Oxidative muscular injury and its relevance to hyperthyroidism

Free Radical Biology & Medicine, Vol. 8, pp. 293-303, 1990 Printed in the USA. All rights reserved.

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0891-5849/90 $3.00 + .00 © 1990 Pergamon Press plc

Review Article OXIDATIVE

MUSCULAR TO

INJURY

AND

ITS

RELEVANCE

HYPERTHYROIDISM

K O H T A R O A S A Y A M A * AND KIYOHIKO K A T O Department of Pediatrics, Yamanashi Medical College, I 110 Shimokato, Tamahocho, Nakakomagun, Yamanashi Pref. 409-38, Japan (Received 24 October 1989; Revised and Accepted 18 December 1989)

Abstract--ln experimental hyperthyroidism, acceleration of lipid peroxidation occurs in heart and slow-oxidative muscles, suggesting the contribution of reactive oxygen species to the muscular injury caused by thyroid hormones. This article reviews various models of oxidative muscular injury and considers the relevance of the accompanying metabolic derangements to thyrotoxic myopathy and cardiomyopathy, which are the major complications of hyperthyroidism. The muscular injury models in which reactive oxygen species are supposed to play a role are ischemia/reperfusion syndrome, exercise-induced myopathy, heart and skeletal muscle diseases related to the nutritional deficiency of selenium and vitamin E and related disorders, and genetic muscular dystrophies. These models provide evidence that mitochondrial function and the glutathione-dependent antioxidant system are important for the maintenance of the structural and functional integrity of muscular tissues. Thyroid hormones have a profound effect on mitochondrial oxidative activity, synthesis and degradation of proteins and vitamin E, the sensitivity of the tissues to catecholamine, the differentiation of muscle fibers, and the levels of antioxidant enzymes. The large volume of circumstantial evidence presented here indicates that hyperthyroid muscular tissues undergo several biochemical changes that predispose them to free radical-mediated injury. Keywords--Free radical, Hyperthyroidism, Lipid peroxide, Superoxide dismutase, Glutathione, Mitochondria, Skeletal muscle, Myocardium

chain reactions eventually leading to oxidative damage to biomembrane lipids and other structures. 6 Although mitochondria metabolize most of the molecular oxygen, only 15% of the total reactive oxygen generated in the cells is ascribed to the mitochondrial products. This implies that the mitochondria have a highly efficient antioxidant defense system. However, the fact that the production rate increases depending on the oxygen consumption even in the intact mitochondria may have a pathophysiological implication. There is an assumption that superoxide generated in the intact mitochondria produces changes at a rate related to the rate of oxygen consumption. 7 Such alterations could have an accumulative deleterious effect on mitochondrial functions, and could explain the aging process of the cells. This hypothesis is supported by the findings of Tolmasoff et al. 8 that the ratio of superoxide dismutase (SOD) activity to a specific metabolic rate correlates with maximum life-span potential for mammalian spe-

1. I N T R O D U C T I O N

Over 90% of the oxygen consumed by a mammal is utilized in the mitochondria, and the reduction of molecular oxygen by the mitochondria electron transport system coupled with oxidative phosphorylation supplies most of the biological energy necessary for the maintenance of life. Two percent of the oxygen consumed in the mitochondrion is partially reduced by electrons which leak from electron carriers in the respiratory chain of healthy, intact mitochondria.~ Two distinct sites of leakage have been identified: ubiquinol-cytochrome c oxidoreductase (Complex III)2 and NADH-ubiquinone oxidoreductase (Complex I). 3 The reactive oxygen species, which are partially reduced forms of molecular oxygen, are reported to be generated in various other subcellular sites such as microsomes, peroxisomes, cytosol, 4 and nuclear membranes. 5These species can be an initiator of free radical *Author to whom correspondence should be addressed.

