Review
Blood as a reactive species generator and redox status regulator during exercise

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Abstract

The exact origin of reactive species and oxidative damage detected in blood is largely unknown. Blood interacts with all organs and tissues and, consequently, with many possible sources of reactive species. In addition, a multitude of oxidizable substrates are already in blood. A muscle-centric approach is frequently adopted to explain reactive species generation, which obscures the possibility that sources of reactive species and oxidative damage other than skeletal muscle may be also at work during exercise. Plasma and blood cells can autonomously produce significant amounts of reactive species at rest and during exercise. The major reactive species generators located in blood during exercise may be erythrocytes (mainly due to their quantity) and leukocytes (mainly due to their drastic activation during exercise). Therefore, it is plausible to assume that oxidative stress/damage measured frequently in blood after exercise or any other experimental intervention derives, at least in part, from the blood.

Introduction

Exercise is perhaps one of the most characteristic examples demonstrating that reactive oxygen and nitrogen species (hereafter, reactive species) and oxidative stress are not necessarily “harmful” entities, considering that the well-known benefits of regular exercise on muscle function and health are accompanied by repeated episodes of oxidative stress [1]. Nowadays, the field of exercise and reactive species is being rapidly expanded. Indeed, a recent issue of the official journal of the Society for Free Radical Biology and Medicine was devoted to this topic and hosted a dozen of review articles written by eminent researchers (Free Radic. Biol. Med. 44 (2008) 123–230). However, none of these reviews has dealt with the potential role that blood may play at rest or during exercise on reactive species production and/or with the meaning of these changes in blood redox status. This is the case even though the vast majority of the relevant studies have determined redox status in blood. To the best of our knowledge, the same holds true for all the available reviews devoted to this topic, the number of which is enormous (a search in PubMed for “oxidative stress” and “exercise” on 3rd August, 2009 produced 387 review articles). The excellent reviews by Lamprecht et al. [2] and Jenkins [3] stand as notable exceptions as they tried to highlight the role of blood in reactive species production during exercise. Hence, the main aim of this perspective paper is to present a critical synopsis of basic redox biology knowledge relevant to blood and exercise biology rather than a detailed analysis of every subject related to this topic.

In the present paper, by the term “exercise” we include any type of physical activity that has been mostly performed only once and was of sufficient intensity (normally 50–80% of maximal effort) and duration (normally 30–90 min). Most of the human studies that are presented here have used running, cycling or resistance exercise. The most commonly used type of animal physical activity is a rat running on a motor-driven treadmill. Acute muscle-damaging exercise can induce oxidative stress lasting 1–4 days after exercise [4], [5], which is in contrast to the return to the resting values few hours after non-muscle-damaging exercise [6], [7]. To this end, the studies presented in this paper have used only non-muscle-damaging exercise protocols (i.e., they did not use physical activities that are biased toward eccentric muscle actions).

Exercise induces a multitude of physiological and biochemical changes in blood that may ultimately affect its redox status. Some of the well-described events that arise during exercise are increases in blood temperature [8], decreases in blood pH [9], decreases in blood oxygen partial pressure [10] and increases in the concentration of blood lactate [10]. All these exercise-associated homeostasis disruptions are able to modify blood redox status. Indeed, hyperthermia increased the levels of reactive species within the splanchnic circulation of the rat [11]. The formation of reactive species seems to be dependent on pH. In fact, experiments performed in intact respiring mitochondria, with the pH varying from 6 to 8, revealed that alkalization of the medium strongly increased the rate of reactive species generation [12]. Inside hypoxic tissues (i.e., when oxygen partial pressure is low), xanthine dehydrogenase can be converted into xanthine oxidase [13]. During reoxygenation, superoxide radical (O2•−) can be formed by a reaction catalysed by xanthine oxidase between oxygen, hypoxanthine and xanthine [13]. Finally, lactate has been shown to scavenge hydroxyl radical (HO) and O2•−[14]. It is worth mentioning that the above exercise-modifiable factors can also act by affecting one another. For example, one of the early responses during hypoxia includes increased levels of glycogen degradation and glycolysis leading to increased lactate production [15].

Section snippets

Reactive species production

The vast majority of the relevant human studies have measured the redox status of plasma or serum (for the sake of simplicity, we use the term “plasma” even for studies in which serum was analysed). This is probably done because it is assumed that plasma better reflects tissue redox status and due to the ease of plasma collection. Blood plasma is the liquid component of blood, in which the blood cells are suspended. It makes up about 55% of the total blood volume. It is composed mostly of water

The origin of blood oxidative stress/damage after exercise

From the discussion so far, it is clear that plasma and blood cells are able to produce significant amounts of reactive species and contain considerable quantities of oxidizable substances. Therefore, it is plausible to assume that the oxidative stress/damage measured frequently in blood after exercise or any other experimental intervention derives, at least in part, from the blood. Supporting this hypothesis, several studies have reported increased production of various reactive species after

Interpreting changes in blood redox status after exercise: the case of antioxidant enzymes

The primary antioxidant enzymes in erythrocytes are copper- and zinc-containing superoxide dismutase (no manganese SOD is present, as there are no mitochondria), glutathione peroxidase and catalase [39]. Low levels or traces of these enzymes are also found in plasma [15]. The activity of these antioxidant enzymes have been repeatedly measured in both blood compartments (i.e., erythrocytes and plasma) after acute and chronic exercise [115], [116], [117], [118]. The assessment of these

