Magnes Res 1990 Sep;3(3):219-26
Historical review of the effects of marginal intake of
magnesium in chronic experimental magnesium deficiency
K. S. Kubena1 and J. Durlach2
1Graduate Faculty of Nutrition, Department of
Animal Science, Texas A & M University, College Station,
Texas, USA; 2President of SDRM, 64 Rue de Longchamp,
Neuilly sur Seine, France
Summary: After the discovery of
magnesium as an essential nutrient in 1926, research focused upon
the identification of effects of an acute deficiency state and
determination of the requirement for the mineral for normal
growth and reproduction. In this early work, marginal intakes of
magnesium were reported to result in alterations of tissue
composition. Since the 1970s, research has shown that the ability
to adapt to a marginal intake of magnesium, which is commonplace
in developed countries, is limited. In fact, a low intake of the
mineral for an extended period of time may be associated with
abnormalities in reproduction, growth, and development and may be
a factor in the pathogenesis of disorders of neuromuscular,
cardiovascular, renal, and immune function. Problems related to
the use of pharmacological agents or to trace metals, such as
aluminium, may be worsened in the presence of a low intake of
magnesium. Evidence presented illustrates that, although physical
signs of magnesium deficiency may be absent, that is to say in
cases of latent clinical forms, a marginal dietary inadequacy of
the mineral over a long period of time could result in
significant problems.
Key words: Chronic magnesium
deficiency, magnesium, magnesium deficit, magnesium deficiency,
marginal intake, suboptimal intake.
Introduction
Dietary intake of magnesium in developed countries is often
far below recommended amounts1. Furthermore, the
recommendations have been set at levels less than those amounts
of magnesium required to achieve equilibrium in balance studies
with humans2. Consequently, a chronic dietary
inadequacy of magnesium is commonplace.
Magnesium deficiency and its effects were first reported about
19303,4. This early work involved feeding diets
containing very little magnesium, inducing an acute deficiency
state. Repletion of the animals with magnesium allowed
elucidation of the physiological roles of the
mineral5. However, it was some time before chronic
marginal magnesium deficiency, a circumstance which is much
closer to that seen in humans, was investigated.
The purpose of this paper is to review briefly studies which
included, if not necessarily focused upon, marginal intakes of
magnesium in experimental magnesium deficiency. The National
Research Council (NRC) has recommended levels of energy and
nutrients to be included in diets of laboratory
animals6. For example, diets for the laboratory rat
should include 16.5 mmol magnesium/kg diet6. However,
the level of magnesium used as 'normal' varies considerably
between authors. For example, a commonly-used commercial rat chow
has been reported to contain 86.4 mmol magnesium/kg
diet7. In addition, the particular level of magnesium
in the diet which would allow the diet to be considered
marginally deficient varies depending upon a number of factors,
including stress8, other dietary
components8,9, and species10. For the
purpose of this discussion, a marginal intake of magnesium is
defined as one which is tolerated by the subject for a prolonged
period of time without the development of major abnormalities
which, in the case of the studies reviewed here, involves a
magnesium concentration approximating 4 mmol/kg.
Early studies were often conducted for a brief period of time.
With severe restriction of magnesium, deficiency signs occur
rapidly, while with more moderate restriction, more time is
required before symptoms of deficiency become evident. In
(illegible), Osborne and Mendel attempted to induce a deficiency
state in rats with a diet containing more than 4.1 mmol
magnesium/kg diet11. They observed no 'untoward
effects' of this regime and stated that magnesium deficiency had
not developed in these rats.
In early work with minerals, environmental contamination,
coprophagy, and other circumstances often increased magnesium
availability such that the actual level of magnesium consumed by
the animals was much higher than that which was contained in the
diet. These potential problems are routinely controlled in
research with minerals today, but their importance was not
recognized in early work. In addition, the ability to analyse
substances for small amounts of magnesium was not as reliable as
desired until the advent of atomic absorption
spectrophotometry.
Magnesium requirements
A conclusion of a study reported in 194812 was that
8.2 mmol/kg was an adequate level of magnesium to permit optimal
growth in the rat. Although the data supported the conclusion,
the study lasted only 12 days.