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cies. According to this hypothesis, food restriction decreases oxygen consumption, and, in turn, free radical production in the mitochondria, resulting in a decreased rate of progression of degenerative disorders including lipid peroxidation.9 Conversely, hypermetabolism ~° and excessive work load ~j are known to aggravate free radical-mediated tissue injury. Lipid peroxidation has also been found to be accelerated in hypertrophied anabolic tissues. ~2,~3On the other hand, the metabolic suppression brought about by hypothyroidism has been associated with a decrease in free radical production, 14 and has protected tissues against acceleration of lipid peroxidation and histologic changes. ~5 Furthermore, the tissue level of manganese SOD (MnSOD) measured by a specific radioimmunoassay ~6'17~ appears to change in response to the activity of mitochondrial oxidative metabolism, ~6.~9suggesting that the latter regulates superoxide production, and, in turn, the MnSOD level in the mitochondria. Accumulating evidence has suggested that a hypermetabolic state in hyperthyroidism should accelerate free radical production in the mitochondria and induce changes in the antioxidant defense system in certain tissues, whereas such a biochemical process has not been investigated previously. We have demonstrated in experimental hyperthyroidism that mitochondrial oxidative metabolism and the level of lipid peroxide, determined as thiobarbituric acid-reactive substances (TBARS), are increased in a parallel manner in the heart and slow-oxidative soleus muscle but not in liver, kidney, nor fast-glycolytic extensor digitorum longus muscle. 2° MnSOD, but not copper zinc SOD (CuZnSOD), is also increased in the heart and soleus muscle. The observed selective alteration of reactive oxygen metabolism in muscular tissues is consistent with clinical findings that the complications of hyperthyroidism directly mediated by thyroid hormone per se are confined to skeletal and heart muscles. The activities of both glutathione peroxidase (GPX) and catalase (CAT) have been found to be decreased in all hyperthyroid tissues studied. 2° Although the pathophysiological consequences of the accelerated lipid peroxidation in the hyperthyroid muscles are not yet fully elucidated, this biochemical change certainly predisposes the tissues to free radical-mediated injury. The present review deals with muscular injury models supposed to be, at least possibly, mediated by reactive oxygen species, the biochemical effect of thyroid hormones on muscular tissues and its implications in the thyrotoxic myopathy and myocardial dysfunction. Then, the review will consider oxidative injury as a possible mechanism for the muscular damage in hyperthyroidism.

2. OXIDATIVE MUSCULAR INJURY MODELS

Muscular injury related to mitochondrial superoxide generation

Several excellent reviews of myocardial ischemiareperfusion injury are available, 2~ 26 and similar mechanisms have been investigated in skeletal muscles. 27-3° An irreversible tissue necrosis is known to occur in myocardium when the coronary artery is occluded for longer than 20 rain, and viable myocytes with prolonged dysfunction (i.e., stunned myocardium) are salvaged when the reperfusion is carried out within 15-20 min. 3~For reperfusion injury, generation of reactive oxygen species from a variety of sources has been described: the mitochondrial electron transport chain in the myocytes; the biosynthesis of prostaglandins in the myocytes; the enzyme xanthine oxidase in the vascular endothelial cells; and the activated neutrophils in the circulation. 26 The intracellular antioxidant defense system is also affected during ischemia. The reduced form of glutathione, which protects against free radical-mediated injury nonenzymatically as an antioxidant and also as a substrate of GPX, is known to decrease. 32 The activities of mitochondrial SOD 33 and GPX 34 have been reported to decrease during ischemia, although the mechanism of the rapid loss of the enzyme activity is not known. Ischemia induces a change in the subsequent metabolism of molecular oxygen in the mitochondria. The percentage of electron leak from the mitochondrial electron transport chain increases during postischemia/reperfusion. During ischemia, the adenine nucleotide pool is partially degraded, so that the mitochondrial carriers are in a more fully reduced state when reperfusion occurs. The lack of ADP and the autoxidation of reduced substrates accumulated during ischemia lead to a burst of free radical production during reoxygenation. This increase in free radical production associated with the decrease in radical-scavenging capability mentioned above results in a rapid free radical-mediated deterioration of the mitochondria. Various pharmacologic interventions for the protection of the ischemic-reperfusion injury are partially, but not totally successful. These are SOD, CAT, hydroxyl radical scavengers such as dimethylsulfoxide, and their combinations, 3~.36,-~7allopurinolfl 8 vitamin E, 3~ and many others. Among these, hydrophilic macromolecules such as SOD and CAT are poorly transported to myocytes, 4° and their intracellular levels are hard to fortify substantially because of the relative abundance of the endogenous enzymes. However, they can still protect against the reactive oxygen products from outside the myocytes when they are administered exogenously. The stunning of the myocardium induced by

