Amazoniac
Member
I was actually looking for the initial discussion that came up with the idea that magnesium and malic acid are beneficial for fibromyalgia (FM throughout the text) and fatigue in general. I came across this material that explains the story quite eloquently. The authors are known and popular.
http://www.tandfonline.com/doi/abs/10.3109/13590849208997961
Details were kept out:
"Local hypoxia was postulated to play an etiologic role in the development and the symptoms of FM [17]."
"Patients with FM have normal muscle blood flow under resting conditions, but decreased blood flow under aerobic exercises [l8]."
"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 myolysis 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 aminoacids [21] in spite of increased muscle proteolysis [1] suggest a very active gluconeogenesis in FM patients."
"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]."
"Through a magnesium-dependent mechanism, the mitochondria can accumulate large amounts of CA++ in order to maintain low levels of Ca++ 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]."
"Aluminium inhibits glycolysis and oxidative phosphorylation with decreased intramitochondrial ATP and increased AMP levels [34]. Because of its high afhity 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 resuited 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 now and oxygen tension are decreased."
"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]."
"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]."
"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]."
"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 [53]. Following endurance training of athletes, muscles were characterized by a 50% increase in the malate-aspartate redox shuttle enzymes [59], 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."
"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 [26]. 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."
"Hypothyroidism, which is very common in FM patients, is associated with FM like symptoms which improve following thyroid replacement [16]. Thyroid hormones stimulate malate dehydrogenases at the transcriptional and post-transcriptional levels, and hypothyroidism is associated with a decrease in malate dehydrogenases [63]."
"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]."
"Magnesium deficiency is associated with swelling of the mitochondria; increased permeability and decreased selectivity of mitochondrial inner membrane and uncoupling of oxidative phosphorylation [38]."
"B vitamins become biologically active after a magnesium-dependent phosphate transfer reaction."
http://www.tandfonline.com/doi/abs/10.3109/13590849208997961
Details were kept out:
"Local hypoxia was postulated to play an etiologic role in the development and the symptoms of FM [17]."
"Patients with FM have normal muscle blood flow under resting conditions, but decreased blood flow under aerobic exercises [l8]."
"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 myolysis 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 aminoacids [21] in spite of increased muscle proteolysis [1] suggest a very active gluconeogenesis in FM patients."
"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]."
"Through a magnesium-dependent mechanism, the mitochondria can accumulate large amounts of CA++ in order to maintain low levels of Ca++ 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]."
"Aluminium inhibits glycolysis and oxidative phosphorylation with decreased intramitochondrial ATP and increased AMP levels [34]. Because of its high afhity 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 resuited 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 now and oxygen tension are decreased."
"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]."
"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]."
"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]."
"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 [53]. Following endurance training of athletes, muscles were characterized by a 50% increase in the malate-aspartate redox shuttle enzymes [59], 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."
"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 [26]. 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."
"Hypothyroidism, which is very common in FM patients, is associated with FM like symptoms which improve following thyroid replacement [16]. Thyroid hormones stimulate malate dehydrogenases at the transcriptional and post-transcriptional levels, and hypothyroidism is associated with a decrease in malate dehydrogenases [63]."
"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]."
"Magnesium deficiency is associated with swelling of the mitochondria; increased permeability and decreased selectivity of mitochondrial inner membrane and uncoupling of oxidative phosphorylation [38]."
"B vitamins become biologically active after a magnesium-dependent phosphate transfer reaction."
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