Hegsted et al.13 conducted one of the
first studies in which problems associated with a marginal intake
of magnesium were described. In this study, rats fed 10.3 mmol
magnesium/kg diet grew as well as those fed higher levels of the
mineral and better than those fed 4.9 mmol/kg. However, when rats
fed the 10.3 mmol diet were maintained at a cold temperature
(13° C), they grew less than those fed higher levels of
magnesium. Even more striking was the fact that no animal which
was fed a high calcium diet with 10.3 mmol magnesium/kg and which
was kept at this temperature survived, while many which were fed
higher levels of magnesium survived. These workers concluded that
stress, in this case cold stress, increased the requirement for
magnesium, as did a high calcium diet.
The objective of studies performed with levels of magnesium
which varied from severe restriction to a generous intake
generally was to determine the requirement of the mineral for
growth, reproduction, and maintenance of the animal. Through
these studies, some effects of moderate magnesium restriction
were identified in spite of the fact that this had not been an
original intent of the work.
McAleese & Forbes14 used regression analysis to
determine that maximal growth in rats could be achieved with 4.1
mmol magnesium/kg while greater amounts were needed for maximal
bone and blood magnesium, 8.2 and 14.4 mmol/kg, respectively.
This research was the basis for the NRC recommendation for
magnesium for (illegible) reported earlier13,
additional magnesium was needed if the diet was high in calcium.
McAleese & Forbes suggested that, since the use of weight
gain as the only criterion for magnesium adequacy was
insufficient in their study, and index such as kidney
calcification might be used as an indication of borderline
deficiency. The relationship of marginal magnesium deficiency to
renal function and disease thus was identified.
Magnesium metabolism is closely related to that of many other
nutrients, especially calcium. A study in which this was
illustrated was conducted by Forbes15. Typical signs
of magnesium deficiency were noted in rats fed 5.8 mmol
magnesium/kg only when it contained a high calcium level as well.
In this work, the moderately low magnesium diet was associated
with the development of brittle bones, a finding which was
confirmed by Miller et al.16 in a study with
pigs. Bone strength in the pigs which were fed 5.1 mmol
magnesium/kg was less than in those animals fed normal amounts of
the mineral. A possible role for marginal magnesium deficiency in
bone disease was suggested by these findings.
Early studies which had assessed magnesium adequacy by weight
gain had been replaced by those which also included assessment of
mineral content and function of tissues, e.g. renal
calculosis and bone strength. The interaction of a marginal
magnesium intake with other nutrients, especially minerals, was
being recognized.
A 1966 study by Forbes17 resulted in the
observation that a diet containing half of the recommended level
of magnesium was associated with significant alterations of
electrolytes in tissues of rats. Serum magnesium and phosphate
and bone magnesium and potassium were lower, while renal calcium
was increased, in the animals fed the low magnesium diet.
Effects of magnesium deficiency, which had been reported to be
exacerbated by high protein intakes in severe magnesium
restriction18, were also intensified by high protein
with a more moderate level of restriction, 4.1
mmol/kg19. Protein intake was directly correlated with
growth rate, with faster growth apparently increasing the
requirement for magnesium.
Hunt20 fed young, mature, and old rats 1/2, 1/4, or
1/8 of the control level (0.8-1.2 mmol/100 g body weight) of
magnesium. Weight was about the same in all groups by the end of
the study. Bone magnesium was less as magnesium intake decreased,
although this effect was attenuated in the older rats. This
researcher suggested that new bone mirrored magnesium intake
while composition of bone in older animals was less labile.
Magnesium in skeletal muscle was not affected by any of the
deficient diets; however, cardiac magnesium was reduced with the
low magnesium diets.
Magnesium and cardiovascular disease
The study by Hunt20 demonstrated the potential
impact of marginal magnesium deficiency on cardiovascular
function. An earlier study by Hellerstein et
al.21 illustrated the influence of moderate
magnesium restriction on serum lipids. Rats fed 9.9 mmol
magnesium/kg with added cholesterol and cholic acid had higher
serum cholesterol levels than did those which were fed four or
eight times that amount of magnesium.
In 1975, Heroux et al.22 reported results
of an experiment which lasted 517 days in which rats were fed 4.9
or 20.6 mmol magnesium/kg. Magnesium balance, magnesium content
of plasma, tibia, and fat free dry carcass, and bone strength
were reduced in the low magnesium group. Another 517 day study,
again by Heroux et al.23, involved exposure
of rats to cold stress. This stress resulted in the development
of calcified cardiac lesions in the low magnesium (4.1 mmol/kg)
group as compared to uncalcified lesions in the control-fed rats.