Oxidative muscular injury a brief period of ischemia is also reported to be partially mediated by reactive oxygen species, although the source or mechanisms of free radical production remains to be elucidated. 41 In human skeletal muscle, obtained by needle biopsy from patients with circulatory shock, the cytochrome c oxidase activity and the capacity of the mitochondria to oxidize either succinate or pyruvate have been found to decrease. 42 The SOD activity and reduced form of glutathione have also been decreased. These findings suggest that oxidative damage to the mitochondrial electron transport chain associated with free radical-mediated cell injury similar to those found in ischemia/reperfusion can occur without complete occlusion of arteries. It would be a matter of debate whether or not any of the free radical mechanisms similar to those occurring during ischemia/reperfusion contributes to cell injury in a milder ischemia found in hypertrophied myocardium in hyperthyroidism. 43 Exercise-induced myopathy is another model of oxidative muscular injury related to mitochondrial superoxide production. During heavy prolonged exertion, the energy for increased demand is produced by a mitochondrial oxidative metabolism. Free radical production from mitochondria detected by electron spin resonance is known to be increased during a tetanic contraction of isolated skeletal muscle 44 and also in skeletal muscle obtained immediately after an acute bout of exhaustive exercise. 45 Acute exercise is associated with an increase in lipid peroxidation products, which are detected in vivo as expired pentane 46 and in vitro in skeletal muscle as TBARS and other prodHcts, 45"47-51 depending on the intensity of the exercise.52 Exhaustive exercise also results in decreased mitochondrial respiratory control and loss of sarcoplasmic reticulum and endoplasmic reticulum integrity in skeletal muscle, 45 and myocardial subcellular membrane damage. 53 By enhancing 02 consumption, daily exercise of low work intensity but prolonged duration (endurance training) induces a proliferation of skeletal muscle mitochondria accompanied by an increase in oxidative enzymes 50,51,54-60Similarly, cardiac hypertrophy induced in experimental animals is accompanied by an increase in the mitochondrial mass in the myocardium. 6j'62 Davies et al. 57 have reported that the muscle oxidative capacity represented by the activities of mitochondrial oxidative enzymes is a better predictor of endurance exercise capacity than the whole animal maximal 02 consumption, the latter being closely related to the maximal intensity of work which can be attained aerobically. Endurance training inhibits the acceleration of lipid peroxidation in skeletal muscle induced by acute exertion, 48'5~ and reduces the susceptibility of the

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heart to peroxidative damage induced by doxorubicin, 63 which can generate free radicals during redox cycling at the mitochondrial electron transfer chain in myocardium. 64 Likewise, hypertrophied rat heart induced by aortic banding is reported to be less vulnerable to the exogenously administered superoxide anion radical than the control heart. 65 In contrast to the exercise training, reduced muscular activity caused by denervation results in decreased activities of mitochondrial oxidative enzymes in skeletal muscle.19'66'67 This is associated with a concurrent decrease in MnSOD, followed by a restoration of both oxidative enzyme activity and MnSOD during reinnervation. 19Such a parallel change in both systems observed in the denervation-reinnervation model strongly suggest that enhanced antioxidant capacity in response to the increased oxidative activity contributes to the protection against free radicals in the endurance-trained skeletal muscle. In fact, Higuchi et al. 5s found that MnSOD activity was increased in trained muscle, whereas other investigators failed to observe a significant change in total SOD activity. 5°'51 Ji et al. 49'5° reported that both endurance training and acute exercise increased the muscle GPX activity, and that the latter was related to the endurance capacity of the animal. On the other hand, Alessio et al. 5~ found an increase in muscle CAT activity after acute exercise, but not after endurance training. Thus, most previous studies have found some increase in different antioxidant enzymes after exertion, but the data are conflicting. In the rat heart hypertrophy model, Gupta et al. 65 observed an increase in total SOD activity and a concomitant decrease in TBARS. On the other hand, in the hypertrophied rabbit heart model, the SOD was found to be unchanged, and GPX was increased and TBARS was decreased only when the animals were treated with coenzymes Q~o.68 It has been reported that CAT is increased significantly, and that both total SOD and GPX tend to be increased in endurance-trained murine heart. 63 Among the antioxidant enzymes measured previously in the models of muscle training and heart hypertrophy, only GPX has an invariable tendency to be increased. Part of the confusion in the reported levels of CAT and SOD may be due to the limitations of the assay methods used in the studies mentioned above. The CAT concentration in skeletal muscle is much lower than in liver, kidney, or erythrocytes. And, in our experience, neither spectrophotometric nor titrimetric assays have enough sensitivity to give an accurate measure of CAT activity in skeletal muscle; we use a polarographic method for skeletal muscle samples.Z° Furthermore, the biological activity assays for SOD generally used measure all SOD-like activities and are not specific to each

