Li Li Ji

Exercise training-induced alterations in skeletal muscle antioxidant capacity: a brief review.

Cellular oxidants include a variety of reactive oxygen, nitrogen, and chlorinating species. It is well established that the increase in metabolic rate in skeletal muscle during contractile activity results in an increased production of oxidants. Failure to remove these oxidants during exercise can result in significant oxidative damage of cellular biomolecules. Fortunately, regular endurance exercise results in adaptations in the skeletal muscle antioxidant capacity, which protects myocytes against the deleterious effects of oxidants and prevents extensive cellular damage. This review discusses the effects of chronic exercise on the up-regulation of both antioxidant enzymes and the glutathione antioxidant defense system. Primary antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase will be discussed as well as glutathione, which is an important nonenzymatic antioxidant. Growing evidence indicates that exercise training results in an elevation in the activities of both superoxide dismutase and glutathione peroxidase along with increased cellular concentrations of glutathione in skeletal muscles. It seems plausible that increased cellular concentrations of these antioxidants will reduce the risk of cellular injury, improve performance, and delay muscle fatigue.

Decreasing xanthine oxidase‐mediated oxidative stress prevents useful cellular adaptations to exercise in rats

Reactive oxygen or nitrogen species (RONS) are produced during exercise due, at least in part, to the activation of xanthine oxidase. When exercise is exhaustive they cause tissue damage; however, they may also act as signals inducing specific cellular adaptations to exercise. We have tested this hypothesis by studying the effects of allopurinol‐induced inhibition of RONS production on cell signalling pathways in rats submitted to exhaustive exercise. Exercise caused an activation of mitogen‐activated protein kinases (MAPKs: p38, ERK 1 and ERK 2), which in turn activated nuclear factor κB (NF‐κB) in rat gastrocnemius muscle. This up‐regulated the expression of important enzymes associated with cell defence (superoxide dismutase) and adaptation to exercise (eNOS and iNOS). All these changes were abolished when RONS production was prevented by allopurinol. Thus we report, for the first time, evidence that decreasing RONS formation prevents activation of important signalling pathways, predominantly the MAPK–NF‐κB pathway; consequently the practice of taking antioxidants before exercise may have to be re‐evaluated.

Exercise and hormesis: activation of cellular antioxidant signaling pathway.

Abstract:  Contraction‐induced production of reactive oxygen species (ROS) has been shown to cause oxidative stress to skeletal muscle. As an adaptive response, muscle antioxidant defense systems are upregulated after heavy exercise. Nuclear factor (NF) κB and mitogen‐activated protein kinases (MAPKs) are the major oxidative stress–sensitive signal transduction pathways in mammalian tissues. Activation of NF‐κB signaling cascade has been shown to enhance the gene expression of important enzymes, such as mitochondrial superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS). MAPK activations are involved in a variety of cellular functions including growth, proliferation, and adaptation. We investigated the effect of an acute bout of exercise on NF‐κB and MAPK signaling, as well as on the time course of activation, in rat skeletal muscle. In addition, we studied the role of ROS in the exercise‐induced upregulation of MnSOD and iNOS, and the potential interactions of NF‐κB and MAPK in the signaling of these enzymes. Our data suggest that ROS may serve as messenger molecules to activate adaptive responses through these redox‐sensitive signaling pathways to maintain cellular oxidant‐antioxidant homeostasis during exercise.

Strenuous endurance training in humans reduces oxidative stress following exhausting exercise.

