Gene Expression Profiling in Vastus Lateralis Muscle During an Acute Exacerbation of COPD

Crul, Tim; Testelmans, Dries; Spruit, Martijn A.; Troosters, Thierry; Gosselink, Rik; Geeraerts, Ineke; Decramer, Marc; Gayan‐Ramirez, Ghislaine

doi:10.1159/000303054

Cited by 66 publications

(68 citation statements)

References 40 publications

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“…Another novel finding in the investigation is that muscle-wasted severe COPD patients exhibited greater protein ubiquitination levels in their atrophying muscles. In view of the present findings and of those previously published in limb [5][6][7] and respiratory muscles [8,39] of severe COPD patients, it could be assumed that the ubiquitin-proteasome system seems to play a relevant role in the process of muscle atrophy in severe COPD patients.…”

Section: Redox Balance and Content Of Key Muscle Proteinssupporting

confidence: 75%

“…More recently, limb muscle mRNA levels of atrogin-1, but not MURF-1, were also shown to be upregulated in stable nonwasted severe COPD patients [7]. Additionally, MURF-1 and atrogin-1 mRNA levels were shown to be upregulated in the vastus lateralis of hospitalised nonwasted patients during an acute exacerbation [5]. Differences in the number of patients, their body composition, study conditions and in the methodologies employed in each case (mRNA expression versus protein content herein) might account for the minor discrepancies between studies.…”

Section: Redox Balance and Content Of Key Muscle Proteinsmentioning

confidence: 98%

“…These systemic manifestations have a considerable impact on the exercise tolerance and quality of life of the patients, and are also associated with increased mortality [1,2]. The ubiquitin-proteasome has been identified as the major proteolytic system involved in the degradation of muscle proteins of several catabolic states, including cancer-induced cachexia [3,4] and COPD, in both limb [5][6][7] and respiratory [8] muscles of patients with relatively well-preserved body composition. Despite this progress, in severe COPD, the degree of total protein ubiquitination or the upstream signal regulation of muscle protein degradation has not yet been fully explained.…”

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confidence: 99%

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Does oxidative stress modulate limb muscle atrophy in severe COPD patients?

et al. 2012

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Oxidative stress may differentially regulate protein loss within peripheral muscles of severe chronic obstructive pulmonary disease (COPD) patients exhibiting different body composition.Oxidation levels of proteins, myosin heavy chain (MyHC) and myonuclei, superoxide anion, antioxidants, actin, creatine kinase, carbonic anhydrase-3, ubiquitin-proteasome system, redoxsignalling pathways, inflammation and muscle structure, and damage were quantified in limb muscles of severe COPD patients with and without muscle wasting, and in sedentary controls.Compared with controls, in the quadriceps of muscle-wasted COPD patients, levels of protein carbonylation, oxidation of MyHC and myonuclei, superoxide anion production, superoxide dismutase, total protein ubiquinitation, E2 14k , atrogin-1, FoxO1 and p65 were higher, while content of MyHC, creatine kinase, carbonic anhydrase-3, myogenin, and fast-twitch fibre size were decreased. Importantly, in nonwasted COPD patients, where MyHC was more oxidised than in controls, its content was preserved. Muscle inflammation and glutathione levels did not differ between patients and controls. In all patients, muscle structure abnormalities were increased, while muscle force and exercise capacity were reduced.In severe COPD, while muscle oxidative stress increases regardless of their body composition, protein ubiquitination and loss of MyHC were enhanced only in patients exhibiting muscle atrophy. Oxidative stress does not seem to directly modulate muscle protein loss in these patients.

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Section: Redox Balance and Content Of Key Muscle Proteinssupporting

confidence: 75%

Section: Redox Balance and Content Of Key Muscle Proteinsmentioning

confidence: 98%

mentioning

confidence: 99%

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Does oxidative stress modulate limb muscle atrophy in severe COPD patients?

et al. 2012

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“…Acute exacerbations of chronic obstructive pulmonary disease (COPD) are accompanied by pulmonary and transient systemic inflammation and malnutrition, which have been implicated in the onset of stepwise weight loss, muscle wasting and increased mortality (1)(2)(3)(4)(5)(6). The underlying mechanisms are unknown and difficult to unravel in patients during the acute phase of an exacerbation.…”

mentioning

confidence: 99%

NF-κB Activation Is Required for the Transition of Pulmonary Inflammation to Muscle Atrophy

