Journal of Nutritional Medicine (1992) 3, 49-59
Primary fibromyalgia (FM) is a common clinical 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 for 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 2l.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.
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 is considered primary when not associated with systemic causes, trauma, 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 . FM is now recognized as being one of the most common rheumatic complaints with clinical prevalence of 6%-20% . The association of FM with irritable bowel syndrome, tension headache, primary dysmenorrhea , mitral valve prolapse  and chronic fatigue syndrome  has been reported.
Various treatment modalities have been tested in FM patients with poor results: tryptophan administration worsened musculoskeletal symptoms . Ibuprofen was not better than placebo . Tricyclic agents resulted in modest improvement with a short-lived remission in only 20% of the patients . The combined administration of ibuprofen and the anxiolytic alprazolam to FM patients resulted in significant improvement of disease severity and severity of tenderness on palpation . However, the decrease in tenderness did not reach 50% even after 8 weeks of an open label phase following a 2 week double-blind phase.
The century-old postulate of an inflammatory reaction in FM  has not been confirmed by recent histologic examination . Disturbance in stage IV sleep, resulting from tryptophan-serotonin deficiency was suggested as a possible causative factor in the musculoskeletal pain in FM patients . Plasma-free tryptophan levels in FM patients correlated inversely with the severity of pain. Depriving normal college students of stage IV sleep resulted in musculoskeletal symptoms similar to those of FM patients . Tryptophan administration to FM patients did improve sleep patterns but in fact worsened musculoskeletal pain .
A multifactorial etiology, with stress being the common pathway, has been proposed [14, 15]. Elevated catecholamines are observed in urine of FM patients . 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 . 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 . 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 , 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. . Low levels of high energy phosphates such as ATP, ADP and phosphocreatine were observed at tender points, together with increased AMP levels . 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 .
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  could be the result of increased gluconeogenesis due in part to chronic hypoxia, which has been demonstrated in FM patients . Acute viral diseases are associated with myolysis and myalgia similar to symptoms of FM patients . The muscle pain in FM could therefore be the result of proteolysis of muscle tissue, due to enhanced gluconeogenesis. The low serum aminoacids  in spite of increased muscle proteolysis  suggest a very active gluconeogenesis in FM patients.
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 .
The synthesis of ATP by intact respiring mitochondria requires the presence of oxygen, magnesium, substrate, ADP and inorganic phosphate, hereafter referred to as phosphate . 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 these 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.
Anaerobic glycolysis to lactate delivers 2 moles of ATP per mole of glucose whereas aerobic glycolysis to carbon dioxide and water through the citric acid cycle delivers 36-38 moles of ATP per mole of glucose . 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 .
Relative hypoxia has been demonstrated in FM patients [19, 20]; and FM symptoms improved following aerobic conditioning .
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 . The uptake of phosphate is required for phosphorylation of ADP, and the proton extrusion is the driving force in the oxidative phosphorylation of ADP .
Through a magnesium-dependent mechanism, the mitochondria can accumulate large amounts of CA in order to maintain low levels of Ca in the cytosol . 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 . Mitochondrial calcification eventually results in cell death . Adequate levels of magnesium are required to maintain low cytosolic calcium .
Aluminium inhibits glycolysis and oxidative phosphorylation with decreased intramitochondrial ATP and increased AMP levels . Because of its high affinity for phosphate groups, aluminium 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 aluminium . Malic acid is one of the most potent chelators of aluminium. As an antidote to aluminium intoxication in mice, malic acid resulted in the highest survival ratio of several chelators tested . Malic acid was the most effective in decreasing brain aluminium levels .
An oxygen-sparing effect of magnesium has been demonstrated in magnesium- deficient competitive swimmers . 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 . Similar mitochondrial abnormalities have been reported in muscle biopsies of tender points obtained from FM patients . The most common symptoms associated with FM—myalgia , chronic fatigue syndrome , irritable bowel syndrome , mitral valve prolapse [42-44], tension headache  and dysmenorrhea — 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  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 . 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 . 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 malate is depleted following exhaustive physical activity , 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 , and that malate is the common mediator of increased mitochondrial respiration by catecholamines, glucagon, and exercise . 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 , believed to be the driving force for the mitochondrial synthesis of ATP .
