Research on fibromyalgia syndrome
The following articles are presented as support for the possible use of
ionic minerals as a dietary supplement and nutritional supplement for natural therapy. You
will find more on fibromyalgia here. You can also
purchase this diet supplement disease treatment package below.
HYPOTHESIS
MANAGEMENT OF FIBROMYALGIA:
RATIONALE FOR THE USE OF MAGNESIUM AND MALIC ACID
Magazine: Journal of Nutritional Medicine, Winter 1992
Primary fibromyalgia (FM) is a common condition
affecting mainly middle-aged women. Of the etiologies previously proposed, chronic hypoxia
seems the one best supported by recent biochemical and histological findings. We postulate
that FM symptoms are predominantly caused by enhanced gluconeogenesis with breakdown of
muscle proteins, resulting from a deficiency of oxygen and other substances needed for ATP
synthesis. We present data supporting a critical role of magnesium and malate in ATP
production under aerobic and hypoxic conditions: and indirect evidence for magnesium and
malate deficiency in FM. After treating 15 FM patients for an average of 8 weeks with an
oral dosage form with dosages of 1200-2400 mg of malate and 300-600 mg of magnesium, the
tender point index (TPI) scores (x +/- SE) were 19.6 +/- 2.1 prior to treatment and 8 +/-
1.1 and 6.5 +/- 0.74, respectively, after an average of 4 and 8 weeks on the magnesium
malate combination (p<0.001). Subjective improvement of myalgia occurred within 48 h of
supplementation. In six FM patients, following 8 weeks of treatment, the mean TPI was 6.8
+/- 0.75. After 2 weeks on placebo tablets, the TPI values increased to a mean +/- SE of
21.5 +/- 1.4 (p<0.001). Again, subjective worsening of muscle pain occurs within 48 h
of placebo administration. A double-blind placebo control trial is currently underway.
Keywords: fibromyalgia, magnesium, malate.
INTRODUCTION
Fibromyalgia (FM) is a common clinical syndrome
of generalized musculoskeletal pain, stiffness and chronic aching, characterized by
reproducible tenderness on palpation of specific anatomical sites, called tender
points[1-3]. This condition considered primary when not associated with systemic causes,
cancer, thyroid diseases and pathologies of rheumatic or connective tissues. FM is nine
times more common in middle-aged women (between the ages of 30 and 50 years) than in
men[4]. Fm is now recognized as being one of the common rheumatic complaints with clinical
prevalence of 6%-20%[4]. The association of FM with irritable bowel syndrome, tension
headache, primary dysmenorrhea[1], mitral valve prolapse[5] and chronic fatigue
syndrome[6] has been reported.
Various treatment modalities have been tested in FM patients with patients
with poor results: tryptohan administration worsened musculoskeletal symptoms[7].
Ibuprofen was not better than placebo[8]. Tricylic agents resulted in modest improvement
with a short-lived remission in only 205 of the patients[9]. The combined administration
of ibuprofen and the anxiolytic alprazolam to FM patients resulted significant improvement
of disease severity and of tenderness on palpation[10]. However, the decrease in
tenderness did not reach 50% ever after 8 weeks of an open label phase following a 2 week
double-blind phase.
PROPOSED ETIOLOGIES OF FM
The century-old postulate of an inflammatory reaction in FM[11] has not
been confirmed by recent histologic examination[1]. Disturbance in stage IV sleep,
resulting from tryptophan-serotonin deficiency was suggested as a possible causative
factor in the musculoskeletal pain in FM patients[12]. Plasma-free tryptophan levels in FM
patients correlated inversely with the severity of pain. Depriving a normal college
students of stage IV sleep resulted in musculoskeletal symptoms similar to those of FM
patients[13]. Tryptophan administration to FM patients did improve sleep patterns but in
fact worsened musculoskeletal pain[7].
A multifactorial etiology, with stress being the common pathway, has been
proposed [14,15]. Elevated catecholamines are observed in urine of FM patients[16].
However, anxiolytic agents are of limited therapeutic value[9, 10].
