Role of oxidative stress in impaired insulin signaling associated with exercise-induced muscle damage

Free Radical Biology and Medicine 65 (2013) 1265–1272

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Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed

Review Article

Role of oxidative stress in impaired insulin signaling associated with exercise-induced muscle damage Wataru Aoi a,n, Yuji Naito b, Toshikazu Yoshikawa b a

Laboratory of Health Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan

b

art ic l e i nf o

a b s t r a c t

Article history: Received 27 August 2013 Received in revised form 18 September 2013 Accepted 19 September 2013 Available online 27 September 2013

Skeletal muscle is a major tissue that utilizes blood glucose. A single bout of exercise improves glucose uptake in skeletal muscle through insulin-dependent and insulin-independent signal transduction mechanisms. However, glucose utilization is decreased in muscle damage induced by acute, unaccustomed, or eccentric exercise. The decrease in glucose utilization is caused by decreased insulin-stimulated glucose uptake in damaged muscles with inhibition of the membrane translocation of glucose transporter 4 through phosphatidyl 3-kinase/Akt signaling. In addition to inflammatory cytokines, reactive oxygen species including 4-hydroxy-2-nonenal and peroxynitrate can induce degradation or inactivation of signaling proteins through posttranslational modification, thereby resulting in a disturbance in insulin signal transduction. In contrast, treatment with factors that attenuate oxidative stress in damaged muscle suppresses the impairment of insulin sensitivity. Muscle-damaging exercise may thus lead to decreased endurance capacity and muscle fatigue in exercise, and it may decrease the efficiency of exercise therapy for metabolic improvement. & 2013 Elsevier Inc. All rights reserved.

Keywords: Muscle-damaging exercise Delayed-onset muscle damage Insulin signal transduction 4-Hydroxynonenal

Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Improvement of insulin sensitivity after moderate exercise . . . . . . . . . Exercise-induced delayed-onset muscle damage. . . . . . . . . . . . . . . . . . Impaired insulin sensitivity after muscle-damaging exercise . . . . . . . . Importance of exercise-induced muscle damage in sports and health. Perspectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction A habitual exercise regimen is a major lifestyle factor that reduces the risk of various common diseases related to metabolic dysfunction.

Abbreviations: 4-HNE, 4-hydroxy-2-nonenal; AMPK, AMP-activated kinase; CaMK, Ca2 þ /calmodulin-dependent protein kinase; CK, creatine kinase; GLUT4, glucose transporter 4; IKK, IκB kinase; IL, interleukin; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; PGC-1α, peroxisome proliferator-activated receptor γ coactivator-1α; PI3-K, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α n Corresponding author. E-mail address: [email protected] (W. Aoi). 0891-5849/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.freeradbiomed.2013.09.014

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Exercise improves the energy consumption capacity of muscles and prevents the loss of muscle mass. Therefore, a key factor that can prevent metabolic syndrome is the metabolic function of skeletal muscle, which is a major consumer of nutrients. Regular exercise adaptively improves the metabolism of glucose and lipids in skeletal muscles during the resting state; the expression and activation of key metabolic proteins are involved in the development of this adaptation [1–3]. Even a single bout of exercise elevates glucose uptake in skeletal muscles through activation of an insulin-independent signal pathway during muscle contraction [4–6]. Insulin-dependent glucose uptake in skeletal muscles continues for some time after exercise [7,8]. However, strenuous exercise results in muscle fatigue and frequently causes postexercise muscle damage that does not induce metabolic

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improvement but rather impairs it. Growing evidence has shown that muscle damage suppresses insulin sensitivity compared to the resting state (i.e., nonexercise condition), and this reduction is caused by oxidative stress and inflammatory factors generated by muscle damage. There are various recent considerations regarding the physiological effect of exercise-induced reactive oxygen species (ROS). ROS function as a signaling factor in several signaling transduction pathways associated with glucose and lipid metabolism [9,10]. Therefore, ROS generated during exercise are necessary in the transient and adaptive improvement of muscle nutrient metabolism. By contrast, ROS generation at an excessive high level, i.e., corresponding to the level of muscle damage, impairs insulin sensitivity. In this paper, we review an aspect of the importance of exercise-induced generation of ROS.

