For almost a century, the biological role of vitamin E has been a scientific puzzle. Since its discovery, vitamin E has been extensively researched by many scientists in an attempt to fully understand its role in a variety of diseases. The vast majority of published work has focused on vitamin E’s antioxidant properties, which is why it is well known as antioxidant that protects membranes from oxidative damage caused by free radicals. Recent research has shown that vitamin E’s capacity to incorporate into plasma membrane and its ability to act there as antioxidant appears to be essential for the vitamin’s role in pro-moting membrane repair - the first evidence of one of vitamin E’s normal body functions.
The role of vitamin E has been investigated in the prevention and/or minimization of oxidative stress-dependent brain damage and related diseases such as demen-tia and Alzheimer’s disease. The basis for these investigations was the theory that brain ageing can result from damage caused by free radicals. In addition to its role as a potent antioxidant, vitamin E seems to be involved in a wide range of physio-logical processes, ranging from immune function, control of inflammation and cognitive performance to regulation of gene expression and signal transduction. Balanced diets are gene-rally rich in foods containing vitamin E. Data from dietary intake surveys indicate, however, that inadequate vitamin E intakes are widespread, even in affluent western countries.
Introduction
The discovery of vitamin E began in 1922 when rats failed to reproduce when fed a diet composed of the then known essential vitamins. When cotton seed oil was added to the diet, fertility was restored in the rats and the unidentified substance in cotton oil was given the name vitamin E. Today the term vitamin E encom-passes eight congeners: alpha-, beta-, gamma- and delta-tocopherol; and alpha-, beta-, gamma- and delta-tocotrienol. All eight isoforms are naturally synthesized by plants in various concentrations while the human body is unable to produce vitamin E and must obtain it from exogenous sources. By far the most abundant dietary component and bioactive form in the body is alpha-tocopherol (1).
Since all forms of vitamin E are lipid soluble they are easily absorbed from the intestinal lumen after dietary intake. Vitamin E is then incorporated into lipoprotein particles and secreted into the blood stream where, transported by various lipoproteins, it travels to the liver. The liver plays a central role in regulating alpha-tocopherol levels by directly acting on the distribution, metabolism, and excretion of the vitamin (2). Plasma concentrations of vitamin E depend completely on the absorption, tissue delivery, and excretion rate. While alpha-tocopherol levels are maintained, the other forms of vitamin E are removed much more rapidly. Carried by lipoproteins, vitamin E is delivered to tissues where the vitamin’s hydrophobic tail partitions into cell membranes. The concentration of vitamin E differs from one cell to the next, but accumulates in organs such as the liver, muscle, and adipose tissue.
The documented cases of vitamin E deficiencies in humans, although uncommon, are typically caused by diet-unrelated problems such as impaired absorption (malabsorption) diseases and liver cirrhosis (3). A deficiency can cause skeletal myopathy and low levels of vitamin E can be correlated with a loss of muscle strength in the elderly (4). A recent review of national dietary surveys has shown that vitamin E intakes below recommended levels are common in representative Western populations in countries such as Germany, the UK, the Netherlands, and the USA (5). Long-term insufficient intake of vitamins is thought to promote the development of chronic diseases without obvious symptoms.
Ongoing research of vitamin E’s role in several chronic diseases - particularly in cancer, diabetes, and cardiovascular disease – is proposed for the prevention and treatment of numerous health conditions. Several studies have examined the association between vitamin E supplementation and risk reduction of chronic diseases, often with inconsistent results. Gene variations involved in vitamin E uptake, distribution, metabolism, and molecular action may be important determinants for the protective effects of vitamin E supplementation. The haptoglobin 2-2 polymorphism, for example, seems to be associated with increased production of oxygen free radicals and reduced levels of vitamin E and C; the consequent elevated risk of cardiovascular disease may be prevented by vitamin E supplementation (6).
The mystery surrounding vitamin E’s cell function has been heavily investigated, and several molecular mechanisms have been suggested. There is mounting evidence for two main cellular roles of vitamin E: antioxidant defense and membrane stability.
Antioxidant function
Vitamin E is a strong antioxidant that potentially prevents damage caused by free radicals which can modify components of the cell such as proteins, DNA and lipids. Vitamin E (alpha-tocopherol) has been shown to prevent oxidation of low-density lipoprotein cholesterol in vascular (endothelial) cells (7), nucleotides of DNA and RNA (8) and cell membrane lipids (9). Thus, the vitamin may play a role in the prevention of atheroscle-rotic cardiovascular diseases and cancer, and may be critical in maintaining cellular functionality in general. In addition, vitamin E may inhibit cell proliferation (10), induce apoptosis (11) and enhance immune function (12). While many epidemiological and experimental data indicate an association between disease risk reduc-tion and increased vitamin E intake from dietary sources and/or supplements, randomized controlled trials have produced inconclusive results. It has been suggested that this may be related to the relatively short period of treatment and observation (generally 3–5 years) of these trials and that longer studies are needed (13).
