Magnesium is the most important intracellular cation in the human body — it is the essential cofactor for every ATP-consuming and ATP-producing reaction in the cell, because the ATP is almost always present in the cell as the Mg-ATP complex (the magnesium ion is coordinated to the phosphate tail of the ATP, and this Mg-ATP complex is the substrate or the product of virtually all of the enzymes that use the ATP). The magnesium is therefore involved in virtually every aspect of the cellular energy metabolism — it is required for the function of the ATP synthase (which synthesises the ATP from the ADP and the phosphate using the energy of the proton gradient across the inner mitochondrial membrane), for the function of the myosin ATPase (which provides the energy for the muscle contraction), for the function of the Na+/K+-ATPase (which maintains the intracellular potassium and the extracellular sodium concentrations that are essential for the membrane potential and for the nerve impulse transmission), for the function of the calcium-ATPase (which pumps the calcium into the sarcoplasmic reticulum to terminate the muscle contraction), and for the function of hundreds of other ATP-dependent enzymes. Without adequate magnesium, the ATP metabolism is impaired at every level, the cellular energy status declines, and the fatigue, the muscle cramps, the cardiac arrhythmias, and the neurological dysfunction develop — the hallmark of the magnesium deficiency. The typical dietary magnesium intake is 200-400mg daily (from the leafy green vegetables, the nuts, the seeds, the legumes, and the whole grains), and the RDA is 420mg daily for men and 320mg daily for women — but the magnesium deficiency is extremely common (affecting 50-80% of the population in the developed world), because the modern diet is low in magnesium (due to the processing of the grains and the removal of the magnesium-rich germ and bran), because the soil is depleted of magnesium in many regions, and because the common medications (diuretics, proton pump inhibitors, antibiotics) increase the urinary or the gastrointestinal magnesium loss.
Magnesium and the ATP Synthase
The ATP synthase (also called the F1F0-ATPase or the complex V of the electron transport chain) is the enzyme that synthesises the ATP from the ADP and the inorganic phosphate using the energy of the electrochemical proton gradient across the inner mitochondrial membrane. It is a large, multi-subunit enzyme complex that is embedded in the inner mitochondrial membrane, and it consists of two main domains — the F1 domain (which contains the catalytic sites that synthesise the ATP) and the F0 domain (which contains the proton channel that couples the proton flow to the rotation of the central stalk and the catalytic activity). The Mg-ATP and the Mg-ADP are the substrates and the products of the ATP synthase — the magnesium ion is not just a cofactor but is an essential component of the active site, because the enzyme only recognises the magnesium-complexed form of the nucleotides. Without adequate magnesium, the ATP synthase cannot bind the ATP or the ADP (because the enzyme requires the Mg-ATP or the Mg-ADP complex as its substrate), the ATP synthesis is impaired, and the cellular ATP levels fall — producing the energy failure that is the primary mechanism of the magnesium deficiency.
The clinical importance of the magnesium for the ATP metabolism is underscored by the observation that the magnesium deficiency produces a characteristic reduction in the cellular ATP levels and an increase in the AMP/ATP ratio — which activates the AMPK (AMP-activated protein kinase), the master regulator of the cellular energy homeostasis. The AMPK activation triggers the compensatory responses that are intended to restore the energy balance — including the increased glucose uptake, the increased fatty acid oxidation, and the inhibition of the anabolic pathways (protein synthesis, fatty acid synthesis) — but when the magnesium deficiency is severe and prolonged, the AMPK activation cannot compensate for the impaired ATP synthesis, and the cellular energy failure develops.
Magnesium and the Muscle Function
Magnesium is as essential for the muscle function as it is for the ATP synthesis — it is required for the relaxation of the skeletal muscle (after the calcium has triggered the contraction), because the magnesium competes with the calcium for the binding sites on the troponin C and on the myosin head, and it promotes the dissociation of the calcium from the troponin C and the release of the myosin head from the actin filament. This magnesium-dependent relaxation is essential for the normal muscle contraction-relaxation cycle — without adequate magnesium, the muscle contraction is prolonged, the muscle tension is increased, and the muscle cramps and the tetany develop. The magnesium deficiency is one of the most common causes of the muscle cramps (particularly the nocturnal leg cramps, which affect 30-50% of the population over the age of 60), and it is one of the most treatable causes — the magnesium supplementation (particularly as magnesium glycinate or magnesium citrate, the well-absorbed forms) rapidly relieves the muscle cramps in most people with the magnesium deficiency.
Practical Application
For general magnesium supplementation, the evidence-based approach is to supplement with 300-600mg of magnesium daily (as magnesium glycinate, magnesium citrate, magnesium malate, or magnesium chloride — the forms that are well absorbed and well tolerated, and which are less likely to cause the diarrhoea than the magnesium oxide and the magnesium sulfate forms). The magnesium should be taken in divided doses (200mg or less per dose) and with food (to enhance the absorption and to reduce the gastrointestinal side effects). The RDA of magnesium is 420mg daily for men and 320mg daily for women, and the tolerable upper intake level is 350mg daily for adults from supplements (because the high-dose magnesium from supplements can cause the diarrhoea and the gastrointestinal distress). For comprehensive energy and muscle support, magnesium pairs well with the CoQ10 (which is required for the electron transport chain and which works synergistically with magnesium for the ATP synthesis), with the B-complex vitamins (which are required for the function of many of the enzymes that use the ATP), with the potassium (which is the primary intracellular cation and which works synergistically with magnesium for the muscle function and for the nerve impulse transmission), and with the calcium (which is the primary regulator of the muscle contraction and which should be balanced with the magnesium for the optimal muscle function).
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