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Compendium May 2010 (Vol 32, No 5)

Abstract Thoughts — Iron and Exercise: A Ferric Balancing Act

by David J. Hurley, PhD, James N. Moore, DVM, PhD

    Abstract

    The estimated prevalence of iron deficiency in the world suggests that there should be widespread negative consequences of this nutrient deficiency in both developed and developing countries. In considering the reality of these estimates, the Belmont Conference seeks to reconsider the accepted relationships of iron status to physiological, biochemical and neurological outcomes. This review focuses on the biological processes that we believe are the basis for alterations in the immune system, neural systems, and energy metabolism and exercise. The strength of evidence is considered in each of the domains and the large gaps in knowledge of basic biology or iron-dependent processes are identified. Iron is both an essential nutrient and a potential toxicant to cells; it requires a highly sophisticated and complex set of regulatory approaches to meet the demands of cells as well as prevent excess accumulation. It is hoped that this review of the more basic aspects of the biology of iron will set the stage for subsequent in-depth reviews of the relationship of iron to morbidity, mortality and functioning of iron-deficient individuals and populations.

    Commentary

    Iron (Fe) in its ferrous (Fe2+), ferric (Fe3+), or (less commonly) ferryl (Fe4+) oxidation state is at the core of important biochemical reactions, as iron-containing enzymes are critical to the healthful use of oxygen as well as central to many of its damaging effects. The ability of iron to keep an individual electron in a relatively stable status in its outer shell provides its catalytic function. Iron, in its ferrous or ferric ion form, regulates the reactivity of oxygen, providing orderly control of bioenergetics, nucleic acid synthesis, gene regulation, cell-growth control, and cellular differentiation. Consequently, iron is critical to immune function, muscle action, and neuronal activity. However, iron can also be a "seed for damage" because it is an ideal "partner" in chemical reactions that generate free radicals from molecular oxygen.

    The article by Beard cited above is a clear, brief, comprehensive review of the chemistry of iron as it relates to biologic functions, the metabolic cascade of iron cycling, iron storage and use in the body, and the effect of iron deficiency or excess total iron on immune function, mental and nervous system function, and physical performance (particularly regarding exercise). One interesting aspect of the article is the inclusion of models depicting the effect of iron "loading" on hemoglobin and oxygen capacity, muscle function and energetics, neural development and function, and immune system activation. The article also includes an integrated map summarizing the role of iron in the interactions of these various functions.

    Although inclusion of iron in the diet is important, the daily demand for iron is relatively small. For example, humans require only approximately 2 mg/day of new iron from the diet. An adult horse, which has a "budget" of approximately 40 g of total body iron, based on relative mass, needs to absorb approximately 25 mg/day of iron. Dietary intake of iron replaces iron lost in sloughed cells and through blood loss. Iron is taken up in the small intestine, where enterocytes produce enzymes that convert Fe3+ to Fe2+ to allow divalent ion transporters to move iron into cells. Once the iron enters the cells, it is rapidly converted back to Fe3+ for storage and transport (in which iron is primarily bound to transferrin).

    The amounts of stored and circulating iron in the body regulate the expression of the specific enzymes responsible for regulating iron uptake.1 The primary regulators of iron uptake are hepcidin, an iron-regulating protein that complexes at the cell surface with β2 microglobulin, and the transferrin receptor. When iron loading is high, these proteins make iron uptake less efficient; when iron loading is low, they enhance the process.

    The major players in iron regulation in mammals are erythrocytes (which cycle iron among hemoglobin molecules), iron-containing (heme and nonheme) enzymes and proteins (including myoglobin and other proteins that modulate oxygen use), iron-storing proteins (ferritin and hemosiderin), and macrophages (which ingest worn-out erythrocytes). Iron can be readily moved from intracellular to extracellular stores, including plasma, through protein-mediated transport mechanisms. The liver is a major storage site, and bone marrow is a major utilization center for body iron, at least relative to body mass. For example, erythrocytes (the greatest users of iron by weight in the body) and leukocytes require a significant iron level for full function.

    The body can tolerate a fairly broad range of iron concentrations because of a reasonable storage capacity. However, when the iron concentration decreases below the level at which it can be restored from storage sites, there are consequences on the interrelated family of iron-dependent functions. These consequences occur before anemia is evident. For example, hemoglobin concentration decreases in proportion to the decline in iron concentration once the total body iron concentration decreases below the level required to maintain a steady-state level by mobilization from iron stores. Furthermore, cytochrome C concentration in muscle decreases approximately twice as fast as the hemoglobin concentration, and muscle function, neurologic function, and immune response also decrease quite rapidly with the loss of stored iron.

    Because of the importance of iron in muscle and neurologic function, even a marginal iron deficiency negatively affects an animal's ability to exercise. These deleterious effects on exercise performance occur via a complex set of interactions among iron-dependent functions. First, when the hemoglobin concentration is reduced, transport of oxygen to facilitate work is reduced. Second, when iron is limited, the iron-containing proteins (including iron–sulfur proteins) in muscle that facilitate oxygen use function less efficiently and are replaced more slowly, reducing the efficacy of muscle action. Third, when iron is limited, the production and function of neurotransmitters are limited, diminishing the activity of γ-aminobutyric acid (GABA), dopamine, serotonin, and norepinephrine. Finally, inflammatory processes that are necessary to repair exercise-mediated muscle damage depend on iron-containing proteins and may have diminished function when iron is limited.

    Therefore, it is important for veterinarians to be aware of the iron level in diets and to ensure that horses in their care (1) receive a sufficient amount of iron to replace daily losses and (2) have sufficient iron stores for support during exercise. These iron requirements must be provided in forage, dietary feed, or supplements. So, in retrospect, Popeye was right when he said, "I'm strong to the finish, 'cause I eats me spinach."

    Abstract reprinted verbatim from Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr 2001;131:568S-580S; with permission from the American Society for Nutrition.

    1. Ganz T, Nemeth E. Regulation of iron acquisition and iron distribution in mammals. Biochema et Biophysica Atca 2006; 1763:690-699.

    References »

    NEXT: Applied Dermatology — Crusty Cats: Feline Pemphigus Foliaceus

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