Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants.

Buck, Martina; Chojkier, Mario

doi:10.1002/j.1460-2075.1996.tb00524.x

Cited by 290 publications

(269 citation statements)

References 71 publications

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“…In addition, the contribution of lipid peroxidation toward ROS was discounted by the observation that TBARS levels were down‐regulated by Mstn. Previously, it has been reported that TNF‐α induces oxidative stress in skeletal muscles (Buck & Chojkier, 1996) and its expression is regulated through NF‐κB transcription factor. We also clearly show by molecular analysis that treatment of myoblasts with Mstn increases NF‐κB translocation into nucleus, which induced the transcription of TNF‐α (Fig.…”

Section: Discussionmentioning

confidence: 99%

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

et al. 2011

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SummaryAbnormal levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed in the skeletal muscle during muscle wasting including sarcopenia. However, the mechanisms that signal ROS production and prolonged maintenance of ROS levels during muscle wasting are not fully understood. Here, we show that myostatin (Mstn) is a pro‐oxidant and signals the generation of ROS in muscle cells. Myostatin, a transforming growth factor‐β (TGF‐β) family member, has been shown to play an important role in skeletal muscle wasting by increasing protein degradation. Our results here show that Mstn induces oxidative stress by producing ROS in skeletal muscle cells through tumor necrosis factor‐α (TNF‐α) signaling via NF‐κB and NADPH oxidase. Aged Mstn null (Mstn−/−) muscles, which display reduced sarcopenia, also show an increased basal antioxidant enzyme (AOE) levels and lower NF‐κB levels indicating efficient scavenging of excess ROS. Additionally, our results indicate that both TNF‐α and hydrogen peroxide (H2O2) are potent inducers of Mstn and require NF‐κB signaling for Mstn induction. These results demonstrate that Mstn and TNF‐α are components of a feed forward loop in which Mstn triggers the generation of second messenger ROS, mediated by TNF‐α and NADPH oxidase, and the elevated TNF‐α in turn stimulates Mstn expression. Higher levels of Mstn in turn induce muscle wasting by activating proteasomal‐mediated catabolism of intracellular proteins. Thus, we propose that inhibition of ROS induced by Mstn could lead to reduced muscle wasting during sarcopenia.

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Section: Discussionmentioning

confidence: 99%

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

et al. 2011

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“…Our interest in examining the effects of cardiac dysfunction on free radical generation in skeletal muscle derives from recent reports by our laboratory and others examining the effects of sepsis on limb and respiratory skeletal muscle (4,24). Animal models have consistently demonstrated significant sepsis-induced reductions in diaphragm muscle force generation (4,24).…”

Section: Discussionmentioning

confidence: 99%

“…Recent work indicates, however, that congestive heart failure is associated with an increase in generation of free radicals (i.e., molecules derived from superoxide anions) and other reactive oxygen species in some tissues (2,32). Moreover, in several conditions (e.g., sepsis, wasting syndromes), heightened free radical formation in skeletal muscle has been recently linked to the development of muscle weakness and protein loss (4,24).…”

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confidence: 99%

Diaphragmatic free radical generation increases in an animal model of heart failure