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form of intracellular SOD when applied to a crude tissue homogenate. We think that immunoassays are more specific, although they do not give activity. To determine whether endurance training enhances antioxidant enzyme activities, the effect of exertion on the levels of CAT, MnSOD, and CuZnSOD needs to be investigated using such assay methods. The lack of data indicating a consistent increase in the muscle antioxidant enzymes after endurance training leads to the contention that the enhanced antioxidant capacity is related to the nonenzymatic antioxidants but not the antioxidant enzymes. Free radical concentrations, lipid peroxidation, and damage to sarcoplasmic reticulum, endoplasmic reticulum, and mitochondria are similar in the skeletal muscles of exercise-exhausted non-vitamin E deficient animals and nonexercised vitamin E deficient animals. 45 Furthermore, vitamin E deficiency, but not the decreased activity of GPX induced by dietary selenium deficiency, has been reported to result in a decrease in the animal endurance capacity. 6° However, exercise training causes a decrease in vitamin E in the skeletal muscle mitochondrial membrane 59 and vitamin C supplementation does not modify muscle endurance capacity. 69 Thus, the biochemical mechanism of the antioxidant effect of endurance training still needs to be elucidated. The primary importance of the oxidative enzyme activity on the exercise capacity has been supported by the interaction between hypothyroidism and exercise. Reduced oxidative capacity of skeletal muscle, cardiac contractile capacity, and maximal O2 consumption in hypothyroid rats can be reversed by an exercise training, resulting in the restoration of the animal endurance capacity, v° These results suggest that thyroid hormones induce part of the metabolic changes in skeletal muscle similar to those caused by exercise.

Muscular injury related to the derangement of glutathione metabolism An essential role of the glutathione-dependent antioxidant system on the physiology of muscular tissues has been recognized for decades by the occurrences of nutritional muscular dystrophy of lamb in the areas where the soil contained low selenium, 7~ which is shown to compose the active center of the selenoenzyme, selenium-dependent GPXfl 2 A nutritional interrelationship between selenium and vitamin E has also been shown, v3 Similar muscular disorders due to a combined deficiency of selenium and vitamin E have been found in many other species. These include chicks,V4 pecking ducks,V5 calves 76 pigs,V7and so on. The skeletal muscle is affected more severely than the myocardium in lambs,

