comparisons were used. *P<0.01 vs normal Mg (nl‐Mg); #P<0.001 vs low‐Mg. ΔMFI indicates difference of mean fluorescent intensity between cells and background in the same images.

Possible Mechanisms for the Mg Deficiency–Induced Diastolic Dysfunction

Mg deficiency–induced diastolic dysfunction is associated with impaired sarcomere relaxation and S‐glutathionylated cMyBPC.6, 7 Herein, we observed significant elevation of S‐glutathionylated cMyBPC in low‐Mg heart tissue (1.4±0.2‐fold; P=0.020 versus nl‐Mg; Figure 5), consistent with increased oxidative stress and diastolic dysfunction in low‐Mg mice (Figure 2). These protein changes were reversed in low→nl‐Mg mouse hearts (P=0.038 versus low‐Mg).
image
Figure 5. Mg deficiency increased the S‐glutathionylation of cMyBPC (cardiac myosin‐binding protein C) (S‐Glu‐cMyBPC), a marker protein of diastolic function, which was normalized in mice fed with low‐Mg diet for 6 weeks and then normal Mg diet for another 6 weeks (low→nl‐Mg) mouse hearts.
A, The protein levels of S‐Glu‐cMyBPC were normalized by the loading control protein, β–actin. B, Images of protein bands were obtained with 3 hearts from each group by Western blotting. The mean and SEM (error bars) values are shown. The 2‐tailed Student t test and 1‐way ANOVA with Bonferroni post hoc tests for multiple group comparisons were used. *P=0.020 vs normal Mg (nl‐Mg); #P=0.038 vs low‐Mg.

mitoTEMPO Improved Cardiac Diastolic Function

Previously, we have reported that a mitochondrial‐specific ROS scavenger, mitoTEMPO, improves cardiac diastolic function.6 Herein, we treated low‐Mg mice with mitoTEMPO (IP injection, 1 mg/kg per day) for 2 weeks after a 6‐week low‐Mg diet and observed significant improvement in diastolic function. Figure 6A showed representative tissue Doppler traces with e’ and a’ waves. Figure 6B showed decreased E/e’ ratio after mitoTEMPO treatment (16.7±2.0 after treatment versus 23.2±2.0 before treatment; P=0.046) determined by echocardiography. Cellular ATP levels were significantly increased by mitoTEMPO treatment (4.4±0.6 µmol/g heart weight versus 1.2±0.2 µmol/g heart weight of low‐Mg mouse hearts; P<0.0001; Figure 6C). The increased S‐glutathionylated cMyBPC in low‐Mg mouse hearts was decreased by mitoTEMPO treatment from 1.6±0.1‐fold of the nl‐Mg group to 1.2±0.1‐fold (P=0.007 versus low‐Mg and P=0.25 versus nl‐Mg), as shown in Figure 6D and E.
image
Figure 6. mitoTEMPO (2‐[2,2,6,6‐tetramethylpiperidin‐1‐oxyl‐4‐ylamino]‐2‐oxoethyl)triphenylphosphonium chloride; MT) treatment (1 mg/kg per day, IP injection for 2 weeks) of low‐Mg mice improved the cardiac diastolic function with increased ratio between the early and late diastole tissue velocity of the mitral valve anterior annulus e’ and a’ (e’/a’) (A), decreased ratio between mitral peak early filling velocity E/longitudinal tissue velocity of the mitral anterior annulus e’ (E/e’) (B), increased cellular ATP levels (C), and decreased S‐glutathionylation of cMyBPC (cardiac myosin‐binding protein C) (S‐Glu‐cMyBPC) protein levels (D).
A, Representative images of tissue Doppler echocardiography showed decreased e’/a’ ratio in low‐Mg mice, which was reversed by MT treatment (MT‐low‐Mg). E, Images of protein bands were obtained with 4 hearts from each group by Western blotting. Protein levels were normalized by the loading control protein GAPDH. The mean and SEM (error bars) values and the tested mouse numbers (in parentheses) are shown in C and D. The 2‐tailed Student t test and 1‐way ANOVA with Bonferroni post hoc tests for multiple group comparisons were used. *P<0.05 vs normal Mg (nl‐Mg); #P<0.05 vs low‐Mg or before MT treatment. In B, “before,” low‐Mg mice before MT treatment; “after,” same low‐Mg mice after MT treatment. The 2‐tailed paired Student t test was used in (B) and P=0.034.