The authors concluded that results from their work confirmed the
hypothesis that chronic suboptimal intake of magnesium may not
cause overt signs of deficiency but may reduce stress resistance
with time and, in fact, may predispose humans to myocardial
infarction. Evidence was presented that the ability of animals to
adapt to a low magnesium intake over a long period of time was
limited. Previously, Britton & Stokstad24 observed
aortic calcification in magnesium-deficient rats (4.1 mmol/kg
diet). Elastin was the site of calcification, and elastin
metabolism was altered in the deficient animals.
In the 1980s, several studies have addressed the relationship
between marginal dietary magnesium intake and cardiovascular
disease. The report by Altura et al.25 of
microvascular changes and elevated arterial pressure associated
with moderate magnesium deficiency (4.9 mmol/kg with or without
3.9 mmol Mg/litre water) in rats received a great deal of
attention. They reported reduced lumen size, less blood flow in
capillaries, and more vasoconstriction in rats with a marginal
intake of magnesium.
However, other reports contain contradictory results.
Magnesium deficiency has been reported to exert a normotensive or
hypotensive rather than hypertensive effect in
vivo26,27. In addition, individuals with primary
magnesium deficit generally have normal serum levels of magnesium
while hypertensives are usually normomagnesaemic. Nishiyama
et al.28 stated that blood pressure was not
altered in rats which were magnesium-deficient for 7 months. It
has been suggested that, rather than magnesium being a major
antihypertensive nutrient, magnesium deficiency may enhance the
effect of a hypertensive factor because of the effects of the
mineral on renal, (illegible). This point is illustrated by
results of the study by Berthelot & Esposito which indicated
that a low magnesium diet (3.3 mmol/kg) accelerated the
development of hypertension in the spontaneously hypertensive rat
(SHR)29. Another example of this point is a report by
Overlack et al.30 who did not observe an
effect of magnesium deficiency (4.1 mmol/kg) on blood pressure in
rats but reported that this moderate deficiency of magnesium
attenuated the action of a calcium antagonist in lowering blood
pressure. Likewise, a recent report by Stein &
Classen31 indicated that action of a beta-adrenergic
blocking agent was impaired in the presence of a moderate
magnesium deficiency (4.1 mmol/kg).
Fischer & Giroux32 found that activity of
cardiac Na+-K+ ATPase was less in rats fed
8.2 mmol magnesium/kg than in controls, although the
concentration of molecules of the enzyme was unchanged. This
would partially explain changes in electrolyte levels within
cells, including the heart, found in magnesium deficiency (higher
levels of sodium and calcium and lower levels of magnesium and
potassium)33. Previously, Fischer &
Giroux34 had suggested that the elevated calcium to
magnesium ratio which they observed in cardiac tissue of
magnesium-deficient rats (3.3 mmol/kg diet) could result in an
increased contractile response in the coronary arteries and
venous smooth muscles. Subsequently, coronary artery spasm could
develop leading to ischaemia and arrhythmia. These researchers
also stated that the increased cardiac sodium of the
magnesium-deficient rats might change the membrane potential,
making the heart more susceptible to arrhythmias34.
Ito et al.34a observed in swine that a
suboptimal magnesium intake (around half the recommended
requirement) in combination with a moderate excess of Vitamin D
(usual for the average American population), intensifies
ultrastructural changes in the coronary arteries.
Experiments with diets severely deficient in magnesium have
shown that lipid metabolism is abnormal and platelet function is
altered, with a predisposition to thrombosis. Moderate magnesium
deficiency has the potential to be linked to an increased risk of
cardiovascular disease. An elevation in serum total cholesterol
which was seen in rats fed a low magnesium diet (3.3 mmol/kg) by
Brilla & Lombardi35 was also reported by
Luthringer et al.36 in rats fed a diet which
contained the same amount of magnesium. The latter group noted
hypertriglyceridaemia and a drop in high-density lipoprotein
cholesterol (although hypertension did not occur in their
hypomagnesaemic animals). Also of interest in Luthringer's report
was the fact that vascular reactivity to noradrenaline was higher
in magnesium-deficient animals. Cunnane et
al.37 reported changes in fatty acid composition
of diet (4.4 mmol/kg).
