Oxidative stress as a potential pathogenic mechanism in an animal model of Duchenne muscular dystrophy

Ragusa, Robert J.; Chow, Ching K.; Porter, John D.

doi:10.1016/s0960-8966(97)00096-5

Cited by 118 publications

(77 citation statements)

References 43 publications

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“…Moreover the low levels of reduced glutathione, an essential tripeptide that reacts with free radicals, indicate that the antioxidant defense mechanism is most likely unable to blunt the increased oxygen radical formation. These findings are in keeping with the reported increase of glutathione cycling components in DMD muscle fibers 15 and of other lipid peroxidation products (thiobarbituric acid-reactive substances) in mdx mice 9 associated with an up-regulation of several antioxidant enzymes activity, such as superoxide dismutase, catalase, and glutathione peroxidase. 10 Interestingly, IRFI 042 treatment resulted in a significant reduction of CD levels and an increase in GSH content, accompanied by enhanced muscle function, blunted serum CK levels, and reduced myofiber degeneration.…”

Section: Discussionsupporting

confidence: 89%

“…9 -11 Markers of oxidative stress have been detected in muscles of either DMD patients or mdx mice. 9,12,13 An involvement of reactive oxygen intermediates is also supported by observations of increased biological by-products of oxidative stress, 14 reduced cellular antioxidants (glutathione and vitamin E), and altered concentrations of antioxidant enzymes. 12,15 Recently, the role of nuclear factor-B (NF-B) in the skeletal muscle-wasting process is gaining increasing attention, mainly because NF-B is activated in response to several inflammatory molecules that cause muscle loss.…”

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confidence: 86%

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Lipid Peroxidation Inhibition Blunts Nuclear Factor-κB Activation, Reduces Skeletal Muscle Degeneration, and Enhances Muscle Function in mdx Mice

Messina

Altavilla

Aguennouz

et al. 2006

The American Journal of Pathology

107

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Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease resulting from lack of the sarcolemmal protein dystrophin. However, the mechanism leading to the final disease status is not fully understood. Several lines of evidence suggest a role for nuclear factor (NF)-B in muscle degeneration as well as regeneration in DMD patients and mdx mice. We investigated the effects of blocking NF-B by inhibition of oxidative stress/lipid peroxidation on the dystrophic process in mdx mice. Five-week-old mdx mice received three times a week for 5 weeks either IRFI-042 (20 mg/kg), a strong antioxidant and lipid peroxidation inhibitor, or its vehicle. IRFI-042 treatment increased forelimb strength (؉22%, P < 0.05) and strength normalized to weight (؉23%, P < 0.05) and decreased fatigue (؊45%, P < 0.05). It also reduced serum creatine kinase levels (P < 0.01) and reduced muscle-conjugated diene content and augmented muscle-reduced glutathione (P < 0.01). IRFI-042 blunted NF-B DNA-binding activity and tumor necrosis factor-␣ expression in the dystrophic muscles (P < 0.01), reducing muscle necrosis (P < 0.01) and enhancing regeneration (P < 0.05). Our data suggest that oxidative stress/lipid peroxidation represents one of the mechanisms activating NF-B and the consequent pathogenetic cascade in mdx muscles.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 86%

Lipid Peroxidation Inhibition Blunts Nuclear Factor-κB Activation, Reduces Skeletal Muscle Degeneration, and Enhances Muscle Function in mdx Mice

Messina

Altavilla

Aguennouz

et al. 2006

The American Journal of Pathology

107

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“…22 In previous studies, markers of oxidative stress such as protein carbonyls, 45 lipid peroxidation by-products, 46 and lipofuscin 47 were noted to be abnormally elevated in DMD patients or mdx mice. Some studies have also attempted to mitigate the disease process using antioxidant therapy, but the results have been inconclusive.…”

Section: Discussionmentioning

confidence: 93%

Sarcolemmal Damage in Dystrophin Deficiency Is Modulated by Synergistic Interactions between Mechanical and Oxidative/Nitrosative Stresses

