ARTICLE
Auteur(s) : Stefano Iotti, Emil
Malucelli
Dipartimento di Medicina Interna, dell’Invecchiamento e Malattie
Nefrologiche, Università di Bologna, Italy
Many relevant pathological conditions, such as cardiovascular
diseases [1], essential hypertension [2], diabetes mellitus [3]
neuropsychiatric disorders [4, 5], metabolic syndrome [6, 7],
different types of migraine [8, 9] and mitochondrial cytopathies
[10] are associated with reduced Mg availability and/or increased
excretion either at a systemic level or in specific tissues.
Moreover, the beneficial effect of Mg administration in brain
pathological conditions has been also investigated. Several studies
have examined the clinical efficacy of Mg2+ therapy in
animal models of traumatic brain injury, showing that
administration of Mg2+ pre- or post-injury effectively
improved recovery of cognitive deficits following injury [11, 12]
and several pieces of evidence establish a connection between
magnesium deficiency and aging [13], providing a rationale for the
administration of Mg as a co-adjuvant agent for the retardation of
neurodegenerative processes typical of senescence.
Although the clinical effects of variations in serum
[Mg2+] have not been widely recognised [14], in routine
clinical practice [Mg2+] is assayed in serum and not
directly in tissues.
Phosphorus magnetic resonance spectroscopy (31P-MRS)
offers a unique opportunity to measure in vivo free cytosolic
magnesium concentration in several tissues [10, 15, 16]. The main
phosphorylated molecules present in the cell cytosol detected by
31P-MRS are inorganic phosphate (Pi), phosphocreatine
(PCr) and ATP [17]. Magnesium is almost completely bound to ATP in
the cytosol matrix. The amount of magnesium bound to ATP shifts the
resonance frequencies of signals coming from the three phosphoric
groups of the molecule (chemical shift). Due to the chemical
equilibrium between the Mg bound to ATP and free Mg2+,
the chemical shift of ATP signals is a function of free
Mg2+ concentration. With the availability of calibration
curves which take into account both: i) other ions present in the
cell cytosol competing with Mg2+ in binding ATP such as:
H+, Na+, K+ and ii) other ligands
as ADP, PCr and Pi competing with ATP in binding Mg2+,
it is possible to measure in vivo, not invasively and with high
accuracy the cytosolic free Mg2+ concentration in brain
and skeletal muscle in different metabolic conditions [18, 19].
In vivo assessment of Mg2+ in human skeletal
muscle
Skeletal muscles contain approximately 35% of total human body
magnesium. Magnesium ions influence the equilibria of many
reactions involved in cellular bioenergetics by interacting with
phosphorylated molecules [20] and interfere with the kinetics of
ion transport across plasma membranes. In particular,
Mg2+ is known to regulate Ca2+ traffic in
smooth [21] and skeletal [22] muscle cells by acting as a blocker
of Ca2+ channels. All this implies that an accurate
knowledge of intracellular magnesium concentration
([Mg2+]) is crucial for a deeper understanding of both
cellular bioenergetics and reaction kinetics in vivo., and that any
change in cellular [Mg2+] may alter critical regulatory
mechanisms, causing abnormal metabolism.
In skeletal muscle, variations of cytosolic pH, [PCr] and [Pi]
occurring in the transitions from rest to exercise and vice-versa,
influence the complex multi-equilibrium system of the molecular
species which bind magnesium ions. As a consequence, free cytosolic
[Mg2+] can change considerably in different metabolic
conditions such as rest, exercise and recovery.
It has been shown by 31P-MRS that the increase of
cytosolic free [Mg2+] occurring in skeletal muscle of
healthy subjects during exercise and initial recovery is matched by
a decrease in cytosolic pH, (figure 1) and the changes
in cytosolic free [Mg2+] were mainly the result of the
predominant effect of [H+] [19]. This result was
attributed to the mechanisms of the binding competition which
exists between Mg2+ and H+ towards the
negatively-charged molecules present in the cell cytosol.
The values of cytosolic free [Mg2+] measured in the
calf muscle of 42 healthy subjects during exercise and recovery,
plotted as a function of pH, showed an exponential pattern with a
sharp increase of [Mg2+] below pH 6.5 (figure 2). However, this
does not necessarily imply a causal relationship between pH and
[Mg2+], as it could be argued that muscular exercise per
se elicits an increase in cytosolic free [Mg2+].
Therefore, to understand to what extent homeostasis of
intracellular free Mg2+ is linked to pH, we studied
patients affected by McArdle’s and Tarui’s disease, which are
metabolic pathologies characterised by the absence of intracellular
acidification [23]. The results of the study show that, in the calf
muscle of these patients, the lack of intracellular acidification
was accompanied by a lack of Mg2+ increase. This outcome
provides experimental evidence that the increase in cytosolic
[Mg2+] occurring in skeletal muscle during exercise is
actually the consequence of an increase of H+
concentration and not of other mechanisms related to muscle
contraction.