In theory, the potent antioxidant properties of vitamin E act as an active cell membrane defense system by ridding the cell of unwanted oxidative stress. Unlike other cellular antioxidants that are either enzymes or enzyme-dependent, the antioxidant action of vitamin E is unique in that it is non-enzymatic and therefore quite rapid (9). However, once a single vitamin E molecule neutralizes a free radical, its antioxidant capacity is lost. Vitamin E can be regenerated by other antioxidants such as vitamin C (14). As vitamin E deficiencies can lead to skeletal muscular disease and the vitamin is located in the cell membrane, recent research on the biological role of vitamin E has focused on a potential function in muscle cell. Muscle also generates oxidants during cellular metabolism, which increases during exercise. Not surprisingly, vitamin E deficient muscle is more prone to oxidative damage. Vitamin E treatment is effective in preventing skeletal muscle membrane oxidation (15). Oxidants are also frequently generated in diabetes, and vitamin E administration has been shown to decrease oxidant production (16). Muscle contractions significantly increase oxidant production and vitamin E supplementation has been shown to decrease the generation of exercise-induced oxidation (17). These and many other observations suggest a possible link between vitamin E as an antioxi-dant and muscle health.
Membrane stabilizing and repairing function
Although vitamin E is only a minor component of the cell membrane, it may play a significant structural role in the plasma membrane. Vitamin E is a lipophilic molecule that partitions into hydrophobic portions of the bilayer. Once attached, the vitamin’s mobility within the membrane is impaired, and this is thought to stabi-lize the membrane (9). There is evidence that alpha-tocopherol can either act to stabilize or destabilize the membrane depending on vitamin concentration (18).
The plasma membrane is a crucial cell barrier that separates interior and exterior environments. Disrup-tions, such as membrane rupture, can rapidly lead to cell death unless these tears are immediately re-paired. Cells in mechanically active tissues, such as skeletal and cardiac muscle, frequently suffer mem-brane disruptions under physiological conditions, and skeletal muscle disease may be an important patho-logical consequence of repair failure. Recent research has demonstrated that vitamin E functions to promote plasma membrane repair: cells treated with alpha-tocopherol displayed an enhanced repair response after membrane injury, and were able to repair when oxidants were present (19). Unlike vitamin E, other antioxi-dants that were incapable of binding to the plasma membrane failed to promote membrane repair. The only exception was vitamin C, an antioxidant that can regenerate the cellular vitamin E antioxidant capacity.
With diseases like diabetes, membrane repair is faulty, which may lead to muscle pathology (20). Vitamin E seems to not only effectively enhance membrane repair in healthy cells, but supplementation has shown to restore this natural repair process also in a diabetic cell model (19). Muscle is susceptible to membrane injuries from contractions and membrane repair diseases negatively impact muscle. Vitamin E’s ability to promote membrane repair is therefore thought to have strong implications as a supplement for muscle health.
Application for muscle health
Vitamin E’s newly discovered repair function may offer a novel treatment option for people with membrane deficient diseases. Research suggests that even low doses of vitamin E are sufficient to promote repair in cell membranes (19). The vitamin E provided by a healthy diet should ensure sufficient levels of nutrients for muscle membrane repair. However, intake surveys have shown that significant parts of the population in many industrial nations have a vitamin E intake below the recommended level (5). In the United States, for example, more than 25 percent of adults have insufficient serum levels of vitamin E despite no physical manifestation of malnutrition (21), with 60 percent of the population failing to meet the 15 mg daily dietary vitamin E requirement (22).
Studies investigating the potential benefits of vitamin E supplementation in preventing human skeletal muscle cell damage have produced inconsistent results. Additional nutritional supplements failed to decrease the number of circulating neutrophils (an indicator of cell damage) after running downhill (23). However, circulating neutrophils merely determine the extent of injury; they do not accurately assess the extent of membrane repair. More recent studies report that supplementation can be beneficial: in humans, vitamin E supplementation prevented loss of muscle force and decreased muscle pain after excessive exercise (24). Perhaps exercise intensity and better assessment tools explain the contradictions between current and previous supplemental studies. Vitamin E supplementation failed to ameliorate symptoms of Duchenne muscular dystrophy, which is characterized by an increased frequency of plasma membrane disruption injury (25). Vitamin E does not appear to protect against injury, but instead may promote successful repair of the injured membrane (19).
Vitamin E’s novel role in promoting membrane repair may provide new opportunities for its therapeutic application and enable scientists to discover even more potent compounds. Since membrane disruptions occur in many other cell types than skeletal muscle cells, the new findings may have much broader impli-cations.