Dudley

Danialou

Govindaraju

et al. 2006

The American Journal of Pathology

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Dystrophin deficiency is the cause of Duchenne muscular dystrophy, but the precise physiological basis for muscle necrosis remains unclear. To determine whether dystrophin-deficient muscles are abnormally susceptible to oxidative and nitric oxide (NO)-driven tissue stress, a hindlimb ischemia/reperfusion (I/R) model was used. Dystrophic mdx mice exhibited abnormally high levels of lipid peroxidation and protein nitration, which were preceded by exaggerated NO production during ischemia. Visualization of NO with the fluorescent probe 4,5-diaminofluorescein diacetate suggested that excess NO production during ischemia occurred within a subset of mdx fibers. In mdx muscles only, prior exposure to I/R dramatically increased the level of sarcolemmal damage resulting from stretch-mediated mechanical stress, indicating greatly exacerbated hyperfragility of the dystrophic fiber membrane. Treatment with NO synthase inhibitors (L-N G -nitroarginine methyl ester hydrochloride or 7-nitroindazol) effectively blocked the synergistic interaction between I/R and mechanical stress-mediated sarcolemmal damage under these conditions. Taken together, our findings provide direct experimental evidence that several prevailing hypotheses regarding the cause of muscle fiber damage in dystrophin-deficient muscle can be integrated into a common pathophysiological framework involving interactions between oxidative stress, abnormal NO regulation, and hyperfragility of the sarcolemma.

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“…On one hand, levels of antioxidant enzymes are elevated in dystrophic muscle prior to the onset of muscle degeneration, suggesting that oxidative stress precedes the development of the disease [14]. On the other hand, these levels are also higher in extraocular skeletal muscle, which is spared from mdx pathology, and in dystrophic muscle already undergoing active regeneration [38,39]. It is possible that oxidative/ nitrosative stress itself does not drive muscle degeneration in dystrophy but rather acts synergistically with other factors, such as elevated resting Ca 2+ concentrations, abnormal Ca 2+ influx during repetitive muscle contraction and mechanical stress, to drive the pathological responses (e.g., [15]).…”

Section: Oxidative/nitrosative Stress and Muscular Dystrophymentioning

confidence: 99%

Reciprocal amplification of ROS and Ca2+ signals in stressed mdx dystrophic skeletal muscle fibers

Shkryl

Martins

Ullrich

et al. 2009

Pflugers Arch - Eur J Physiol

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Muscular dystrophies are among the most severe inherited muscle diseases. The genetic defect is a mutation in the gene for dystrophin, a cytoskeletal protein which protects muscle cells from mechanical damage. Mechanical stress, applied as osmotic shock, elicits an abnormal surge of Ca(2+) spark-like events in skeletal muscle fibers from dystrophin deficient (mdx) mice. Previous studies suggested a link between changes in the intracellular redox environment and appearance of Ca(2+) sparks in normal mammalian skeletal muscle. Here, we tested whether the exaggerated Ca(2+) responses in mdx fibers are related to oxidative stress. Localized intracellular and mitochondrial Ca(2+) transients, as well as ROS production, were assessed with confocal microscopy. The rate of basal cellular but not mitochondrial ROS generation was significantly higher in mdx cells. This difference was abolished by pre-incubation of mdx fibers with an inhibitor of NAD(P)H oxidase. In addition, immunoblotting showed a significantly stronger expression of NAD(P)H oxidase in mdx muscle, suggesting a major contribution of this enzyme to oxidative stress in mdx fibers. Osmotic shock produced an abnormal and persistent Ca(2+) spark activity, which was suppressed by ROS-reducing agents and by inhibitors of NAD(P)H oxidase. These Ca(2+) signals resulted in mitochondrial Ca(2+) accumulation in mdx fibers and an additional boost in cellular and mitochondrial ROS production. Taken together, our results indicate that the excessive ROS production and the simultaneous activation of abnormal Ca(2+) signals amplify each other, finally culminating in a vicious cycle of damaging events, which may contribute to the abnormal stress sensitivity in dystrophic skeletal muscle.

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Oxidative stress as a potential pathogenic mechanism in an animal model of Duchenne muscular dystrophy

Cited by 118 publications

References 43 publications

Lipid Peroxidation Inhibition Blunts Nuclear Factor-κB Activation, Reduces Skeletal Muscle Degeneration, and Enhances Muscle Function in mdx Mice

Lipid Peroxidation Inhibition Blunts Nuclear Factor-κB Activation, Reduces Skeletal Muscle Degeneration, and Enhances Muscle Function in mdx Mice

Sarcolemmal Damage in Dystrophin Deficiency Is Modulated by Synergistic Interactions between Mechanical and Oxidative/Nitrosative Stresses

Reciprocal amplification of ROS and Ca2+ signals in stressed mdx dystrophic skeletal muscle fibers

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