In vivo assessment of Mg2+ in human brain
The free cytosolic [Mg2+] assessed in the human brain by
31P-MRS was 0.182 mM [18]. This value measured in the
occipital lobes of 36 healthy subjects is about half of that
assessed in the human calf muscle [19]. This result is most likely
related to the lower ATP concentration of brain tissue compared to
that of skeletal muscle, ATP being the major binding site present
in the cellular milieu. The possibility of assessing the free
cytosolic [Mg2+] in the human brain offered the chance
of studying the involvement of Mg in different neurological
pathologies. Particularly interesting are mitochondrial cytopathies
and migraines, in which the defective mitochondrial energy
production is respectively the primary causative or putative
pathogenetic factor.
Mg2+ in mitochondrial cytopathies
31P-MRS was used to assess the free Mg2+ in
the occipital lobes of patients affected by different types of
mitochondrial cytopathies due to known enzyme and/or mitochondrial
DNA defects, to clarify the functional relationship between energy
metabolism and the concentration of cytosolic free magnesium [10].
Cytosolic free [Mg2+] was found to be abnormally low in
all patients. Nine of the 19 patients investigated were treated
with CoQ which improved the efficiency of the respiratory chain, as
shown by an increased [PCr], decreased [Pi] and [ADP].
Administration of CoQ also increased cytosolic free
[Mg2+] in all treated patients (figure 3). These findings
suggest that low brain free [Mg2+] in mitochondrial
cytopathies is secondary to failure of the respiratory chain, and
they are consistent with the view that cytosolic [Mg2+]
is regulated in the intact brain cell to equilibrate, at least in
part, any changes in rapidly available free energy.
Mg2+ in migraine
Migraine headache is a common feature in patients with
mitochondrial encephalomyopathies where deficient brain
mitochondrial oxidation is due to mutations of mitochondrial DNA.
In addition, several studies have contributed to show an altered
energy metabolism in the brain of patients with different types of
migraine and cluster headache [24-26], although the molecular
mechanisms leading to oxidative deficit in migraine and cluster
headache are unknown. Total and ionised magnesium has been found to
be reduced in serum and erythrocytes of patients with different
forms of migraine and cluster headache [27, 28]. All these findings
offered the rationale for an extended study to assess the brain
Mg2+ by 31P-MRS in different forms of
migraines and in cluster headache [9]. This study was conducted in
78 patients with different forms of migraine in attack-free periods
(7 with migraine stroke, 13 with migraine with prolonged aura, 37
with migraine with typical aura or basilar migraine, 21 with
migraine without aura), and 13 patients with cluster headache. In
the occipital lobes of all subgroups of migraine and in cluster
headache patients, cytosolic free [Mg2+] was
significantly reduced. Among migraine patients the level of
cytosolic free [Mg2+] correlated with the severity of
clinical phenotype and the bioenergetics deficit, showing the
lowest values in patients with migraine stroke and the highest in
patients with migraine without aura [9]. The results of this study
confirm the hypothesis that the reduction in free [Mg2+]
in tissues with defective mitochondrial functionality is secondary
to the bioenergetics deficit, excluding a primary role for low
brain cytosolic free [Mg2+] in the pathogenesis of
headache. Nevertheless, a recent study [29] has shown a beneficial
effect of magnesium supplementation in patients with migraine
without aura, highlighting the possibility of using magnesium as a
prophylactic agent in the treatment of migraine subtypes.
Mg2+ in multiple system atrophy and idiopathic
Parkinson’s disease
Multiple System Atrophy (MSA) is a group of multisystem
degenerative diseases that have several clinical features of
Parkinson’s disease. Therefore, differentiating MSA from
Parkinson’s disease can be difficult and the diagnosis of Multiple
System Atrophy (MSA) represents a clinical challenge. An in vivo
study by 31P-MRS showed that the combined measurement of
[PCr], and free [Mg2+], could help to differentiate
patients with MSA from those with PD [30]. The study was carried
out on the occipital lobes of 15 patients with multiple system
atrophy (MSA), 13 patients with idiopathic Parkinson’s disease
(PD). The MSA group showed significantly reduced [PCr], increased
[Pi] and unchanged cytosolic free [Mg2+] and pH. On the
other hand, PD patients showed a significantly increased [Pi],
decreased cytosolic free [Mg2+] and unchanged [PCr] and
pH. Comparing the MSA vs. PD groups, [PCr] was significantly lower
in MSA than in PD, while cytosolic free [Mg2+] was
significantly lower in PD. In spite of a certain degree of overlap
of [PCr] and [Mg2+] values between the two groups, by
considering both variables at the same time it was possible to
classify correctly 93% of cases by discriminant analysis (figure 4). The
results of the study revealed abnormal bioenergetics and
Mg2+ contents in MSA and PD respectively, offering a new
diagnostic clue that may help to differentiate MSA from PD.
Concluding remarks
31P-MRS has shown the unique capability of assessing in
vivo cytosolic [Mg2+] in human brain and skeletal
muscle. This technique allowed us to prove that, in skeletal
muscle, dramatic changes of free Mg2+ can occur in
different metabolic conditions, in contrast to what is found in
other cell types and tissues. It was demonstrated that these
variations are modulated by pH, disclosing a new mechanism of
cytosolic Mg2+ regulation. Moreover, the study of the
involvement of Mg2+ in different neurological disorders
provided new insights into the role of Mg2+ in cellular
bioenergetics, also opening new diagnostic possibilities for some
neurodegenerative diseases.
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