Local hypoxia was postulated to play an etiologic role in the development
and the symptoms of FM[17]. Recently published reports of clinical, morphological and
biochemical pathologies in FM patients seem compatible with this theory of chronic
hypoxia.
Patients with FM have normal muscle blood flow under resting conditions,
but decreased blood flow under aerobic exercises[18]. Muscle tissue oxygen pressure is low
in tender muscles of FM patients, and the total mean oxygen pressure is significantly
lower than in normal controls in subcutaneous tissue of FM patients[19], suggesting that
the hypoxic condition is not limited to the tender muscles although the hypoxia is more
severe at tender points.
Muscle biopsies from tender points showed proteolysis of myofibrils,
glycogen deposition, swollen mitochondria with distortion of cristae and dilatation of
sarcoplasmic reticulum.[1]. Low levels of high energy phosphates such as ATP, ADP and
phosphocreatine were observed at tender points, together with increased AMP levels [20].
The levels of high energy phosphates were significantly lower in tender muscles than in
non-tender muscles of FM patients and in muscles of normal controls. Decreased serum
levels of several amino acids were observed in FM patients[21].
In hypoxic muscle tissues, there is an excess of cytosolic reducing
equivalents which inhibit glycolysis. Stimulation of gluconeogenesis occurs, with
breakdown of muscle proteins and amino acids which are used following transamination as
substrates for ATP synthesis[22,23]. The protein breakdown observed in muscle biopsies[1]
could be the result of increased gluconeogenesis due in part to chronic hypoxia, which has
been demonstrated in FM patients[19]. Acute viral diseases are associated with myolosis
and myalgia similar to symptoms of FM patients[24]. The muscle pain in FM could therefore
be the result of proteolysis of muscle tissue, due to enhanced gluconeogenesis. The low
serum amino acids[21] in spite of increased muscle proteolysis[1] suggest a very active
gluconeogenesis in FM patients.
A HYPOTHESIS: FM IS A RESULT OF DEFICIENCIES OF SUBSTANCES NEEDED
FOR ATP SYNTHESIS
Synthesis of proteins, fats and carbohydrates necessary for cellular
integrity, normal activity and functions is dependent on ATP availability which supplies
the energy for their synthesis and actions[25].
The synthesis of ATP by intact respiring mitochondria requires the
presence of oxygen, magnesium, substrated, ADP and inorganic phosphate, hereafter referred
to as phosphate[24]. When all substances are present in optimal concentrations, the
integrity of the mitochondrial membrane and the capacity of the enzymatic system in the
respiratory chain become rate limiting.
The five ingredients required for the synthesis of ATP are listed in Table
1, together with some conditions postulated to cause a deficiency of each of these.
We will review the role of these ingredients in ATP synthesis; present
data in favor of a deficiency of some of theses ingredients in FM; and demonstrate the
pivotal role of magnesium and malate in mitochondrial membrane integrity, mitochondrial
respiration and oxidative phosphorylation, both under aerobic and hypoxic conditions; and
present preliminary data on the clinical response of 15 FM patients to supplementation
with magnesium and malic acid.
Oxygen
Anaerobic glycolysis to lactate delivers 2 moles of ATP per mole of
glucose whereas aerobic glycolysis to carbon dioxide and water through the critic acid
cycle delivers 36-38 moles of ATP per mole of glucose[26]. Therefore, adequate oxygen
supply enhances ATP yield by 18-19 fold. The importance of oxygen for ATP synthesis in
humans has been confirmed in vivo. In patients with chronic circulatory and/or respiratory
insufficiency, mitochondrial ATP levels were only one-half the levels found in normal
controls[27].
Relative hypoxia has been demonstrated in FM patients[19-20]; and FM
symptoms improved following aerobic conditioning[28].
Magnesium
Magnesium plays a critical role in key enzymatic reactions (Fig. 1) for
both aerobic and anaerobic glycolysis[29, 30]. The uptake and accumulation of magnesium by
mitochondria is associated with enhanced uptake of phosphate and proton extrusion [31].
The uptake of phosphate is required for phosphorylation of ADP, and the proton extrusion
is the driving force in the oxidative phosphorylation of ADP[26].
