Inhibition of the Ubiquitin–Proteasome Pathway Does Not Protect against Ventilator-induced Accelerated Proteolysis or Atrophy in the Diaphragm

Smuder, Ashley J.; Nelson, W. Bradley; Hudson, Matthew B.; Kavazis, Andreas N.; Powers, Scott K.

doi:10.1097/aln.0000000000000245

Cited by 34 publications

(41 citation statements)

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“…This finding is in line with former publications from our groups [6, 11, 21], defining it as one major pathway of VIDD [22]. The reduction in oxidative damage during the weaning process might result in less cleavage of sarcomeric proteins.…”

Section: Discussionsupporting

confidence: 91%

Influence of weaning methods on the diaphragm after mechanical ventilation in a rat model

et al. 2016

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BackgroundMechanical ventilation (MV) is associated with diaphragm weakness, a phenomenon termed ventilator-induced diaphragmatic dysfunction. Weaning should balance diaphragmatic loading as well as prevention of overload after MV. The weaning methods pressure support ventilation (PSV) and spontaneous breathing trials (SBT) lead to gradual or intermittent reloading of a weak diaphragm, respectively. This study investigated which weaning method allows more efficient restoration of diaphragm homeostasis.MethodsRats (n = 8 per group) received 12 h of MV followed by either 12 h of pressure support ventilation (PSV) or intermittent spontaneous breathing trials (SBT) and were compared to rats euthanized after 12 h MV (CMV) and to acutely euthanized rats (CON). Force generation, activity of calpain-1 and caspase-3, oxidative stress, and markers of protein synthesis (phosphorylated AKT to total AKT) were measured in the diaphragm.ResultsReduction of diaphragmatic force caused by CMV compared to CON was worsened with PSV and SBT (both p < 0.05 vs. CON and CMV). Both PSV and SBT reversed oxidative stress and calpain-1 activation caused by CMV. Reduced pAKT/AKT was observed after CMV and both weaning procedures.ConclusionsMV resulted in a loss of diaphragmatic contractility, which was aggravated in SBT and PSV despite reversal of oxidative stress and proteolysis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0285-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Influence of weaning methods on the diaphragm after mechanical ventilation in a rat model

et al. 2016

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“…Inhibition of lysosomal proteases and calpain with leupeptin or the proteasome using bortezomib may be of interest as data indicate potential to completely or partially prevent VIDD. However, results could not be reproduced with epoxomicin . Overall, effects may be time dependent .…”

Section: Vidd Management: a Role For Ventilatory And Pharmacological mentioning

confidence: 84%

Dysfunction of respiratory muscles in critically ill patients on the intensive care unit

Berger

Bloechlinger

Haehling

et al. 2016

J cachexia sarcopenia muscle

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Muscular weakness and muscle wasting may often be observed in critically ill patients on intensive care units (ICUs) and may present as failure to wean from mechanical ventilation. Importantly, mounting data demonstrate that mechanical ventilation itself may induce progressive dysfunction of the main respiratory muscle, i.e. the diaphragm. The respective condition was termed ‘ventilator‐induced diaphragmatic dysfunction’ (VIDD) and should be distinguished from peripheral muscular weakness as observed in ‘ICU‐acquired weakness (ICU‐AW)’.Interestingly, VIDD and ICU‐AW may often be observed in critically ill patients with, e.g. severe sepsis or septic shock, and recent data demonstrate that the pathophysiology of these conditions may overlap. VIDD may mainly be characterized on a histopathological level as disuse muscular atrophy, and data demonstrate increased proteolysis and decreased protein synthesis as important underlying pathomechanisms. However, atrophy alone does not explain the observed loss of muscular force. When, e.g. isolated muscle strips are examined and force is normalized for cross‐sectional fibre area, the loss is disproportionally larger than would be expected by atrophy alone. Nevertheless, although the exact molecular pathways for the induction of proteolytic systems remain incompletely understood, data now suggest that VIDD may also be triggered by mechanisms including decreased diaphragmatic blood flow or increased oxidative stress. Here we provide a concise review on the available literature on respiratory muscle weakness and VIDD in the critically ill. Potential underlying pathomechanisms will be discussed before the background of current diagnostic options. Furthermore, we will elucidate and speculate on potential novel future therapeutic avenues.

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“…In the majority of these studies, however, the pharmacological agent was administered prior to initiating muscle atrophy by hindlimb suspension or did not prevent muscle atrophy . The use of MG132 is discussed controversially with a subset of studies reporting positive effects on muscle atrophy induced by hindlimb unloading, or tumour, whereas others saw no effects . Importantly, when assessing the impact of MG132 on muscle force, no positive effect was obvious .…”

Section: Discussionmentioning

confidence: 99%

Small‐molecule‐mediated chemical knock‐down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure

Adams

Bowen

Werner³

et al. 2019

J cachexia sarcopenia muscle

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Background Chronic heart failure (CHF) leads to diaphragm myopathy that significantly impairs quality of life and worsens prognosis. In this study, we aimed to assess the efficacy of a recently discovered small‐molecule inhibitor of MuRF1 in treating CHF‐induced diaphragm myopathy and loss of contractile function. Methods Myocardial infarction was induced in mice by ligation of the left anterior descending coronary artery. Sham‐operated animals (sham) served as controls. One week post‐left anterior descending coronary artery ligation animals were randomized into two groups—one group was fed control rodent chow, whereas the other group was fed a diet containing 0.1% of the compound ID#704946—a recently described MuRF1‐interfering small molecule. Echocardiography confirmed development of CHF after 10 weeks. Functional and molecular analysis of the diaphragm was subsequently performed. Results Chronic heart failure induced diaphragm fibre atrophy and contractile dysfunction by ~20%, as well as decreased activity of enzymes involved in mitochondrial energy production (P < 0.05). Treatment with compound ID#704946 in CHF mice had beneficial effects on the diaphragm: contractile function was protected, while mitochondrial enzyme activity and up‐regulation of the MuRF1 and MuRF2 was attenuated after infarct. Conclusions Our murine CHF model presented with diaphragm fibre atrophy, impaired contractile function, and reduced mitochondrial enzyme activities. Compound ID#704946 rescued from this partially, possibly by targeting MuRF1/MuRF2. However, at this stage of our study, we refrain to claim specific mechanism(s) and targets of compound ID#704946, because the nature of changes after 12 weeks of feeding is likely to be complex and is not necessarily caused by direct mechanistic effects.

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Inhibition of the Ubiquitin–Proteasome Pathway Does Not Protect against Ventilator-induced Accelerated Proteolysis or Atrophy in the Diaphragm

Cited by 34 publications

References 50 publications

Influence of weaning methods on the diaphragm after mechanical ventilation in a rat model

Influence of weaning methods on the diaphragm after mechanical ventilation in a rat model

Dysfunction of respiratory muscles in critically ill patients on the intensive care unit

Small‐molecule‐mediated chemical knock‐down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure

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