chicken, and calves, while the reverse is the case in pigs (i.e., mulberry heart disease). Selenium deficient, vitamin E-supplemented animals tend to show less obvious symptoms. In rats, the combined deficiency of vitamin E and selenium can cause liver necrosis, while the manifestations of pure selenium deficiency are a mild growth retardation, hair loss, and occasional infertility. 7s However, pure selenium deficiency appears to have a more severe pathological consequence, including muscular tissues, in primate than in rats. Adult squirrel monkeys fed a low selenium diet with adequate vitamin E for 9 months developed weight loss, alopecia, and listlessness, and some of them died. v9 Numerous lesions were found in the dead monkeys including hepatic necrosis, skeletal and heart muscle degeneration, and nephrosis. The most severe selenium deficiencies in free living humans have been reported in China. Keshan disease, an endemic cardiomyopathy of children and young women, occurs exclusively in regions where selenium levels are extremely low. Prophylactic selenium supplementation can eradicate the disease. 8° This is the first human disease shown to be related to selenium deficiency. Other factors may be involved in the disease, but selenium deficiency clearly plays a major role. Similar cardiomyopathy and leg muscle weakness associated with low selenium levels have been reported in patients receiving parenteral feeding. ~'~2 Further experimental evidence supporting the importance of glutathione on the integrity of the muscle function has recently been presented by Martensson and Meister. 83 They treated mice with buthionine sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, which catalyzes the first step in glutathione biosynthesis. A marked depletion of reduced glutathione in skeletal and heart muscle resulted in the mitochondrial membrane damage and loss of oxidative enzymes in the skeletal muscle, and these were prevented by giving glutathione monoester. The specificity of the pathological change in the muscle induced by glutathione depletion may be related to the low levels of CAT in the muscles; muscles may be more dependent on the glutathione for detoxification of reactive oxygen species than liver and kidney, s4 Doroshow et al. demonstrated that the cardiotoxic effect of doxorubicin is associated with a dose-dependent decrease in the heart GPX activity. 84 Cardiotoxicity of cadmium, another model of the peroxidative cardiac damage, is also reported to be at least partially explained by the metabolic antagonism of cadmium to the action of selenium (i.e., cadmium aggravates the decrease in GPX activity induced by selenium deficiency), 85 suggesting the importance of GPX activity

Oxidative muscular injury in maintaining normal cardiac function. Thus, the decrease in GPX activity i,aduced by hyperthyroidism 2° may have a pathological consequence in muscular tissues.

Roles of free radicals in the genetic muscular dystrophies It has been postulated that the degenerative process in human and animal models of muscular dystrophy may result from increased concentrations of reactive oxygen species, although the recent discovery of dystrophin, 8~ a gene product of the Duchenne muscular dystrophy locus, has made it unlikely that oxidative muscular injury is the primary pathogenic mechanism. Several investigators have observed that the muscle TBARS measured spectrophotometrically are increased in human, 87'88 avian, 89"9° and murine 89 dystrophic muscles, suggesting that free radical-mediated tissue injury plays a role in some stages of the progressive muscle breakdown. The antioxidant enzymes (either SOD, GPX, or CAT) have been found to be increased in the dystrophic muscles, 87-92 and this has been considered to be an adaptive response to the increased oxidative stress. To reevaluate the contribution of peroxidative injury to the dystrophic process, we measured antioxidant enzymes and TBARS in muscles and nonmuscles of patients with Duchenne muscular dystrophy 93 and C57BL/6J dy/dy m i c e . 94 Immunoreactive CuZnSOD and MnSOD were decreased or tended to be decreased in the muscles of both the patients with Duchenne muscular dystrophy and dystrophic mice. On the other hand, muscle GPX in the patients, and both muscle GPX and CAT in the dystrophic mice were increased markedly. However, the TBARS levels measured fluorimetrically in the muscle homogenates were decreased markedly. Similar changes were observed in the murine dystrophic heart, but not in the liver, kidney, nor erythrocytes, suggesting that the changes in the GPX, CAT, and TBARS were specific to the muscular tissues. There have been reports observing an increase in TBARS in either plasma 95 or erythrocytes, 96 and an increase in the erythrocytes antioxidant enzymes 96 in patients with Duchenne muscular dystrophy. We have confirmed that these are unaltered in both the plasma and peripheral blood cells of the patients (unpublished observations). The increased GPX and CAT, as were also found by others,87-92 may be the adaptive response to the increased production of either H202 or lipid peroxides in the dystrophic muscles, but such oxidative stress does not appear to contribute to the biomembrane damage. Our results, again, suggested the importance

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of the glutathione-dependent antioxidant system for the protection of muscles against free radicals. Jamall et al. reported that selenium supplementation alleviated the myocardial lipid peroxidation and mitochondrial dysfunction in syrian golden hamsters. 97 Although no treatment enhancing antioxidant capacity is successful in Duchenne muscular dystrophy at present, an altered balance in the oxidant-antioxidant status exists and this needs to be studied further.