Improvement of insulin sensitivity after moderate exercise A single bout of exercise generally improves glucose uptake in skeletal muscles through insulin-dependent and insulin-independent signal transduction mechanisms. Muscle contraction causes insulinindependent glucose uptake, which is mediated through various signaling molecules such as AMP-activated kinase (AMPK), Ca2þ / calmodulin-dependent protein kinases (CaMK's), liver kinase B-1, and protein kinase C [4–6]. These signaling molecules facilitate the translocation of glucose transporter 4 (GLUT4) to the plasma membrane, thereby elevating glucose uptake. The exercise-induced improvement in glucose uptake also continues for several hours after exercise and often persists until the next day. The increase in postexercise glucose uptake is mainly mediated by insulin-dependent glucose uptake [7,8]. Insulin signaling involves phosphorylation of the insulin receptor, phosphorylation of insulin receptor substrate (IRS)1/2 on its tyrosine residues, and activation of phosphatidylinositol 3-kinase (PI3-K). These effects lead to GLUT4 translocation through phosphorylation of Akt [9–11]. The initial signals that lead to GLUT4 translocation in skeletal muscle by insulin and exercise are distinct because exercise has little effect on the upstream signaling molecules, insulin receptor, IRS-1 phosphorylation, and PI3-K activity [10–12]. The exercise-induced signaling of insulin-dependent and insulinindependent glucose uptake acts on the Rab-GTPase-activating proteins AS160 and TBC1D1 downstream of their signaling pathway and finally acts on GLUT4 [13]. In addition to the acute action in response to exercise, regular exercise adaptively improves insulin sensitivity in the resting state; this adaptation is associated with the expression and activity of several key proteins in skeletal muscles. Peroxisome proliferatoractivated receptor γ coactivator-1α (PGC-1α) and AMPK, as modulators, specifically play important roles in the improvement of the metabolic rate through regular exercise [14,15]. Increased GLUT4 expression improves glucose metabolism to some extent. Regular exercise may induce long-term activation of AMPK, which may then increase GLUT4 biogenesis [16]. AMPK also induces increased binding of PGC-1α to its promoter through direct phosphorylation of PGC-1α on the amino acids Thr177 and Ser538 [17], which improves lipid metabolism, elevates mitochondrial biogenesis, and facilitates a fast-to-slow fiber-type switch. The expression and activity of PGC-1α in response to regular exercise could result from the repetitive activation of several other upstream signal molecules such as calcineurin, CaMK's, p38 mitogen-activated protein kinase (MAPK), and moderate levels of ROS [17–20]. Exercise-induced delayed-onset muscle damage Acute, unaccustomed, or strenuous exercise causes muscle damage that presents clinically as muscular pain and involves protein