Abstract The aim of this study was to evaluate whether high-intensity endurance training would alleviate exercise-induced oxidative stress. Nine untrained male subjects (aged 19–21 years) participated in a 12-week training programme, and performed an acute period of exhausting exercise on a cycle ergometer before and after training. The training programme consisted of running at 80% maximal exercise heart rate for 60 min · day−1, 5 days · week−1 for 12 weeks. Blood samples were collected at rest and immediately after exhausting exercise for measurements of indices of oxidative stress, and antioxidant enzyme activities [superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT)] in the erythrocytes. Maximal oxygen uptake (V˙O2max) increased significantly (P < 0.001) after training, indicating an improvement in aerobic capacity. A period of exhausting exercise caused an increase (P < 0.01) in the ability to produce neutrophil superoxide anion (O2•−) both before and after endurance training, but the magnitude of the increase was smaller after training (P < 0.05). There was a significant increase in lipid peroxidation in the erythrocyte membrane, but not in oxidative protein, after exhausting exercise, however training attenuated this effect. At rest, SOD and GPX activities were increased after training. However, there was no evidence that exhausting exercise enhanced the levels of any antioxidant enzyme activity. The CAT activity was unchanged either by training or by exhausting exercise. These results indicate that high-intensity endurance training can elevate antioxidant enzyme activities in erythrocytes, and decrease neutrophil O2•− production in response to exhausting exercise. Furthermore, this up-regulation in antioxidant defences was accompanied by a reduction in exercise-induced lipid peroxidation in erythrocyte membrane.

Exercise-induced Modulation of Antioxidant Defense

Maintaining mobility is a critical element for the quality of life. Skeletal muscle, the primary organ for locomotion, undergoes age‐associated deterioration in size, structure, and function. Recent research suggests that oxidative stress is an important etiology for sarcopenia. The level of oxidative stress imposed on aging muscle is influenced by two fundamental biological processes: the increased generation of reactive oxygen species (ROS) and age‐associated changes in antioxidant defense. It appears that despite increased ROS production, aging muscle has a decreased gene expression of antioxidant enzymes possibly due to a diminished ability for cell signaling. A major benefit of nonexhaustive exercise is to induce a mild oxidative stress that stimulates the expression of certain antioxidant enzymes. This is mediated by the activation of redox‐sensitive signaling pathways. For example, gene expression of muscle mitochondrial (Mn) superoxide dismutase is enhanced after an acute bout of exercise preceded by an elevated level of NF‐κB and AP‐1 binding. An increase in de novo protein synthesis of an antioxidant enzyme usually requires repeated bouts of exercise. Aging does not abolish but seems to attenuate training adaptations of antioxidant enzymes. Thus, for senescent muscle, training should be assisted with supplementation of exogenous antioxidants to research the optimal level of defense.

Oxidative stress during exercise: implication of antioxidant nutrients.

Research evidence has accumulated in the past decade that strenuous aerobic exercise is associated with oxidative stress and tissue damage in the body. There is indication that generation of oxygen free radicals and other reactive oxygen species may be the underlying mechanism for exercise-induced oxidative damage, but a causal relationship remains to be established. Enzymatic and nonenzymatic antioxidants play a vital role in protecting tissues from excessive oxidative damage during exercise. Depletion of each of the antioxidant systems increases the vulnerability of various tissues and cellular components to reactive oxygen species. Because acute strenuous exercise and chronic exercise training increase the consumption of various antioxidants, it is conceivable that dietary supplementation of specific antioxidants would be beneficial.

Acute exercise activates nuclear factor (NF)-κB signaling pathway in rat skeletal muscle