3. THYROTOXIC MYOPATHY AND MYOCARDIAL DYSFUNCTION AND ITS RELEVANCE TO OXIDATIVE MUSCULAR INJURY

Effect of thyroid hormones on muscular tissues Thyroid hormones regulate the turnover rates of both overall and specific proteins. Thyroid hormones modify the expression of myosin phenotypes in both heart and skeletal muscles. Hypothyroidism causes fast to slow changes in adult rat skeletal muscle, as evaluated by fiber type composition (decrease in proportion of type II fibers). 9~ Neonatal hypothyroidism inhibits the differentiation of rat soleus muscle by blocking the transformation of type 2C to 2A fibers. 9~ Conversely, slow to fast conversions take place in hyperthyroidism, and this is not neurally mediatedfl 8'1°° The myosin isoenzyme pattern in the ventricular, ~°~ but not atrial, ~°2 myocardium is also known to be affected by thyroid status. Induction of hyperthyroidism results in the rapid replacement of V3 (a homodimer of heavy chain beta) by V~ (a homodimer of heavy chain alpha), and conversely, hypothyroidism leads to a rapid reappearance of V3 in an animal with a Vt phenotype.~°3 The rates of overall protein synthesis and degradation are subjected to hormdnal regulations, and their balance in each organ governs the organ size. In experimental hyperthyroidism, certain organs (i.e., heart and kidneys) undergo hypertrophy, while other organs (i.e., liver and skeletal muscle) do not. 2° The rate of protein synthesis is increased in the heart, "~4 but not in the skeletal muscle, ~°5 of hyperthyroid animals. On the other hand, thyroid hormones accelerate the protein degradation by enhancing the lysosomal enzyme activity in liver and skeletal muscle, but not in the heart nor kidney. ~06There have been reports suggesting that the development of cardiac hypertrophy in hyperthyroidism is secondary to an increase in cardiac work rather than a direct action of the hormones."~7.E°8 However, in other reports, the hypertrophy occurred even when the cardiac work load was alleviated by the treatment with beta-adrenoceptor-blocking agents. 1°9'H° The changes in the levels of antioxidant enzymes in hy-

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perthyroid muscles may be at least partially ascribable to the effect of thyroid hormones on protein synthesis and degradation. Thyroid hormones are known to regulate the energy metabolism of most tissues including liver, kidney, heart, and skeletal muscles. It is well established that thyroid hormones accelerate the basal metabolic rate, and oxidative metabolism by causing an increase in the mitochondrial mass, mitochondrial cytochrome content, and respiratory rate without an uncoupling effect on the oxidative phosphorylation in the target tissues. ~ Mitochondrial oxidative enzymes are also increased in hyperthyroid muscles, and this is more remarkable in the slow red muscle than in the fast white muscle. ~2 The increased activities of both myosin Ca2+-dependent ATPase, and Na+-K +-dependent ATPase modify the contractile property of muscles and may contribute to the increase in oxygen consumption in hyperthyroid muscles. ~ The similarities between the effects of excess thyroid hormones and stimulation of the sympathetic nervous system have suggested a thyroid sympathetic interaction. An adrenergic contribution of the clinical manifestations of hyperthyroidism has been suggested. Furthermore, adrenoceptor-blocking agents alleviate certain abnormalities of hyperthyroidism such as nervousness, palpitations, tachycardia, increased cardiac output, increased oxygen consumption, sweating, and finger tremors. ~3,~~4,1~ Hyperthyroid rat heart rendered by chronic treatment with thyroxine has an increased number of beta-adrenergic receptors with no change in their affinity, and an increased sensitivity and magnitude of stimulation of adenylate cyclase with no change in the total enzyme activity, resulting in the increased sensitivity to catecholamine. 116Hypothyroidism has been reported to decrease beta-adrenergic receptor density and adenylate cyclase activity in skeletal muscle. ~7 Conversely, hyperthyroidism is associated with an increased c-AMP concentration in skeletal muscle.t~s It is well established that beta~-adrenergic mechanisms are predominant in cardiac tissue. On the other hand, there is evidence that beta2-adrenergic mechanisms play an essential role in skeletal muscle, ~9 and finger tremor as a complication of hyperthyroidism has been treated more effectively by nonselective beta-blockers than by betas-selective blockers. ~15 Thus, there is certain evidence for thyroid-sympathetic interactions in both heart and skeletal muscle.