Intraperitoneal injection of malic acid to rats in amounts of 7.5 mg per kg body weight resulted in elevated mitochondrial malate followed by increased mitochondrial respiration, increased mitochondrial uptake and utilization of key substrates for ATP formation, . Relatively small amounts of exogenous malate are required to increase mitochondrial oxidative phosphorylation and ATP production. Once an elevated mitochondrial malate concentration is attained, it may support an increased rate of substrate transport into the mitochondria without depleting its own matrix concentration, for malate is regenerated in the tricarboxylic acid cycle during the oxidation of the substrates with which it exchanges [49, 53]. Under hypoxic conditions, there is an increased demand for malate because malate is not only oxidized to oxaloacetate by the action of succinate-ubiquinone reductase  but also reduced to succinate [49, 51]. Increased proteolysis and transamination of several amino acids occur in order to increase mitochondrial malate levels through gluconeogenesis (Fig. 2) . Also, liver mitochondrial phosphoenolpyruvate carboxykinase may play an important role in generating malate from phosphoenolpyruvate and bicarbonate by a reversal of the activity of this enzyme under conditions of increased gluconeogenesis. This mechanism of malate production has been demonstrated in rabbit liver . The reversal of this enzymatic reaction favors hepatic lipogenesis. Therefore, chronic malate deficiency could play a role in certain types of hyperlipidemia. If gluconeogenesis and possibly phosphoenolpyruvate carboxykinase reversal cannot keep up with malate demand, mitochondrial malate becomes deficient . The transamination of amino acids during gluconeogenesis requires magnesium and vitamin B6. Therefore, a deficiency of these nutrients may decrease the rate of transamination of amino acids with a compensatory increase in proteolysis. As will be shown later, vitamin B6 requires a magnesium-dependent phosphate transfer reaction to become active.
In cats, under conditions of acute myocardial ischemia, intravenous administration of sodium malate in amounts of 20-100 mg per kg body weight increases significantly coronary blood flow without a significant increase in oxygen consumption . In rats, the oral administration of potassium malate increases anaerobic endurance, measured by swimming time prior to exhaustion, without a concomitant increase in carbohydrate and oxygen utilization . This effect of malate showed a dose-response relationship with doubling of swimming time at 250 mg per kg body weight. However, at a higher dosage, a decrease in effectiveness of malate as observed probably due to depletion of other key substances. The above studies suggest that malate has carbohydrate and oxygen-sparing effects.
Malate is the only metabolite of the citric acid cycle which correlates positively with physical activity. In rats, exercise-induced mitochondrial respiration was associated with increased malate levels only, with the other key metabolites remaining unchanged .Following endurance training of athletes, muscles were characterized by a 50% increase in the malate-aspartate redox shuttle enzymes , where malate plays a key role. In humans as well as in other animals tested, when there is increased demand for ATP, there is also an increased demand and utilization of malate.
Bicarbonate loading enhanced anaerobic capacity and exercise performance in men . Although the assumed mode of action is by an extracellular buffering mechanism, the positive effect of bicarbonate loading could also be explained by its role as a precursor of malate via the reverse action of phosphoenolpyruvate carboxykinase . Since gluconeogenesis favors the reversal of phosphoenolpyruvate carboxykinase, and hypoxic conditions enhance gluconeogenesis, bicarbonate may well serve as a precursor of malate under hypoxic conditions.
Vitamin B6  and magnesium  are required for normal activity of malate dehydrogenases involved in malate-aspartate shuttle. Phosphorylation of vitamin B6 is essential for biological activity and this phosphate transfer reaction is magnesium-dependent . The respiratory chain involved in ATP synthesis requires adequate amounts of the B vitamins thiamine and riboflavin, which are the precursors of NAD and FAD respectively . These two B vitamins, like B6, require a magnesium-dependent phosphate transfer reaction to become biologically active. Magnesium deficiency would therefore create a sluggish respiratory chain and a decreased efficiency in the transfer of reducing equivalents from the cytosol to the mitochondria.