Supinski

Callahan²

2005

Journal of Applied Physiology

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Supinski, Gerald S., and Leigh A. Callahan. Diaphragmatic free radical generation increases in an animal model of heart failure. J Appl Physiol 99: 1078 -1084, 2005; doi:10.1152/japplphysiol.01145.2004.-Heart failure evokes diaphragm weakness, but the mechanism(s) by which this occurs are not known. We postulated that heart failure increases diaphragm free radical generation and that free radicals trigger diaphragm dysfunction in this condition. The purpose of the present study was to test this hypothesis. Experiments were performed using halothaneanesthetized sham-operated control rats and rats in which myocardial infarction was induced by ligation of the left anterior descending coronary artery. Animals were killed 6 wk after surgery, the diaphragms were removed, and the following were assessed: 1) mitochondrial hydrogen peroxide (H2O2) generation, 2) free radical generation in resting and contracting intact diaphragm using a fluorescent-indicator technique, 3) 8-isoprostane and protein carbonyls (indexes of free radical-induced lipid and protein oxidation), and 4) the diaphragm force-frequency relationship. In additional experiments, a group of coronary ligation animals were treated with polyethylene glycol-superoxide dismutase (PEG-SOD, 2,000 units⅐kg Ϫ1 ⅐day Ϫ1) for 4 wk. We found that coronary ligation evoked an increase in free radical formation by the intact diaphragm, increased diaphragm mitochondrial H2O2 generation, increased diaphragm protein carbonyl levels, and increased diaphragm 8-isoprostane levels compared with controls (P Ͻ 0.001 for the first 3 comparisons, P Ͻ 0.05 for 8-isoprostane levels). Force generated in response to 20-Hz stimulation was reduced by coronary ligation (P Ͻ 0.05); PEG-SOD administration restored force to control levels (P Ͻ 0.03). These findings indicate that cardiac dysfunction due to coronary ligation increases diaphragm free radical generation and that free radicals evoke reductions in diaphragm force generation. oxidative stress CONGESTIVE HEART FAILURE IS known to evoke significant changes in skeletal muscle function, inducing muscle wasting, reductions in muscle force-generating capacity, and alterations in muscle energy metabolism (9,16,20). Both limb and respiratory skeletal muscle are thought to be affected in this condition (28). Some work indicates that limb skeletal muscle dysfunction plays an important role in determining exercise capacity in patients with congestive heart failure (22). In addition, respiratory muscle dysfunction may predispose these patients to respiratory failure under conditions in which the respiratory workload increases (28).The mechanism by which congestive heart failure alters skeletal muscle function remains unclear. Importantly, evidence indicates that inactivity alone cannot fully account for congestive heart failure-induced reductions in muscle function (25). Recent work indicates, however, that congestive heart failure is associated with an increase in generation of free radicals (i.e., molecules derived from superoxide anions) an...

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“…tumour necrosis factor-a (TNF-a)) have also been implicated in the skeletal muscle atrophy of several physiological/ pathological states. 37,38 In animals treated with exogenous TNF-a 38,39 or expressing a transgene, 40 losses in muscle mass are observed. Moreover, Buck and Chojkier 39 reported structural irregularities consisting of smaller fibres in skeletal muscles from mice receiving exogenous TNF-a.…”

Section: Iiamentioning

confidence: 99%

Morphological and biochemical alterations of skeletal muscles from the genetically obese (ob/ob) mouse

et al. 2009

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Background: Knowledge of the morphological and biochemical alterations occurring in skeletal muscles of obese animals is relatively limited, particularly with respect to non-limb muscles and relationship to fibre type. Objective: Sternomastoid (SM; fast-twitch), extensor digitorum longus (EDL; fast-twitch), and soleus (SOL; mixed) muscles of ob/ob mouse (18-22 weeks) were examined with respect to size (mass, muscle mass-to-body mass ratio, cross-sectional area (CSA)), fibre CSA, protein content, myosin heavy chain (MHC) content, MHC isoform (MHC i ) composition, MHC i -based fibre type composition, and lactate dehydrogenase isoenzyme (LDH iso ) composition. Results: Compared with (control) muscles from lean mice, all the three muscles from ob/ob mice were smaller in size (by 13-30%), with SM and EDL being the most affected. The CSA of IIB and IIB þ IID fibres (the predominant fibre types in SM and EDL muscles) was markedly smaller (by B30%) in ob/ob mice, consistent with differences in muscle size. Total protein content (normalised to muscle mass) was significantly lower in EDL (À9.7%) and SOL (À14.1%) muscles of ob/ob mice, but there were no differences between SM, EDL, and SOL muscles from the two animal groups with respect to MHC content (also normalised to muscle mass). Electrophoretic analyses of MHC i composition in whole muscle homogenates and single muscle fibres showed a shift towards slower MHC i content, slower MHC i containing fibres, and a greater proportion of hybrid fibres in all the three muscles of ob/ob mice, with a shift towards a more aerobic-oxidative phenotype also observed with respect to LDH iso composition. Conclusion: This study showed that SM, EDL, and SOL muscles of ob/ob mice display size reductions to an extent that seems to be largely related to fibre type composition, and a shift in fibre type composition that may result from a process of structural remodelling, as suggested by the increased proportion of hybrid fibres in muscles of ob/ob mice.

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Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants.

Cited by 290 publications

References 71 publications

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF‐κB

Diaphragmatic free radical generation increases in an animal model of heart failure

Morphological and biochemical alterations of skeletal muscles from the genetically obese (ob/ob) mouse

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