Vitamin E and thyroid status There have been observations suggesting that thyroid hormones affect vitamin E metabolism in man and animals. Neradilova et al. reported that the alpha-to-

copherol level is increased in heart and skeletal muscles of hyperthyroid rats. 120,121 They also reported that this is a transient increase, and, however, that the level in the skeletal muscle declined thereafter to a nearly undetectable level. We failed to observe this transient change in heart and skeletal muscle in the rats treated with thyroxine for 4 weeks. ~22 Krishnamurthy et al. found a parallel decrease in the serum concentrations of vitamin E and TBARS in patients with hyperthyroidism.~23 However, this may be related to hypolipidemia commonly found in hyperthyroidism, because lipoproteins carry most of the vitamin E in the serum. Several investigators have reported a therapeutic function for vitamin E in experimental hyperthyroidism. In hyperthyroid rats treated with vitamin E, reduction in the cardiac glycogen concentration was less than in untreated hyperthyroid rats. 124In brain, vitamin E diminished the acceleration of oxidative phosphorylation induced by hyperthyroidism. 12~ However, the nature and physiologic significance of this effect remain controversial.

Current concept of thyrotoxic myopathy and myocardial dysfunction Hyperthyroidism causes muscle weakness and wasting. In clinical hyperthyroidism, the muscles of the patients demonstrate a decrease in muscle fiber size and occasional degenerative (myopathic) changes. 126 Kazakov et al. described a decrease in muscle fiber diameter combined with focal degenerative changes (a decrease in striation; hyaline, granular, and fat degeneration; necrosis; vesicular and internal nuclei; splitting fibers; an increase in the number of sarcolemmal nuclei; gathering of nuclei; spreading of the connective tissue; collection of adipose tissue in endomysium and perimysium) in thyrotoxic murine skeletal muscle. 127 They also found changes in motor neuron endings (excessive axonal branching and a decrease in the mean diameter of motor end-plates), a decrease in acetylcholinesterase, protein kinase affinity to c-AMP and the c-AMP level. Ultrastructurally, enlarged mitochondria accumulated in the subsarcolemmal space. 128 It has also been demonstrated electrophysiologically that hyperthyroidism affects the contractile and fatigue properties of skeletal muscle with a preferential involvement of slow type I muscles. 129 The increased protein degradation not accompanied by a concurrent increase in the synthesis is suggested to contribute to the development of the myopathy, t°5,13°.13~ and this altered balance is not corrected by beta-adrenoceptor blockade. According to these studies, beta-blockers are not beneficial for thyrotoxic myopathy, although other

Oxidative muscular injury investigators have noted a significant improvement in muscle symptoms in hyperthyroidism.l15.132 Hyperthyroidism is associated with impaired functional cardiac reserve (determined by exercise radionuclide angiography) similar to those seen in other cardiomyopathy. 133,134Although the concept of hyperthyroid cardiomyopathy has still been questioned, ~35 the myocardial dysfunction can precipitate congestive heart failure without an underlying organic heart disease in both clinical ~36 and experimental 43 hyperthyroidism. Cardiac arrythmias are frequently complicating other cardiac manifestations, and these can result in cardiac decompensation. Histologic changes of the heart in patients and animals are for the most part nonspecific. Electron microscopical findings of importance have been largely confined to the mitochondria, which are frequently enlarged and increased in number, and which contain localized areas of vacuolization and disorientation of the cristae, ~37 whereas other investigators have failed to observe a significant change in the mitochondrial morphology.'8 The histologic changes are reversible when the animal is allowed to return to the euthyroid state.