Discussion

Hypomagnesemia has been associated with heart failure, but this has generally been assumed to be the result of a systolic cardiomyopathy.49 Nevertheless, we have shown that Mg supplementation can reverse diastolic heart failure caused by diabetes mellitus.5 Therefore, we tested whether hypomagnesemia alone could cause diastolic dysfunction that might contribute to the clinical syndrome of heart failure. After 6 weeks of low‐Mg diet, mice had severe hypomagnesia and showed cardiac diastolic dysfunction, accompanied by systolic dysfunction, disturbed cellular Mg and Ca homeostasis, mitochondrial dysfunction, altered cellular energy metabolism, and increased S‐glutathionylated cMyBPC. Mg repletion was able to reverse these changes and improve diastolic function, suggesting that cardiac structural changes were unlikely to explain the cardiomyopathy. In agreement with our previous study,6 the diastolic myopathy was reversible by inhibition of mitochondrial oxidative stress. A scheme of these mechanism changes is shown in Figure 7. The effect of low Mg on female heart function was prevented by premature death and remains to be determined.
image
Figure 7. A summarized scheme of Mg deficiency–induced cardiac diastolic dysfunction that can be reversed by Mg repletion or mitoTEMPO (2‐[2,2,6,6‐tetramethylpiperidin‐1‐oxyl‐4‐ylamino]‐2‐oxoethyl)triphenylphosphonium chloride) treatment.
MyBPC indicates myosin‐binding protein C.
Mg deficiency has been associated with oxidative stress in diabetes mellitus, hypertension, Alzheimer disease, and Parkinson disease.5, 50, 51, 52 In cardiomyocytes, intracellular Mg concentration is normally tightly maintained (free ionized Mg, 0.8–1.0 mmol/L).53, 54 In our study, the cellular Mg level was significantly decreased in cardiomyocytes isolated from low‐Mg mouse hearts, likely resulting from hypomagnesemia‐induced Mg efflux. Such an intracellular Mg deficiency has been shown to disrupt mitochondrial function by altering coupled respiration55, 56 and increasing mitochondrial ROS production.5, 57 Mitochondrial dysfunction and accompanying oxidative stress have been seen in diastolic cardiomyopathies.6, 58 The degree of hypomagnesemia seen in our study is rare but not unreported.46 Lesser degrees of hypomagnesemia would likely show a less prominent phenotype. Nevertheless, our previous study has shown that mild hypomagnesemia (plasma Mg, 0.80±0.04 mmol/L of diabetic mice versus 1.00±0.03 mmol/L of healthy control mice; P=0.0003) induced by diabetes mellitus was associated with diastolic dysfunction.5 Therefore, it seems likely that even milder hypomagnesemia will be pathogenic.
Mg intake has shown beneficial effects on inhibiting mitochondrial ROS production in heart, liver, and carotid artery stenosis.5, 59 Herein, we showed directly that Mg deficiency can cause diastolic dysfunction by inducing mitochondrial dysfunction. This was evidenced by reduced cellular ATP levels, increased mitochondrial ROS, and depolarized mitochondrial membrane potential in low‐Mg mice. Mg repletion successfully reversed these changes, suggesting that Mg deficiency–induced mitochondrial dysfunction underlies diastolic cardiomyopathy. The amounts of antioxidant proteins were unaltered in low‐Mg hearts, suggesting that the increased mitochondrial oxidative stress likely resulted from ROS overproduction from the mitochondrial electron transport chain.55