The metabolites of the citric acid cycle and the malate shuttle enzyme systems have not been evaluated so far in FM patients. However, there is some evidence in favor of a deficiency of malate dehydrogenases creating a relative malate deficiency in FM patients. We have previously discussed the importance of magnesium in malate dehydrogenases activity and the evidence in favor of magnesium deficiency in FM patients. Hypothyroidism, which is very common in FM patients, is associated with FM like symptoms which improve following thyroid replacement . Thyroid hormones stimulate malate dehydrogenases at the transcriptional and post-transcriptional levels, and hypothyroidism is associated with a decrease in malate dehydrogenases . Since the transport of cytosolic reducing equivalents in the mitochondria depends on adequate activity of cytosolic and mitochondrial malate dehydrogenases, a deficient enzyme system would decrease the effectiveness of malate, creating a relative malate deficiency; this would favor gluconeogenesis and breakdown of muscle proteins . The presence of myolysis in muscle biopsies of FM patients  is highly suggestive of enhanced gluconeogenesis. In patients with hypothyroidism and possibly in FM patients, more malate would be required for ATP synthesis than in normal subjects. Also, it would be expected that malate demand would be greater in hypothyroid FM patients than in euthyroid FM patients. The use of a metabolite of the citric acid cycle to correct an enzymatic deficiency of the respiratory chain has proven successful in the case of NADH coenzyme Ql0 oxidoreductase deficiency . Clinical improvement was observed following succinate administration to bypass the deficient enzymes in the respiratory chain. A similar approach could be used to overcome a deficiency of malate dehydrogenases by supplying bioavailable malate in adequate amounts.
In intact living cells, ATP is usually present in a much higher concentration than ADP and AMP. When increased workload depletes the cell of ATP, this change in ATP/ADP accelerates glycolysis, mitochondrial respiration and oxidative phosphorylation of ADP to ATP. Mitochondrial ADP comes from hydrolysis of mitochondrial ATP and ATP-mediated phosphorylation of AMP . Since these phosphate transfer reactions are magnesium dependent, mitochondrial ADP deficiency could occur in a metabolically active cell if magnesium and/or phosphate concentrations were below optimal levels.
ADP deficiency has been reported in muscle biopsies of tender points obtained from FM patients .
Phosphate uptake by the mitochondria is closely linked to the transport of di- and tri- carboxylate anions. The net uptake of citrate and isocitrate by the tricarboxylate transporter; and transport of α-ketoglutarate by the dicarboxylate transporter require an exchange with malate . Therefore, the mitochondrial uptake of phosphate depends on malate levels which are required for exchange with phosphate. The uptake of phosphate is also enhanced by the uptake and accumulation of magnesium by mitochondria .
Intramitochondrial phosphate deficiency could occur in the presence of low levels of magnesium and malate. Excess calcium and aluminium could also predispose to intramitochondrial phosphate deficiency [26, 34]. Data on mitochondrial phosphate levels in muscle biopsies of FM patients have not yet been published.
Integrity of Mitochondrial Membrane and Capacity of Respiratory Chain
Magnesium plays an important role in the integrity of the mitochondrial membrane. Magnesium deficiency is associated with swelling of the mitochondria; increased permeability and decreased selectivity of mitochondrial inner membrane and uncoupling of oxidative phosphorylation .
As previously discussed, the respiratory chain responsible for oxidative phosphorylation and ATP synthesis requires NAD and FAD which derive from the vitamins thiamine and riboflavin respectively. These B vitamins become biologically active after a magnesium-dependent phosphate transfer reaction.
Abnormalities of mitochondrial membranes have been reported in FM patients . Adequacy of the respiratory chain, including assessment of nutritional status with regard to the vitamins thiamine, riboflavin and pyridoxine, have not been reported in FM patients.
In an open clinical setting, 15 patients (age range 32-60) with a diagnosis of FM based on the American College of Rheumatology 1990 criteria , ingested an oral preparation (Super Malic®, Optimox Corporation, Torrance, CA, USA), containing 50 mg of magnesium as the hydroxide and 200 mg of malic acid per tablet. A total daily dosage of 300-600 mg of elemental magnesium and 1200-2400 mg of malic acid was administered. Tender point index (TPI)  was assessed prior to and following an average of 4 and 8 weeks of treatment. The mean ± SE TPI scores were 19.6 ± 2.1 prior to Super Malic®, 8 ± 1.1 following 4 weeks; and 6.5 ± 0.74 following 8 weeks of treatment. Using paired data statistics , the effect of Super Malic® on TPI values was significant at p<0.001 at 4 and 8 weeks All patients reported significant subjective improvement of pain within 48 h of starting Super Malic®. Following an average of 8 weeks on Super Malic®, six patients were switched to placebo tablets for 2 weeks. The TPI values were 6.8 ± 0.75 and 21.5 ± 1.4 prior to and following placebo administration. Recurrence of myalgia occurs within 48 h in all the patients on placebo tablets. This appears to be a very promising approach to the management of FM, and a double-blind placebo-controlled trial is currently underway.
Since submission of our manuscript, red blood cell (RBC) magnesium levels  were measured in 13 newly diagnosed FM patients , and the levels of RBC magnesium were below the normal range in 12 of the 13 FM patients.
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