Concluding remarks

We believe that there is a “recontextualization” of knowledge going on from basic redox biology to exercise physiology. Recontextualization is a process that “extracts meaning” from its original context (in our case, redox biology) and introduces it into another context (in our case, exercise physiology) [128]. Thus, “meaning” is borrowed from a different context and is integrated in a new context – thus recontextualized. Something acquires meaning depending upon the context it is used in;

Future directions

Researchers planning to investigate the effect of exercise on the blood redox status could:

  • (i)

    Compare the effects of an intervention on redox status of different blood cells and plasma in the same experiment, aiming at obtaining the most detailed information possible (in analogy to the recommendation for measuring a battery of redox status indices instead of a single index; [15]).

  • (ii)

    Examine cells and tissues (such as platelets and smooth muscle cells) on which data are limited but there is a

Acknowledgments

We thank Prof. Richard J. Paul (University of Cincinnati) for providing information regarding the mass of smooth muscle cells. We also appreciate the useful comments of the two anonymous reviewers.

References (131)

  • M. Lamprecht et al.

    Nutrition

    (2004)
  • R.R. Jenkins

    Am. J. Clin. Nutr.

    (2000)
  • V.A. Selivanov et al.

    J. Biol. Chem.

    (2008)
  • B. Halliwell et al.

    FEBS Lett.

    (2000)
  • M.W. Hentze et al.

    Cell

    (2004)
  • T. Spranger et al.

    Chem. Phys. Lipids

    (1998)
  • B. Halliwell et al.

    Arch. Biochem. Biophys.

    (1990)
  • M. Roche et al.

    FEBS Lett.

    (2008)
  • K.J. Yeum et al.

    Arch. Biochem. Biophys.

    (2004)
  • N.L. Anderson et al.

    Mol. Cell. Proteomics

    (2002)
  • M.J. Davies

    Biochim. Biophys. Acta

    (2005)
  • V. Mougios et al.

    J. Nutr. Biochem.

    (2001)
  • M.Y. Cimen

    Clin. Chim. Acta

    (2008)
  • J. Delaunay et al.

    Mol. Aspects Med.

    (1990)
  • R.L. Shelton et al.

    Anal. Biochem.

    (1984)
  • A.J. Hulbert

    J. Theor. Biol.

    (2005)
  • F. Visioli et al.

    Biochem. Biophys. Res. Commun.

    (1998)
  • R.N. Lemaitre et al.

    Metabolism

    (2008)
  • M. Wilhelm et al.

    Am. Heart J.

    (2008)
  • B. Halliwell

    Trends Biochem. Sci.

    (2006)
  • P. Washko et al.

    Am. J. Clin. Nutr.

    (1991)
  • P. Tauler et al.

    J. Nutr. Biochem.

    (2004)
  • B.S. Berlett et al.

    J. Biol. Chem.

    (1996)
  • P. Tauler et al.

    J. Nutr. Biochem.

    (2006)
  • A. Anel et al.

    Biochim. Biophys. Acta

    (1990)
  • S. Kew et al.

    Am. J. Clin. Nutr.

    (2004)
  • N. Kasuya et al.

    Atherosclerosis

    (2002)
  • S. Mutze et al.

    J. Biol. Chem.

    (2003)
  • G.L. Close et al.

    Comp. Biochem. Physiol. A Mol. Integr. Physiol.

    (2005)
  • D.B. Cines et al.

    Blood

    (1998)
  • T. Suvorava et al.

    Biochim. Biophys. Acta

    (2009)
  • K. Fisher-Wellman et al.

    Dyn. Med.

    (2009)
  • M.G. Nikolaidis et al.

    Sports Med.

    (2008)
  • M.G. Nikolaidis et al.

    Med. Sci. Sports Exerc.

    (2007)
  • G.L. Close et al.

    Eur. J. Appl. Physiol.

    (2004)
  • Y. Michailidis et al.

    Med. Sci. Sports Exerc.

    (2007)
  • L. Nybo et al.

    J. Appl. Physiol.

    (2002)
  • L. Hermansen et al.

    J. Appl. Physiol.

    (1972)
  • W. Stringer et al.

    J. Appl. Physiol.

    (1994)
  • D.M. Hall et al.

    J. Appl. Physiol.

    (1994)
  • T. Nishino et al.

    FEBS J.

    (2008)
  • C. Groussard et al.

    J. Appl. Physiol.

    (2000)
  • B. Halliwell et al.

    Free Radicals in Biology and Medicine

    (2007)
  • A. Agil et al.

    Clin. Chem.

    (1995)
  • B. Frei et al.

    Proc. Natl. Acad. Sci. USA

    (1988)
  • S. Welch

    Transferrin: The Iron Carrier

    (1992)
  • M.G. Nikolaidis et al.

    Physiol. Res.

    (2006)
  • R.J. Bloomer et al.

    Int. J. Sports Med.

    (2007)
  • W. Matthews et al.

    Proc. Natl. Acad. Sci. USA

    (1989)
  • E.R. Stadtman et al.

    Amino Acids

    (2003)
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