In vivo treatment with a mitochondria‐targeted ROS scavenger, mitoTEMPO, has shown significant improvement in 2 animal models of diastolic dysfunction induced by hypertension and diabetes mellitus, respectively.6, 7 Herein, we showed that this drug also improved Mg deficiency–induced diastolic dysfunction, suggesting that mitochondrial oxidative stress is a common cause of many forms of diastolic dysfunction. Nevertheless, we cannot rule out other sources of oxidative stress as important in the pathology and have not shown that S‐glutathionylation of cMyBPC is the only possible mechanism for generation of diastolic dysfunction. For example, we cannot rule out changes in the ADP/ATP ratio as contributing to alterations in the cross‐bridge kinetics.
Our previous studies on cardiac diastolic dysfunction have shown no changes in the expression levels or phosphorylation of major myofilament proteins, such as troponin I, myosin light chain 2, and cMyBPC, that correlate with the presence of diastolic dysfunction.7, 60 On the other hand, the S‐glutathionylation of cMyBPC, an oxidative modification, is significantly increased in cardiac diastolic dysfunction in different animal models and can be reversed by antioxidants, such as mitoTEMPO and tetrahydrobiopterin, that prevent or treat diastolic dysfunction.6, 7, 60 Furthermore, this modification alters myofilament properties in a manner that can explain diastolic dysfunction.7, 60 Therefore, we used the protein levels of S‐glutathionylated cMyBPC as a marker of diastolic dysfunction in this study while recognizing that other yet to be elucidated modifications may also contribute to diastolic dysfunction. Moreover, the diastolic dysfunction was reversed by Mg repletion and mitoTEMPO, both of which suppressed mitochondrial ROS overproduction, improved mitochondrial function, and reduced levels of the oxidized myofilament protein. These results suggest that Mg deficiency alone is sufficient to cause diastolic dysfunction and that Mg repletion and mitoTEMPO have protective effects on diastolic function.
In addition to diastolic dysfunction, hypomagnesemia induced a reversible systolic dysfunction. As expected, this systolic dysfunction was associated with alterations in Ca handling. Although the origin of the systolic cardiomyopathy is unclear, the reversal with Mg repletion argues for a physiological change, rather than cell death or another structural alteration.
Female mice appeared more susceptible to seizures induced by hypomagnesemia than did male mice. This occurred despite similar serum Mg levels and similar loss of Mg in the urine. Mg deficiency has been shown to cause irritability of the nervous system, leading to epileptic seizures in clinical and experimental studies,61 and Ca leak induced by gain‐of‐function changes of ryanodine receptor 2 has been linked to sudden unexpected death from epilepsy.62, 63 Nevertheless, it remains unclear why a sexual dimorphism occurred, but it appears to be independent of effects on the heart.
In summary, Mg deficiency independently caused diastolic cardiomyopathy associated with mitochondrial dysfunction. Even with severe hypomagnesemia, the systolic function was only mildly affected, suggesting that diastolic dysfunction may help explain the association of hypomagnesemia and heart failure in patients. Mg repletion could be an effective therapy for heart failure associated with hypomagnesemia.