Langen¹,

Haegens²,

Vernooy³

et al. 2012

Am J Respir Cell Mol Biol

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Disease exacerbations and muscle wasting comprise negative prognostic factors of chronic obstructive pulmonary disease (COPD). Transient systemic inflammation and malnutrition have been implicated in skeletal muscle wasting after acute exacerbations of COPD. However, the interactions between systemic inflammation and malnutrition in their contributions to muscle atrophy, as well as the molecular basis underlying the transition of systemic inflammation to muscle atrophy, remain unresolved. Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS to model acute disease exacerbation. Systemic inflammation, nutritional intake, and body and muscle weights were determined. Muscle inflammatory signaling and atrophy signaling were examined, and the effect of the muscle-specific inactivation of NF-kB on muscle atrophy was assessed in genetically modified mice. The intratracheal LPS instillation was followed by markedly elevated circulating cytokine concentrations and NF-kB activation in extrapulmonary tissues, including skeletal muscle. The administration of intratracheal LPS increased the expression of muscle E3 ubiquitin ligases, which govern muscle proteolysis, in particular MuRF1, and caused a rapid loss of muscle mass. Reduced food intake only partly accounted for the observed muscle atrophy, and did not activate NF-kB in muscle. Rather, plasma transfer experiments revealed the presence of NF-kB-signaling and atrophy-signaling properties in the circulation of intratracheal LPStreated mice. The genetic inhibition of muscle NF-kB activity suppressed intratracheal LPS-induced MuRF1 expression and resulted in a significant sparing of muscle tissue. Systemic inflammation and malnutrition contribute to the muscle wasting induced by acute pulmonary inflammation via distinct mechanisms, and muscle NF-kB activation is required for the transition from inflammatory to muscle atrophy signaling.Keywords: pulmonary inflammation; systemic inflammation; muscle atrophy; NF-kB; cytokines Acute exacerbations of chronic obstructive pulmonary disease (COPD) are accompanied by pulmonary and transient systemic inflammation and malnutrition, which have been implicated in the onset of stepwise weight loss, muscle wasting and increased mortality (1-6). The underlying mechanisms are unknown and difficult to unravel in patients during the acute phase of an exacerbation. In many instances, the acute loss of muscle mass is dependent on increased muscle protein breakdown mediated by the ubiquitin (Ub) 26S-proteasome system (UPS) (7). The rate-limiting enzymes of this process during acute muscle atrophy include the Ub-E3 ligation enzymes atrogin-1/MAFbx and MuRF1. The genetic deletion of these "atrogenes" attenuates muscle atrophy under various conditions (8, 9), and the increased expression of MuRF1 and atrogin-1 has been reported in quadriceps muscle during exacerbations of COPD (1). Inducible transcription factors, including NF-kB, have been implicated in the transcriptional regulation of atrogin-1 and MuRF1 (10). NF-k...

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“…Several mechanisms may contribute to this effect, such as nutritional imbalance [4], medications [5], physical inactivity [2], systemic inflammation [3] and oxidative stress [6,7]. It has been suggested that oxidative stress is increased in COPD patients during an acute exacerbation because these patients show increased plasma [6] and skeletal muscle [7] antioxidant capacities. Indeed, oxidative stress is already considered to play a major role in peripheral muscle dysfunction of COPD patients, both at rest and after exercise [8][9][10].…”

mentioning

confidence: 99%

Skeletal muscle effects of electrostimulation after COPD exacerbation: a pilot study

Abdellaoui

Préfaut²,

Gouzi³

et al. 2011

European Respiratory Journal

123

144

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Muscle dysfunction is a major problem in chronic obstructive pulmonary disease (COPD), particularly after exacerbations. We thus asked whether neuromuscular electrostimulation (NMES) might be directly useful following an acute exacerbation and if such a therapy decreases muscular oxidative stress and/or alters muscle fibre distribution.A pilot randomised controlled study of NMES lasting 6 weeks was carried out in 15 in-patients (n59 NMES; n56 sham) following a COPD exacerbation. Stimulation was delivered to the quadriceps and hamstring muscles (35 Hz). Primary outcomes were quadriceps force and muscle oxidative stress.At the end of the study, quadriceps force improvement was statistically different between groups (p50.02), with a significant increase only in the NMES group (median (interquartile range) 10 (4.7-11.5) kg; p50.01). Changes in the 6-min walking distance were statistically different between groups (p50.008), with a significant increase in the NMES group (165 (125-203) m; p50.003). NMES did not lead to higher muscle oxidative stress, as indicated by the decrease in total protein carbonylation (p50.02) and myosin heavy chain carbonylation (p50.01) levels. Finally, we observed a significant increase in type I fibre proportion in the NMES group.Our study shows that following COPD exacerbation, NMES is effective in counteracting muscle dysfunction and decreases muscle oxidative stress.

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Gene Expression Profiling in Vastus Lateralis Muscle During an Acute Exacerbation of COPD

Cited by 66 publications

References 40 publications

Does oxidative stress modulate limb muscle atrophy in severe COPD patients?

Does oxidative stress modulate limb muscle atrophy in severe COPD patients?

NF-κB Activation Is Required for the Transition of Pulmonary Inflammation to Muscle Atrophy

Skeletal muscle effects of electrostimulation after COPD exacerbation: a pilot study

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