Lipid peroxidation as a possible mechanism of muscular injury in hyperthyroidism The acceleration of lipid peroxidation, determined as TBARS, in hyperthyroid heart and soleus muscle has constantly been observed in several of our series of experiments on rats. 2°t 10.122.139We have speculated that the imbalanced increase in the antioxidant enzymes (i.e., the MnSOD increases but the other enzymes do not) does not afford protection 14° against the increase in superoxide leakage from the mitochondrial electron transport system, which is accelerated by the thyroid hormone excess. We have tried to lower the TBARS level by pharmacologic interventions; we have treated the animals with either vitamin E or beta-adrenoceptor blockers simultaneously with thyroxine. 11°,122,139 First, we evaluated the in vivo effect of vitamin E, as a chain-breaking antioxidant in biomembrane lipid, on the TBARS levels. We supplemented rats with repeated intraperitoneal injections of a large dose (30 mg/kg/dose) of alpha-tocopheryl acetate when they were rendered hyperthyroid by the administration of thyroxine in the drinking water over a 4-week period.122 Vitamin E treatment significantly inhibited the increase in TBARS (totally in the heart and partially in the soleus muscle, with minimal changes in the tissue levels of the mitochondrial oxidative enzymes (cytochrome c oxidase and fumarase) and the antioxidant enzymes (MnSOD, CuZnSOD, GPX, and CAT). We then fed weanling rats with a diet containing either <1

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IU/kg (deficient diet), 20 IU/kg (control E diet), or 500 IU/kg (high E diet) of vitamin E, and, after 4 weeks, hyperthyroidism was induced in a similar way as described previously, while the rats were on the same diets. The TBARS was increased markedly in both tissues of the vitamin E deficient group, and decreased in those of the group fed high E diet. The oxidative enzymes and antioxidant enzymes are, again, affected minimally by the vitamin E status. These results collectively suggest that vitamin E protects against lipid peroxidation in hyperthyroid tissues independently of the changes in oxidative enzymes and antioxidant enzymes. As the next step of pharmacologic intervention, we evaluated the effect of adrenoceptor blockade on the TBARS levels in the tissues. 1~°,~3~Rats were rendered hyperthyroid and treated simultaneously with either a nonselective beta-adrenoceptor blocker with (carteo1ol) or without (arotinolol) partial agonist activity (PAA) or a betat-selective blocker (atenolol). Tachycardia was alleviated completely by the blockers without PAA (arotinolol and atenolol), but partially by the blocker with PAA (carteolol). The levels of the antioxidant enzymes were minimally affected by the beta-blocker treatments. The activities of oxidative enzymes in the hyperthyroid heart were suppressed by atenolol but not by the other blockers. Similarly, the thyroxine-induced acceleration of lipid peroxidation was suppressed by atenolol alone. On the other hand, arotinolol, but neither of the other two blockers, inhibited the increase in the oxidative enzymes and TBARS in the hyperthyroid soleus muscle. This implies that the beta-blockers with different ancillary properties have differential effects on the heart and soleus muscles. The parallel change of oxidative enzymes and TBARS observed here supports the hypothesis that the acceleration of oxidative metabolism results in an increased production of superoxide, and that this eventually leads to the increased peroxidation of biomembrane lipid in hyperthyroid muscles. 4. CONCLUSION This article has reviewed various muscular injury models in which reactive oxygen species are supposed to play a role. These models provide evidence that mitochondrial function and glutathione-dependent antioxidant system are important for the maintenance of the structural and functional integrity of muscular tissues. Thyroid hormones accelerate mitochondrial oxidative metabolism and also lipid peroxidation in heart and slow-oxidative muscle, both of which are prevented by certain types of beta-adrenoceptor-blocking agents. Thyroid hormones also decrease the glutathi-

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one peroxidase. Vitamin E status modifies lipid peroxidation independently of the changes in the oxidative activity and antioxidant enzymes. Thus, hyperthyroid muscles demonstrate similar biochemical derangements found in other oxidative muscular injury models, and these are at least partially prevented by the suppression of oxidative metabolism and a chain-breaking antioxidant vitamin E. Thyrotoxic muscular injuries are largely reversible in nature, and, at present, we have no direct evidence that a progressive organ dysfunction mediated by reactive oxygen species occurs in hyperthyroidism despite the acceleration of lipid peroxidation. However, lipid peroxidation in mitochondria can reduce respiratory capacity and calcium transport, '4' and can cause arrythmia. 142Furthermore, accumulating evidence suggests that a decrease in GPX and CAT may limit the functional capacity of both heart and skeletal muscle, and that a possible derangement in the glutathione metabolism due to the decreased activity of GPX may make them vulnerable to structural and functional disintegration by oxidant challenges. Thus, hyperthyroid muscular tissues undergo several biochemical changes that predispose them to free radicalmediated injury.

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