Atrophy and hypertrophy signalling in the diaphragm of patients with COPD

Testelmans, Dries; Crul, Tim; Maes, Karen; Agten, Anouk; Crombach, M.; Decramer, Marc; Gayan‐Ramirez, Ghislaine

doi:10.1183/09031936.00091108

Cited by 75 publications

(58 citation statements)

References 34 publications

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“…It is composed of a family of five members (p65, Rel-B, c-Rel, p50 and p52), which are all expressed within skeletal muscles. The NF-kB pathway was recently shown to be upregulated in the diaphragm of severe COPD patients [39]. In the muscle-wasted patients of the current study, protein expression of p65, but not p50, was greater in their vastus lateralis, and also showed a positive correlation with levels of total muscle protein ubiquitination.…”

Section: Redox Balance and Content Of Key Muscle Proteinssupporting

confidence: 49%

“…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 Proteinsmentioning

confidence: 45%

“…It has recently been shown that myostatin expression was increased in the vastus lateralis [7,41] and diaphragm [39] of severe COPD patients. It has also been suggested that resistance training reduces myostatin levels in the limb muscles of nonwasted COPD patients [42,43], eventually contributing to enhanced muscle mass in these patients.…”

Section: Redox Balance and Content Of Key Muscle Proteinsmentioning

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: 49%

Section: Redox Balance and Content Of Key Muscle Proteinsmentioning

confidence: 45%

Section: Redox Balance and Content Of Key Muscle Proteinsmentioning

confidence: 99%

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

et al. 2012

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“…Diaphragm muscle atrophy in COPD patients correlated with increased expression and activity of the ubiquitin-proteasome system [59,84,85]. This finding was further substantiated by animal experiments where proteasome inhibitors efficiently counteracted increased protein turnover in a model for diaphragm atrophy, indicating a causal role for increased proteasome activity for diaphragm atrophy [60].…”

Section: Copdmentioning

confidence: 70%

What shall we do with the damaged proteins in lung disease? Ask the proteasome!

Meiners

Eickelberg

2012

Eur Respir J

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The proteasome constitutes the main protein waste disposal and recycling system of the cell. Together with endoplasmic reticulum stress and the autophagosome pathway, it takes centre stage in cellular protein quality control.In lung research, the proteasome is, first of all, a promising therapeutic target to intervene in the malignant growth of lung cancer cells. Therapeutic targeting of the proteasome has also been extended to pulmonary fibrosis and asthma using animal models. Moreover, the proteasome is involved in lung pathogenesis. In cystic fibrosis, rapid proteasomal degradation of mutant cystic fibrosis transmembrane conductance regulator contributes to loss of function of lung epithelial cells. In chronic obstructive pulmonary disease (COPD), pulmonary proteasome expression and activity are downregulated and inversely correlate with lung function. In addition, as the proteasome degrades signalling mediators that have been oxidatively modified in COPD, it contributes to further compromise cellular function.The consequences of proteasomal dysfunction are loss of protein quality control, accumulation of misfolded proteins and exacerbation of cellular stress, which are also hallmarks of protein quality diseases and premature ageing. This suggests that proteasome dysfunction can be regarded as a new pathomechanism for chronic lung diseases, awaiting further therapeutic exploration in the future.

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“…De Troyer and colleagues (11) first noted compromised inspiratory muscle function in patients with cardiac dysfunction. Respiratory muscle dysfunction is now considered a salient feature of patients (11,21,23,35,36,62) and animals (7-9, 24, 28, 53, 58) with HF. Currently, little is known about the development of respiratory muscle dysfunction during the early onset of HF.…”

Section: Diaphragmatic Myofilament Function Becomes Increasingly Impamentioning

confidence: 99%

Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

Gillis

Klaiman

Foster

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Gillis TE, Klaiman JM, Foster A, Platt MJ, Huber JS, Corso MY, Simpson JA. Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice. Am J Physiol Heart Circ Physiol 310: H572-H586, 2016. First published December 23, 2015 doi:10.1152/ajpheart.00773.2015.-Dyspnea and reduced exercise capacity, caused, in part, by respiratory muscle dysfunction, are common symptoms in patients with heart failure (HF). However, the etiology of diaphragmatic dysfunction has not been identified. To investigate the effects of HF on diaphragmatic function, models of HF were surgically induced in CD-1 mice by transverse aortic constriction (TAC) and acute myocardial infarction (AMI), respectively. Assessment of myocardial function, isolated diaphragmatic strip function, myofilament force-pCa relationship, and phosphorylation status of myofilament proteins was performed at either 2 or 18 wk postsurgery. Echocardiography and invasive hemodynamics revealed development of HF by 18 wk postsurgery in both models. In vitro diaphragmatic force production was preserved in all groups while morphometric analysis revealed diaphragmatic atrophy and fibrosis in 18 wk TAC and AMI groups. Isometric force-pCa measurements of myofilament preparations revealed reduced Ca 2ϩ sensitivity of force generation and force generation at half-maximum and maximum Ca 2ϩ activation in 18 wk TAC. The rate of force redevelopment (k tr) was reduced in all HF groups at high levels of Ca 2ϩ activation. Finally, there were significant changes in the myofilament phosphorylation status of the 18 wk TAC group. This includes a decrease in the phosphorylation of troponin T, desmin, myosin light chain (MLC) 1, and MLC 2 as well as a shift in myosin isoforms. These results indicate that there are multiple changes in diaphragmatic myofilament function, which are specific to the type and stage of HF and occur before overt impairment of in vitro force production.calcium-activated force generation; diaphragm function; heart failure; myofilament proteins; protein phosphorylation HEART FAILURE (HF) is a global health problem and is one of the most prevalent causes of morbidity in all ages (15,46). Patients with HF are frequently limited in their daily activities by dyspnea and exertional fatigue. One potential cause is inspiratory muscle (primarily the diaphragm) dysfunction. De Troyer and colleagues (11) first noted compromised inspiratory muscle function in patients with cardiac dysfunction. Respiratory muscle dysfunction is now considered a salient feature of patients (11,21,23,35,36,62) and animals (7-9, 24, 28, 53, 58) with HF. Currently, little is known about the development of respiratory muscle dysfunction during the early onset of HF.In patients with HF, eupneic pressure generation is increased (28, 58), which is considered to impose a stress on the diaphragm. This chronic workload on the diaphragm is thought to overwork the muscle leading to development of a myopathy characterized by a shift in fiber type, atrophy, and co...

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Atrophy and hypertrophy signalling in the diaphragm of patients with COPD

Cited by 75 publications

References 34 publications

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

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

What shall we do with the damaged proteins in lung disease? Ask the proteasome!

Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

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