Prostanoid synthesis is altered in magnesium deficiency. Rats
fed a diet containing 3 mmol magnesium/kg were reported by Nigam
et al.38 to have higher levels of
6-keto-PGFla, TXB2, and PGE2 than control animals. These authors
suggested that magnesium deficiency may reduce inhibition or may
stimulate production of prostaglandins. Soma et
al.39 found increases in these prostanoids, as
well as PGI2, from the mesenteric artery bed in rats fed a diet
with magnesium concentration of 4.5 mmol/kg. They attributed the
increases to a stimulatory effect of magnesium deficiency.
One of the risk factors for cardiovascular disease is diabetes
mellitus. A study which addressed glucose metabolism with
magnesium deficiency (4.1 and 8.2 mmol/kg) was conducted by
Legrand et al.40. Results indicated that
magnesium inadequacy was associated with abnormal glucose
tolerance and reduced pancreatic insulin as compared to rats fed
30.9 mmol magnesium/kg diets. This supported results of an
earlier study by McNeill et al.41 in which a
3.3 mmol magnesium diet was associated with a lower insulin to
glucagon ratio.
Magnesium and renal function
Although its aetiology is unclear, renal calcium accumulation
has been reported to occur with magnesium deficiency, the degree
proportional to the degree of deficiency42. Recently,
renal calculosis was observed in animals fed levels as high as
24.7 mmol magnesium/kg43. One hypothesis for this
phenomenon in mild, as well as acute, deficiency is that renal
conservation of magnesium causes a reduction in the
magnesium-to-calcium ratio within the tubular lumen allowing
calcium to precipitate42.
Magnesium and stress
Neuromuscular hyperexcitability has been shown to occur in
moderate as well as severe magnesium deficiency44.
Through EEF and EMG tracings, Pocnaru et
al.44 observed a diffuse neuromuscular
hyperexcitability in rats fed a low magnesium diet (2.1
mmol/kg).
Hypersensitivity to stress is commonly seen in magnesium
deficiency. In the work of Heroux et al.23,
rats mildly deficient in magnesium had a shorter lifespan than
did the controls when exposed to cold stress. After travelling
from the Houston-based supplier during particularly cold weather
in December, several weanling rats fed a magnesium-deficient diet
(3.1 mmol/kg) for five days suffered audiogenic seizures and
died45. Magnesium deficit may be a conditioning factor
for the development and potentiation of
stress46,47.
Since the mid-1970s, studies examining the role of marginal
magnesium intake on reproduction have been reported 45,
48-61. Results from a study by Broccia et
al.60 indicated that the requirement for
magnesium during gestation of rats was between 10.3 and 20.6
mmol/kg diet.
Buck and colleagues noted problems with lactation of dams fed
diets containing either 8.248 or 5.1 mmol
magnesium/kg52. Growth of rat pups was correlated with
milk yield and magnesium content of milk, both of which were
decreased with the low magnesium diet52.
Rayssiguier et al.49 reported that a
moderate deficiency of magnesium (4.5 mmol/kg) interfered with
normal parturition and uterine involution. These effects may have
been related to magnesium lack impairing function of oxytocin in
the former and collagen metabolism in the latter. A further
investigation of collagen metabolism involved the combination of
a marginal intake of magnesium (4.5 mmol/kg) and ingestion of
ethanol62. In this study, Rayssiguier et al.
saw higher collagen concentrations in livers of
magnesium-deficient alcohol-fed rats than in controls due to
increased collagen production in magnesium deficiency.
In a study conducted by Gunther et al.50,
rats were fed diets containing gradations of magnesium from 4.5
to 14.8, as well as 82.3 mmol/kg. A threshold for maternal serum
magnesium, which was a reflection of dietary intake, seemed to
exist, below which resorptions, growth retardation, and
malformations occurred. Diets providing 4.5, 6.6, and 10.7 mmol
magnesium/kg were inadequate to maintain serum magnesium above
this threshold. Vormann et al.51 showed that
a magnesium gradient across the placenta existed which was
maintained regardless of serum magnesium level of the mother.