degradation and ultrastructural changes. Soluble muscle enzymes, in particular creatine kinase (CK), are released, indicating disruption of the sarcomere architecture [21,22] and surface membrane damage [23,24]. Muscle damage usually occurs with a delay after exercise (rather than during or immediately after exercise) and peaks after approximately 24–48 h; this type of damage is called delayed-onset muscle damage. Muscle-damaging exercise leads to phagocytic infiltration into the damaged muscle. This inflammatory response induces delayed-onset muscle damage [25]. Previous studies have shown that delayed-onset muscle damage is mainly induced by mechanical stress, especially eccentric muscle contraction [26–29]. Concentric exercise shortens contracting muscles; by contrast, eccentric exercise forcibly lengthens a contracting muscle. During stepping down a slope, the contracting quadriceps muscle controls the rate of knee flexion against the force of gravity. In this process, the muscle undergoes eccentric contraction with each step. In fact, compared to uphill running (i.e., concentric exercise), downhill running (i.e., eccentric contraction) causes greater muscle damage [30], which even occurs during the lowintensity physical activity of walking. The disturbance of calcium homeostasis also causes muscle damage by activating protease [31]. A muscle contraction requires a transient increase in intracellular calcium, which is released from the sarcoplasmic reticulum into the cytosol through the excitation–contraction coupling system. An overload of intracellular calcium activates calpain (a calciumdependent protease), which destroys muscle protein [32]. Oxidative stress generated during exercise can also induce delayed-onset muscle damage. Prolonged exercise increases oxygen consumption and leads to ROS generation by the mitochondrial electron transport chain in muscle cells [33]. Xanthine oxidase is also activated during exercise through an ischemia–reperfusion process, which results in ROS generation by the capillary endothelium in the contracting muscles [34]. We demonstrated that delayed-onset muscle damage is partly associated with inflammation through phagocyte infiltration caused by the ROS generated during exercise [35]. In an in vitro study using rat myotube cells, addition of hydrogen peroxide induced the translocation of p65, a component of the redox-sensitive transcription nuclear factor-κB (NF-κB), into the nucleus and subsequently increased the expression of cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1. Prolonged acute exercise caused an increase in the amount of nuclear p65 in rat gastrocnemius muscles at 1 h after exercise, which was similar to the results obtained in vitro, with subsequent phagocyte invasion on the next day that resulted in proteolysis and ultrastructural damage. In addition, the phagocytes infiltrating into muscle tissues generate additional ROS through nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase [33,35–37], thus causing oxidative damage and further accelerating the inflammatory cascade, which amplifies inflammation. Various types of oxidative damage to cellular components in damaged muscle have been observed [38–42], and this damage may result from ROS generated by infiltrated phagocytes. Several studies reported that oral administration of antioxidants inhibits oxidative damage of cellular components in damaged muscle after exercise. In addition, intake of antioxidants before exercise also attenuates muscle damage because it suppresses ROS generation during exercise and the subsequent activation of the redox-sensitive inflammatory cascade. Indeed, the short- or longterm use of antioxidant vitamins has been reported to limit circulating levels of CK, accumulation of oxidative products, and expression of inflammatory factors in damaged muscle in humans and rodents [35,43,44]. Carotenoids, polyphenols, and other phytochemicals have also been reported to prevent muscle damage [39,45–47]. In contrast, several studies have indicated that the intake of antioxidants does not affect muscle damage or the inflammatory response caused by strenuous exercise [48–51]. These contradictory

W. Aoi et al. / Free Radical Biology and Medicine 65 (2013) 1265–1272

Glucose Glucose

Glucose

Improved glucose metabolism

Exercise Muscle damage

Glucose Glucose

Impaired glucose metabolism

Fig. 1. Differential response in muscle metabolic function between concentric and eccentric exercise. Glucose metabolism in skeletal muscle is improved through improvement of insulin sensitivity after concentric exercise. In contrast, eccentric exercise impairs glucose metabolism compared with concentric exercise and nonexercise conditions, along with occurrence of muscle damage.

results may be the result of differences in exercise conditions. When there is excess mechanical stress on the muscles, such as during eccentric contraction and resistance exercise, muscle injury is mainly caused by mechanical damage. In contrast, delayed-onset muscle damage induced by prolonged exercise is partly associated with inflammation through phagocyte infiltration caused by ROS; in this case, antioxidants would be effective to attenuate muscle damage.