Sources of Funding

This work was supported by the National Institutes of Health R01 HL104025 (Dr Dudley) and R01 HL106592 (Dr Dudley).

Acknowledgments

The confocal imaging of MitoSox Red and JC‐1 was performed with the assistance of Dr Mark A. Sanders at the University of Minnesota–University Imaging Center (http://uic.umn.edu).

Footnotes

Supplementary Material for this article is available at Supplemental Material
For Sources of Funding and Disclosures, see page 10.

Supplemental Material

File (jah36324-sup-0001-datas1-figs1-s5.pdf)
Data S1
Figure S1–S5

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PubMed: 34096318

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Received: 17 November 2020
Accepted: 19 April 2021
Published online: 5 June 2021
Published in print: 15 June 2021

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Keywords

  1. Ca handling
  2. diastolic dysfunction
  3. hypomagnesemia
  4. mitochondrial dysfunction

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Notes

(J Am Heart Assoc. 2021;10:e020205. https://doi.org/10.1161/JAHA.120.020205.)

Authors

Affiliations

Division of Cardiology Department of Medicine The Lillehei Heart InstituteUniversity of Minnesota at Twin Cities Minneapolis MN
Hong Liu, MD, PhD
Division of Cardiology Department of Medicine The Lillehei Heart InstituteUniversity of Minnesota at Twin Cities Minneapolis MN
Feng Feng, BS
Division of Cardiology Department of Medicine The Lillehei Heart InstituteUniversity of Minnesota at Twin Cities Minneapolis MN
An Xie, PhD
Division of Cardiology Department of Medicine The Lillehei Heart InstituteUniversity of Minnesota at Twin Cities Minneapolis MN
Gyeoung‐Jin Kang, PhD
Division of Cardiology Department of Medicine The Lillehei Heart InstituteUniversity of Minnesota at Twin Cities Minneapolis MN
Yang Zhao, MD, PhD
Division of Cardiology Department of Medicine The Lillehei Heart InstituteUniversity of Minnesota at Twin Cities Minneapolis MN
Division of Cardiology Department of Medicine The Lillehei Heart InstituteUniversity of Minnesota at Twin Cities Minneapolis MN
Xiaoxu Zhou, MD, PhD
Division of Cardiology Department of Medicine The Lillehei Heart InstituteUniversity of Minnesota at Twin Cities Minneapolis MN
Division of Cardiology Department of Medicine The Lillehei Heart InstituteUniversity of Minnesota at Twin Cities Minneapolis MN

Notes

*
Correspondence to: Samuel C. Dudley, Jr, Division of Cardiology, The Lillehei Heart Institute, VCRC 286–MMC 508, 425 Delaware St SE, Minneapolis, MN 55455. E‐mail: [email protected]

Disclosures

None.

Funding Information

National Institutes of Health: R01 HL104025, R01 HL106592

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  1. Transient receptor potential melastatin 7 cation channel, magnesium and cell metabolism in vascular health and disease, Acta Physiologica, 241, 2, (2025).https://doi.org/10.1111/apha.14282
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  2. Propensity score matched cohort study on magnesium supplementation and mortality in critically ill patients with HFpEF, Scientific Reports, 15, 1, (2025).https://doi.org/10.1038/s41598-025-85931-1
    Crossref
  3. Magnesium and the Hallmarks of Aging, Nutrients, 16, 4, (496), (2024).https://doi.org/10.3390/nu16040496
    Crossref
  4. Role of Magnesium in Skeletal Muscle Health and Neuromuscular Diseases: A Scoping Review, International Journal of Molecular Sciences, 25, 20, (11220), (2024).https://doi.org/10.3390/ijms252011220
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  5. Bringing into focus the central domains C3-C6 of myosin binding protein C, Frontiers in Physiology, 15, (2024).https://doi.org/10.3389/fphys.2024.1370539
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  6. Beyond Ion Homeostasis: Hypomagnesemia, Transient Receptor Potential Melastatin Channel 7, Mitochondrial Function, and Inflammation, Nutrients, 15, 18, (3920), (2023).https://doi.org/10.3390/nu15183920
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  7. Экспериментальное изучение двойной системы Mg3(PO4)2–Mg4Na(PO4)3, Неорганические материалы, 59, 5, (521-528), (2023).https://doi.org/10.31857/S0002337X23050147
    Crossref
  8. PHYSICOCHEMICAL, BIOCHEMICAL, PHARMACOLOGICAL PROPERTIES OF MAGNESIUM, Bulletin of Problems Biology and Medicine, 1, 2, (74), (2023).https://doi.org/10.29254/2077-4214-2023-2-169-74-81
    Crossref
  9. Experimental Study of the Binary System Mg3(PO4)2–Mg4Na(PO4)3, Inorganic Materials, 59, 5, (500-506), (2023).https://doi.org/10.1134/S002016852305014X
    Crossref
  10. TRPM7 kinase mediates hypomagnesemia-induced seizure-related death, Scientific Reports, 13, 1, (2023).https://doi.org/10.1038/s41598-023-34789-2
    Crossref
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