Oxidation Stress in Skeletal Muscle (Reznick, A. Z., Packer, L., Sen, C. K., Holloszy, J. O., and Jackson, M. J. (eds.) Birkhauser Verlag, Basel-Boston-Berlin, 1998)

V. P. Skulachev

This book describes the role of oxidative stress in the pathogenesis of muscle disorders. The introductory chapter by B. Hollywell describes the nature of reactive oxygen species (ROS), how they are formed in cells, the main disfunctions caused by ROS, and the cellular multi-level anti-ROS defense system. The first three aspects are written very well. In the case of the fourth aspect, the author is rather old-fashioned, disregarding the works on ROS-dependent apoptosis and the role of mitochondria in the formation and detoxication of ROS and in apoptosis.

The interesting chapter by J. Comulainen and V. Viko describes muscle disorders due to heavy work and the role of training in avoiding these disorders. A hypothesis is suggested that increase in ATP requirements exceeding its formation in heavily working muscle is the cause of these disorders. The role of Ca²⁺ in the development of pathological process is emphasized. Unfortunately, the authors do not consider the possibility that heavy work results in anoxia and subsequent reoxygenation induces a burst of ROS formation with the corresponding dangerous consequences (see below).

The chapter by Z. Radac and S. Goto summarizes the data suggesting that aging is decelerated by limitation of food consumption and by moderate physical work. Both factors lower intracellular ROS level in muscle and other tissues. A similar mechanism is considered by L. L. Ji. The authors emphasize that muscle work training enhances the synthesis of superoxide dismutase (SOD), catalase, and glutathione peroxidase--the main enzymes of antioxidant defense. The region of binding of nuclear factor kappaB (NFkappaB) with promoter of the mitochondrial SOD gene has been identified. NFkappaB is activated when ROS levels are increased; this process is mediated by certain cytokines including tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1).

C. K. Sen describes the pathways of formation and use of glutathione and its role in the antioxidant system in muscle.

A very interesting chapter by A. Gohman considers the mechanism of oxidative damage of muscle during reperfusion after ischemia. The author emphasizes that ischemia and anoxia by themselves do not induce irreversible damage to muscle. Such damage occurs during reoxygenation and subsequent reperfusion. The author points to three causes of ROS increase in reperfusion.

1. During anoxia, xanthine dehydrogenase is converted to xanthine oxidase, an enzyme that oxidizes xanthine and hypoxanthine by molecular oxygen generating superoxide and H₂O₂. Xanthine oxidase is inactive during anoxia because of the absence of O₂, but it becomes active during reperfusion as soon as O₂ appears.

2. Reperfusion induces activation of phagocytes and their migration into muscle. This is due to the increased level of ROS which are activators and attractants of phagocytes. Phagocytes generate ROS by NADPH-oxidase on their plasma membrane. A vicious circle is formed: reoxygenated muscle forms more ROS, thus attracting phagocytes which synthesize ROS by themselves, worsening the effect that was primarily induced by xanthine oxidase and other sources of ROS in muscle cells.

3. ROS stimulate the formation of thromboxane (and some other regulators) from arachidonic acid. These compounds enhance the formation of ROS by phagocytes, resulting in another vicious circle. Thus, ROS formation in muscle becomes a sort of self-accelerating process.

Unfortunately, the chapter does not consider the importance of mitochondria and ROS-dependent apoptosis in these events. Not only xanthine oxidase, but also mitochondria are sources of ROS during reoxygenation. On the other hand, ROS induce apoptosis and mitochondria play a key role in programmed cell death. Apoptosis eliminates cells with increased level of ROS, resulting in massive cell death which can have dramatic consequences in the heart during infarction and in the brain during stroke.

Also, the author does not consider that reoxygenation changes not only the quantity but also the quality of ROS, i.e., formation of the most aggressive ROS, hydroxyl radical, is increased. This effect can be a simple consequence of conversion of Fe³⁺ (predominant in aerobic tissue due to auto-oxidation of complexes of Fe²⁺ with citrate and other natural chelators) to Fe²⁺ when there is no more oxygen in the tissue. The appearance of Fe²⁺ enables the Fenton reaction (H₂O₂ + Fe²⁺ --> OH^- + OH^· + Fe³⁺), the main source of OH^· in the cell. This reaction does not take place during anoxia because H₂O₂ is formed from O₂^-· that is in turn generated from O₂, which is absent under anoxia. But O₂ appears during reperfusion; hence, O₂^-· and H₂O₂ also appear, thus enabling the Fenton reaction.

The hypothesis outlined above can explain several facts summarized in the chapter of Gohman, i.e., why desferrioxamine and apotransferrin (binding iron ions) and mannitol (inactivating hydroxyl radical) have potent beneficial effect during reperfusion. A similar effect is achieved by co-perfusion with SOD and catalase that consume O₂^-· and H₂O₂. Another antioxidant, ascorbate, has beneficial effects as well.

In general, the book is useful to biochemists interested in ROS and to physicians trying to solve problems of skeletal muscle disorders, infarction, stroke, and aging.