Impaired insulin sensitivity after muscle-damaging exercise Growing evidence has shown that impaired insulin sensitivity occurs physiologically with muscle damage, in contrast to the improvement in insulin sensitivity after non-muscle-damaging exercise (Fig. 1). In hyperglycemic clamp conditions, Kirwan et al. [52] initially reported that in human subjects the peak and incremental areas under the insulin-response curve during clamping of the postexercise condition were higher than those in the nonexercise condition 12 h after an exhausting bout of treadmill running, and they suggested for the first time that intense exercise induces insulin resistance. In a euglycemic–hyperinsulinemic clamp study, they further confirmed that systemic insulin resistance and elevated circulating CK levels persist 48 h after downhill running (eccentric exercise); this effect was not observed after uphill running (concentric exercise) or in the resting state [53]. Asp et al. [54] also showed using euglycemic clamping of bilateral femoral arteries that 2 days after one-legged eccentric exercise, the maximal insulin-mediated glucose uptake in muscle was impaired. Recently, we also showed in an indirect calorimetry method that carbohydrate oxidation after oral glucose administration was decreased 24 h after acute resistance exercise [55]. In contrast, intake of Lactobacillus helveticus-fermented milk, a preventive factor against muscle damage, attenuated the impairment of glucose metabolism [55,56]. In addition, we reported that the insulin-stimulated uptake of 2-deoxy-[3H]glucose in damaged muscle tissue is significantly reduced after downhill running relative to the uptake occurring in sedentary rodents [57]. Interestingly, the reduction of insulin-stimulated glucose uptake is larger in red muscle fibers, which contain more sources of ROS generation such as mitochondria and iron, than in white muscle fibers [58]. Del Aguila et al. [59] and our group [57] reported that downhill running impairs the insulin-stimulated activity of IRS-1, PI3-K, and Akt in damaged muscle tissues from healthy humans [59] and animals [57]. In addition, GLUT4 protein content was decreased in

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the damaged muscles 1 and 2 days after either eccentric resistant exercise [60] or downhill running [57]. It is well known that proinflammatory cytokines impair glucose transport by inhibiting insulin signal transduction in skeletal muscles. A representative cytokine, tumor necrosis factor-α (TNF-α), prevents insulin-induced activation of the insulin receptor, PI3-K, and Akt in muscle tissue [61–63]. Inhibition of TNF-α-induced signaling prevents this impairment of insulin-mediated Akt phosphorylation and glucose uptake [64]. In exercise-induced muscle damage, endotoxin-induced production of TNF-α by mononuclear cells was increased and positively correlated with reduced insulin-stimulated activity of PI3-K [59], which presumably decreases insulin-mediated glucose uptake in skeletal muscles. Other studies also reported that at 24–48 h after muscle-damaging exercise in humans and rodents, levels of interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, and IL-8 are increased in muscle tissues [35,65,66]. These inflammatory factors may be partly associated with the initiation and progression of impaired muscle-damage-induced insulin signaling. In contrast, the transient and physiological level of IL-6, a proinflammatory cytokine, has another anti-inflammatory aspect. In response to exercise and muscle contraction, IL-6 secreted from muscles into the circulation acts locally within the contracting skeletal muscle in a paracrine manner or is released into the blood circulation, where it induces systemic effects and improves nutrient metabolism while producing anti-inflammatory effects [67,68]. This process is known as the myokine theory and both aspects should be distinctly considered. Elevated generation of ROS in delayed-onset muscle damage can impair insulin-stimulated glucose uptake. In the past decade, a close relationship has been suggested between oxidative stress and insulin effects [69,70]. In muscle cells, stimulation by oxidants such as hydrogen peroxide blocks insulin-induced glucose uptake and GLUT4 translocation by impairing upstream signaling [71,72]. Oxidative stress has shown to increase IRS-1 degradation along with the activity of the ubiquitin-dependent proteolytic pathway in muscle cells. In addition, stress-mediated activation of serine kinases, with subsequent modulation of IRS-1 protein levels and functionality, is associated with the effects of oxidative stress on insulin action. It has been shown that hydrogen peroxide induces the activity of various serine kinases, including p38 MAPK, c-Jun N-terminal kinase, IKK-β, and ERK1/2, with subsequent phosphorylation of IRS-1 on Ser307 and selective degradation of IRS-1, ultimately leading to insulin resistance [73–76]. In fact, previous studies have reported that levels of oxidative products are elevated in the muscles of patients with type 2 diabetes [77,78] and diabetic mice [79]. In contrast, several antioxidants improve the insulin signaling of muscle cells for glucose uptake and reduce the production of oxidative products [71,80,81], which supports a role for oxidative stress in the development of insulin resistance. The accumulation of oxidative products found in exercise-induced muscle damage indicates a close relationship of oxidative stress with impaired insulin sensitivity. In addition, we recently reported that intake of milk fermented using a starter culture containing L. helveticus and Saccharomyces cerevisiae, which induces expression of antioxidative enzymes such as manganese-superoxide dismutase (Mn-SOD) and glutathione S-transferase, prevents the impairment of glucose metabolism after acute exercise [55,56]. Increasing evidence has shown that oxidative stress modulates signal transduction by modifying proteins posttranslationally [82,83]. Several lipid peroxide products nonenzymatically modify amino acid residues of a target protein in an irreversible manner, which can inhibit protein activity [82,84]. Therefore, generation of oxidative stress-modified proteins links ROS with physiological and pathological phenotypic changes. Our immunohistochemistry results showed that 4-hydroxy-2-nonenal (4-HNE)-modified proteins accumulate in damaged muscle obtained from mice after acute running [39]. 4-HNE is a lipid peroxidation product that is