Two studies were performed to investigate the effects of an acute bout of physical exercise on the nuclear protein κB (NF‐κB) signaling pathway in rat skeletal muscle. In Study 1, a group of rats (n=6) was run on the treadmill at 25 m/min, 5% grade, for 1 h or until exhaustion (Ex), and compared with a second group (n=6) injected with two doses of pyrrolidine dithiocarbamate (PDTC, 100 mg/kg, i.p.) 24 and 1 h prior to the acute exercise bout. Three additional groups of rats (n=6) were injected with either 8 mg/kg (i.p.) of lipopolysaccharide (LPS), 1 mmol/kg (i.p.) i‐butylhydroperoxide (tBHP), or saline (C) and killed at resting condition. Ex rats showed higher levels of NF‐κB binding and P50 protein content in muscle nuclear extracts compared with C rats. Cytosolic IκBα and IκB kinase (IKK) contents were decreased, whereas phospho‐IκBα and phospho‐IKK contents were increased, comparing Ex vs. C. The exercise‐induced activation of NF‐κB signaling cascade was partially abolished by PDTC treatment. LPS, but not tBHP, treatment mimicked and exaggerated the effects observed in Ex rats. In Study 2, the time course of exercise‐induced NF‐κB activation was examined. Highest levels of NF‐κB binding were observed at 2 h postexercise. Decreased cytosolic IκBα and increased phosphor‐IκBα content were found 0–1 h postexercise whereas P65 reached peak levels at 2–4 h. These data suggest that the NF‐κB signaling pathway can be activated in a redox‐sensitive manner during muscular contraction, presumably due to increased oxidant production. The cascade of intracellular events may be the overture to elevated gene expression of manganese superoxide dismutase reported earlier (Pfluegers Arch. 442, 426–434, 2001).—Ji, L. L., Gomez‐Cabrera, M.‐C., Steinhafel, Ν., Vina, J. Acute exercise activates nuclear factor (NF) κB signaling pathway in rat skeletal muscle. FASEB J. 18, 1499–1506 (2004)

Modulation of skeletal muscle antioxidant defense by exercise: Role of redox signaling.

Contraction-induced production of reactive oxygen species has been shown to cause oxidative stress to skeletal muscle. As an adaptive response, muscle antioxidant defense systems are upregulated in response to exercise. Nuclear factor kappaB and mitogen-activated protein kinase are two major oxidative-stress-sensitive signal transduction pathways that have been shown to activate the gene expression of a number of enzymes and proteins that play important roles in maintenance of intracellular oxidant-antioxidant homeostasis. This mini-review will discuss the main mechanisms and gene targets for these signaling pathways during exercise and the biological significance of the adaptation.

Antioxidants in Foods: State of the Science Important to the Food Industry

Antioxidant foods and ingredients are an important component of the food industry. In the past, antioxidants were used primarily to control oxidation and retard spoilage, but today many are used because of putative health benefits. However, the traditional message that oxidative stress, which involves the production of reactive oxygen species (ROS), is the basis for chronic diseases and aging is being reexamined. Accumulating evidence suggests that ROS exert essential metabolic functions and that removal of too many ROS can upset cell signaling pathways and actually increase the risk of chronic disease. It is imperative that the food industry be aware of progress in this field to present the science relative to foods in a forthright and clear manner. This may mean reexamining the health implications of adding large amounts of antioxidants to foods.

Exercise at Old Age: Does It Increase or Alleviate Oxidative Stress?

Abstract: Aging is associated with increased free radical generation in the skeletal muscle that can cause oxidative modification of protein, lipid, and DNA. Physical activity has many well‐established health benefits, but strenuous exercise increases muscle oxygen flux and elicits intracellular events that can lead to increased oxidative injury. The paradox arises as to whether exercise would be advisable to aged population. Research evidence indicates that senescent organisms are more susceptible to oxidative stress during exercise because of the age‐related ultrastructural and biochemical changes that facilitate formation of reactive oxygen species (ROS). Aging also increases the incidence of muscle injury, and the inflammatory response can subject senescent muscle to further oxidative stress. Furthermore, muscle repair and regeneration capacity is reduced at old age that could potentially enhance the accrual of cellular oxidative damage. Predeposition of certain age‐related pathologic conditions may exacerbate the risks. In spite of these risks, the elderly who are physically active benefit from exercise‐induced adaptation in cellular antioxidant defense systems. Improved muscle mechanics, strength, and endurance make them less vulnerable to acute injury and chronic inflammation. Many critical questions remain regarding the relationship of aging and exercise as we enter a new millennium. For example, how does aging alter exercise‐induced intracellular and intercellular mechanisms that generate ROS? Can acute and chronic exercise modulate the declined gene expression of metabolic and antioxidant enzymes seen at old age? Does exercise prevent age‐dependent muscle loss (sarcopenia)? What kinds of antioxidant supplementation, if any, do aged people who are physically active need? Answers to these questions require highly specific research in both animals and humans.