Through a magnesium-dependent mechanism, the mitochondria can accumulate
large amounts of CA[sup++] in order to maintain low levels of CA[sup++] in the
cytosol[32]. However, this mitochondrial uptake of calcium inhibits ATP synthesis in two
ways: firstly, binding of intramitochondrial calcium to phosphate decreases the phosphate
pool available for oxidative phosphorylation of ADP and secondly the energy generated by
the electron transport system is used up for calcium transport, therefore, it is not
available for ATP synthesis[26]. Mitochondrial calcification eventually results in cell
death[33]. Adequate levels of magnesium are required to maintain low cytosolic
calcium[32].
Aluminum inhibits glycolysis and oxidative phosphorylation with decreased
intramitochondrial ATP and increased AMP levels[34]. Because of its high affinity for
phosphate groups, aluminum blocks the absorption and utilization of phosphate for ATP
synthesis and, therefore may cause intramitochondrial phosphate deficiency. Adequate
magnesium levels prevent this toxic effect of aluminum[34]. Malic acid is one of the most
potent chelators of aluminum. As an antidote to aluminum intoxication in mice, malic acid
resulted in the highest survival ratio of several chelators tested [35]. Malic acid was
the most effective in decreasing brain aluminum levels[36].
An oxygen-sparing effect of magnesium has been demonstrated in
magnesium-deficient competitive swimmers[37]. Magnesium supplementation lowered blood
lactate levels and oxygen consumption despite a higher glucose utilization. As will be
shown later, malate also has oxygen-sparing effect. It is plausible, therefore that
magnesium and malate deficiency could induce a relative hypoxia in cases where the oxygen
availability is compromised, as is the case in FM patients, where blood flow and oxygen
tension are decreased.
Although magnesium status of FM patients has not yet been reported, there
is some indirect evidence in favor of magnesium deficiency in FM patients. Magnesium
deficiency causes swelling and disruption of cristae in mitochondria, with a decreased
number of mitochondria per cell[38]. Similar mitochondrial abnormalities have been
reported in muscle biopsies of tender points obtained from FM patients[1]. The most common
symptoms associated with FM--myalgia[39], chronic fatigue syndrome[40], irritable bowel
syndrome[41], mitral valve prolapse[42-44], tension headache[45] and
dysmenorrhea[46]--have been reported in patients with magnesium deficiency, and magnesium
supplementation improves these symptoms.
Substrate: Pivotal Role of Malate and Magnesium
Peripheral malate derives from food sources and from synthesis in the
citric acid cycle (Fig. 1). It plays an important role in generating mitochondrial ATP
both under aerobic[47] and hypoxic[48, 49] conditions. Under aerobic conditions, the
oxidation of malate to oxaloacetate provides reducing equivalents to the mitochondria by
the malate-aspartate redox shuttle[47]. Under anaerobic conditions, with an excess of
cytosolic reducing equivalents, inhibition of glycolysis occurs. By its simultaneous
reduction to succinate and oxidation to oxaloacetate, malate is capable of removing
cytosolic reducing equivalents, thereby reversing inhibition of glycolysis[49-51]. One
mole of ATP is formed for each mole of malate reduced to succinate via fumarate[49], and 3
moles of ATP for each mole of malate oxidized to oxaloacetate. Through the action of malic
dehydrogenase followed by transamination reactions, malate is converted to aspartate, and
substrates necessary for initiating transmitochondrial exchange of metabolites through the
malate-aspartate shuttle are regenerated.
In the rat, only tissue is depleted following exhaustive physical
activity[52], in spite of the fact that the other key metabolites from the citric acid
cycle necessary for ATP production remain unchanged. It has been proposed therefore that
malate deficiency is the cause of the physical exhaustion[52], and that malate is the
common mediator of increased mitochondrial respiration by catecholamines, glucagon, and
exercise[53]. In certain bacteria which have similar microanatomical and biochemical
properties as mitochondria, malate acts as an electron donor and generates a large proton
motive force[54], believed to be the driving force for the mitochondrial synthesis of
ATP[26].
Mail Order Form Click Here!
View
Shopping Cart / Checkout