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released from the peroxidation of n-6 polyunsaturated fatty acids and that covalently modifies proteins on their cysteine, histidine, and lysine residues, thereby modulating the activity of several proteins [85–87]. 4-HNE treatment impairs insulin signaling and glucose uptake in muscle cells and in isolated skeletal muscle [88]. We recently reported that the modification of 4-HNE in IRS-1 was elevated in damaged muscle from exercised mice, together with reductions in tyrosine phosphorylation of IRS-1, inhibition of PI3K/Akt signaling, and inhibition of the membrane translocation of GLUT4 [57]. Therefore, modification of IRS-1 by 4-HNE is involved in the transient impairment of insulin sensitivity through inactivation of downstream signaling in damaged muscles after exercise (Fig. 2). 4-HNE modification of insulin signaling has also been observed in other metabolic cells. In 3T3-L1 adipocytes and HepG2 hepatoma cells, IRS and Akt were shown to be covalently modified by 4-HNE, which led to impaired insulin signaling and glucose uptake via inactivation of these proteins [89,90]. In addition, 4-HNE treatment was found to increase in intracellular ROS

Fig. 2. Modification of IRS-1 by 4-HNE and insulin resistance in damaged muscle. 4-HNE is a lipid peroxidation product that covalently modifies proteins on their cysteine, histidine, and lysine residues, thereby modulating the activity of several proteins. Modification of IRS-1 by 4-HNE is involved in transient insulin resistance through inactivation of downstream signaling and abnormal gene expression in damaged muscles after exercise.