A series of studies was conducted by Kubena and
colleagues45,53,54,57-59,61 in which weanling rats
were fed diets varying in magnesium from 5.1 to 9.3 mmol/kg
during postweaning growth, breeding, gestation, and, in most of
the studies, lactation. These investigations showed that, over
time, tissue content of magnesium decreased so that effects of a
moderate magnesium deficiency were more severe than would have
been observed in shorter studies. For example, in a report of
severe maternal magnesium restriction, Hurley et
al.63 noted a reduction in zinc status of pups.
This effect was also seen with long-term moderate magnesium
restriction (5.1 mmol/kg)54.
The relationship between dietary magnesium and calcium
continues to be unclear as shown by the fact that a high calcium
low magnesium (8.2 mmol/kg) diet fed to rats from weaning through
lactation was associated with larger and more viable pups than
those in the low magnesium, normal calcium group59.
(illegible) effect of high calcium with a low magnesium diet
comes from a recent study by Wright et al.64
in which chicks were fed 40% of the recommended level of
magnesium. Intestinal calcium absorption in these birds was
reduced. The second hydroxylation of vitamin D that takes place
in the kidney is a magnesium-requiring step. The combination of
renal calculosis and magnesium lack could reduce availability of
activated vitamin D which would result in less calcium-binding
protein. The end result would be impaired absorption of calcium.
However, when intestinal calcium binding protein (CaBP) in
duodenum, ileum, and jejunum was measured by RIA, no significant
differences were detected between control rats and those fed a
diet containing only 2.1 mmol magnesium/kg diet65.
In a recent study61, a magnesium-deficient (8.2
mmol/kg) diet fed to rats from weaning through gestation was
associated with impaired humoral immunity in pups, an effect
which was not reversible with magnesium repletion of dams during
lactation. The role of magnesium in the function of complement
and phagocytic activity was further elucidated in a study of rats
fed a diet containing 4.1 mmol magnesium/kg66.
Magnesium and other systems
Kleber & Fehlinger67 reported impaired
development of odontogenesis and posteruptive adaptability to
dental microbial plaque in progeny of rat dams
magnesium-deficient during gestation and lactation (7.0 mmol/kg).
Previously, a slowing of the rate of clinical emergence of
incisors in pups from dams fed low magnesium diets (6.2 mmol/kg)
from weaning through lactation had been reported58.
The impetus for the recent animal study by Kleber &
Fehlinger67 was observations which they had made in
patients suffering from the tetanic syndrome.
Arpad et al.67a observed after an 8 month
period of chronic magnesium deficiency in rats, not only the
known consequences on kidney, bone, cartilage, and teeth but also
effects on the sexual organs including atrophy of testes, ovaries
and uterus.
Magnesium and new areas of research
During the past few years, investigations of marginal
magnesium deficiency have focused on areas such as nutrient-drug
interaction. Caddell68 observed that magnesium
deficiency (7.8 mmol/kg) exacerbated calcification of kidney
associated with furosemide administration.
Cerklewski69 reported that rats fed marginal
magnesium-deficient diets (6.2 mmol/kg) had higher tissue
accumulation of lead than did controls. He suggested that this
may have resulted because calcium, iron, and zinc all affect
toxicity of lead and (illegible) later study, this researcher
observed an inverse relationship between magnesium and absorption
of fluoride in rats fed 8.2 mmol magnesium/kg70.
Nielsen et al.71 reported interactions
between magnesium deficiency and the trace metals, boron and
aluminum. Magnesium-deficient rats (4.9 mmol magnesium/kg)
experienced more severe symptoms in the presence of dietary
aluminium, while boron deprivation was worsened by magnesium
deficiency.
With the growing interest in nutrition in sports and exercise,
two studies in which rats were fed moderately magnesium-deficient
diets (4.1 or 8.2 mmol/kg72, 8.2 mmol/kg73)
have been published recently. In both of these investigations,
magnesium deficiency was associated with reduced endurance.
Conclusion
Information on the influence of a marginal magnesium-deficient
diet is accumulating. It is clear from these studies that
magnesium deficiency may be present in spite of the absence of
overt signs of deficiency and may be instrumental in changes
within tissues which impair function and/or promote disease.
The philosophy that absence of overt deficiency symptoms in
countries with low intakes of the nutrient is an indication that
the recommended levels are too high and should be reduced does
not agree with evidence presented here8.
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