production in L6 muscle cells [88]. The resulting redox imbalance creates ROS that induce lipid peroxidation, thus generating aldehydes that generate more ROS, leading to amplification of the damage caused by oxidative stress (Fig. 3). Another possible inducer of exercise-induced insulin resistance may be NO-related reactive nitrogen species such as peroxynitrite, a powerful oxidizing and nitrating species that causes DNA damage, lipid peroxidation, oxidation of protein-associated thiol groups, and nitration of protein tyrosine residues [91,92]. Increased nitrotyrosine formation has been found in both experimental diabetic animals [93–95] and diabetic patients [96,97]. Peroxynitrite may affect insulin signal transduction through nitration of key tyrosine residues on proteins involved in insulin signaling. In line with this concept, it has been shown that peroxynitrite impairs the effects of insulin in vitro by decreasing tyrosine phosphorylation of IRS-1 and simultaneously increasing nitration of its tyrosine residues [98]. Moreover, peroxynitrite has been shown to be involved in the development of insulin resistance in mice. Duplain et al. [99] provided in vivo evidence that high concentrations of peroxynitrite are formed and are responsible for high-fat-diet-induced insulin resistance in skeletal muscle by increasing Akt nitration. Exogenous peroxynitrite donated by 3-morpholinosydnonimine hydrochloride was shown to induce in vivo nitration of the insulin receptor β subunit, IRS-1, and Akt in the skeletal muscle of mice and dramatically reduce whole-body insulin sensitivity and muscle insulin signaling. Lima-Cabello et al. [100] showed that acute downhill running markedly increases levels of tyrosine-nitrated cytosolic proteins, along with expression of neuronal, inducible, and endothelial nitric oxide synthases, in skeletal muscle obtained from rats, which suggests involvement of NO damage in exercise-induced muscle insulin resistance (Fig. 3). In addition to their direct effects, ROS may indirectly induce insulin resistance by activating the inflammatory signal cascade. Exposure of cells to oxidative stress causes the activation of a series of upstream kinases such as MAPK, IKK, protein kinase C, and PI3-K, which then activate NF-κB by the phosphorylationmediated degradation of IκBα [101–103]. Free, activated NF-κB, in the form of the p65–p50 heterodimer, is translocated to the nucleus, where it binds to the κB sequences located in the promoter of the target gene. Alternatively, MAPKs can also activate the activator protein-1 components c-Jun and c-Fos, leading to binding of activator protein-1 (c-Jun-c-Fos heterodimer) to the

Fig. 3. Schematic illustration of exercise-induced glucose uptake in skeletal muscle. Exercise and muscle contraction improve insulin-dependent glucose uptake by the translocation of GLUT4 to the plasma membrane through the PI3-K/Akt signaling pathway after exercise. This signaling acts on the Rab-GTPase-activating protein AS160 and finally acts on GLUT4. Insulin-independent glucose uptake is also elevated through the expression and activation of AMPK during exercise. It also translocates GLUT4 after AS160 activation. ROS, particularly 4-HNE and peroxynitrate (ONOO  ), and inflammatory factors impair the insulin-stimulated activity of IRS-1, PI3-K, and Akt. These factors cause further intracellular reactive oxygen intermediate (e.g., O2  , H2O2) generation and thus insulin resistance develops through a circular mechanism among oxidative stress and inflammatory cytokines.

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cyclic AMP response element sequences of the target promoter gene [102,103]. Such redox-sensitive transcription factors increase the expression of inflammatory cytokines, which further impairs insulin signaling. In contrast, inflammatory cytokines such as TNFα cause ROS generation from mitochondria; therefore, insulin resistance may have developed through a circular mechanism among ROS and inflammatory cytokines (Fig. 3).

Importance of exercise-induced muscle damage in sports and health We feel soreness in damaged muscles after exercise, which is believed to be a psychological barrier to maintaining the motivation for daily exercise in many people [104]. In addition, in sports events such as precompetition for athletes and recreational sports activities, participating individuals have been instructed to avoid muscle damage because it leads to deconditioning and fatigue and thus inhibits physical performance [105–107]. Insulin resistance resulting from muscle damage may underlie such decreases in performance. Impaired glucose uptake strongly influences the condition of athletes. Muscles must continuously use blood glucose as a major energy substrate to maintain muscle contraction during exercise. On the following day, decreased insulin sensitivity consequently suppresses the supply of glucose to muscles and induces muscular fatigue by impaired contractile endurance during exercise. Furthermore, muscle damage has been reported to delay the replenishment of muscle glycogen, a major energy substrate during exercise. After 10 days, the glycogen content remains depleted [108], which also decreases endurance performance. Muscle insulin sensitivity is in fact strongly associated with endurance capacity [109]. Therefore, the transient reduction in glucose metabolism among athletes may represent a disadvantage during pregame conditioning. In physical activity performed for the purpose of metabolic improvement, muscle damage is also inefficient at improving insulin sensitivity. Although regular exercise is generally recommended as a therapeutic treatment and preventative measure for type 2 diabetes, the effect of regular muscle-damaging exercise on adaptive improvement of insulin sensitivity should be examined in a future study. Furthermore, reduced force generation and elevated arterial stiffness also occur in subjects with delayed-onset muscle damage [110,111]. These observations suggest that muscle-damaging exercise is inappropriate for promoting health in patients with metabolic diseases and in endurance and power athletes, at least before sports events (Fig. 4). In contrast, there is an argument supporting the role of muscle damage in adaptation to exercise training. It has been believed that muscle damage after exercise must precede the restoration that leads to increased strength and muscle hypertrophy. In fact, compared with concentric contraction, resistance training using an eccentric load causes more severe muscle damage and often induces an early increase in muscle mass. In contrast, it has been reported that there is no correlation between inflammation and muscle strength adaptation [112]. Recurrent inflammation caused by exercise leads to muscle fibrosis with an increase in collagen deposition [113,114]. A muscle under these conditions cannot exert the strength that corresponds to its mass. Therefore, muscle damage may be disadvantageous in physical activity for promoting health and conditioning in athletes, even considering the longterm effects. Further studies are needed to elucidate the physiological and pathological relevance of the effects of muscle damage. Perspectives Oxidative stress suppresses insulin sensitivity in damaged muscles, which temporarily reduces exercise performance and is

Fig. 4. Functional changes in delayed-onset muscle damage. Delayed-onset muscle damage induced by strenuous, unaccustomed, or eccentric exercise induces excess oxidative stress and inflammation with phagocyte infiltration. It also impairs glucose metabolism through impaired insulin sensitivity. Muscle contractile dysfunction and elevated arterial stiffness also occur during muscle damage. These events consequently lead to decreased endurance capacity and muscle fatigue in exercise and attenuate the efficacy of exercise therapy for promoting health.

not appropriate for therapy in individuals with diabetes or cardiovascular disease. In contrast, exercise-induced oxidative stress may play an important role in improving metabolic adaptation through exercise. Therefore, an argument needs to be considered with regard to the role of exercise-induced oxidative stress. Several recent studies suggest that a moderate degree of oxidative stress enhances the production of muscle force, nutrient metabolism, and antioxidant enzyme production [115–117]. This exercise-induced effect does not occur without oxidative stress, which is recognized as the theory of hormesis. Although it is unclear why discrepant effects have been reported for ROS generated by exercise, the differences may involve variability in the volume and generation source of ROS. Excess levels of ROS or ROS generated from phagocytes under inflammatory conditions may damage cellular components. In fact, it has been shown that treatment with hydrogen peroxide stimulates glucose uptake into isolated muscles at low to moderate concentrations, but uptake is impaired at high concentrations [118]. In addition, the intake of dietary antioxidants during exercise is also controversial. Dietary supplementation of vitamin C and vitamin E cancels many exercise-induced benefits, such as improvement of insulin sensitivity, blood pressure, and endurance capacity [115,116,119]. These effects are caused by suppression of the expression of redox-sensitive proteins including PGC-1α, AMPK, and SOD2 [115,116]. Therefore, the benefit of dietary intake of antioxidants during exercise therapy for treating and preventing diseases and for training to improve athletic performance is debatable. However, it may be useful to maintain the physiological redox level by temporarily consuming antioxidant nutrients during high-intensity exercise because the oxidative stress associated with muscle damage and derived from phagocytes would be excessive. The future development and evaluation of a marker for determining the optimal oxidative stress level are necessary. In contrast, some antioxidants increase energy metabolism and insulin sensitivity induced by exercise through elevation of the level and activity of key modulators [120–123]. This effect, and not

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only chemical and physical properties, may be responsible for the specific actions of each compound. Therefore, all antioxidants cannot be grouped together, and the respective properties of each antioxidant should be considered individually and not by the absolute antioxidative capacity. Further studies are needed to examine the various aspects, e.g., volume, type, and generation source, of ROS under various exercise conditions to determine the characteristics of oxidative stress induced by exercise.

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