Diaphragm Atrophy and Weakness in the Absence of Mitochondrial Dysfunction in the Critically Ill

Berg, Marloes van den; Hooijman, Pleuni E.; Beishuizen, Albertus; Waard, Monique C. de; Paul, Marinus A.; Hartemink, Koen J.; Hees, Hieronymus W. H. van; Lawlor, Michael W.; Brocca, Lorenza; Bottinelli, Roberto; Pellegrino, Maria Antonietta; Stienen, Ger J; Heunks, Leo; Wüst, Rob C I; Ottenheijm, Coen A.C.

doi:10.1164/rccm.201703-0501oc

Cited by 62 publications

(54 citation statements)

References 57 publications

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“…Diaphragmatic weakness of 15-20% as reported for heart failure in the present study is comparable with other diseases like mechanical ventilation and sepsis, 45,46 critically ill patients, 47 or pulmonary hypertension 48 and is reported to be of clinical relevance with respect to mortality. 49 In the present study, we tested the effects of compound ID#704946 when fed to animals 7 days after the MI for 9 weeks as a secondary prevention.…”

Section: Treatment Of Diaphragm Dysfunction and Atrophy By Compound Isupporting

confidence: 85%

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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Section: Treatment Of Diaphragm Dysfunction and Atrophy By Compound Isupporting

confidence: 85%

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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“… 104 More recently, the same group revealed that mitochondrial alterations and oxidative stress did not play a causative role in the development of diaphragm atrophy and contractile dysfunction in these patients. 105 It remains to be investigated whether SARS-CoV-2 patients present different cellular modifications and whether a direct attack of the virus on the muscle could be possible.…”

Section: Disorders Of Control Of Breathing and The Neuromuscular Breamentioning

confidence: 99%

COVID-19 and Respiratory System Disorders

Brosnahan

Jonkman

Kugler

et al. 2020

ATVB

138

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The severe acute respiratory syndrome coronavirus-2 emerged as a serious human pathogen in late 2019, causing the disease coronavirus disease 2019 (COVID-19). The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Airway, lung parenchymal, pulmonary vascular, and respiratory neuromuscular disorders all feature in COVID-19. This article reviews what is known about the effects of severe acute respiratory syndrome coronavirus-2 infection on different parts of the respiratory system, clues to understanding the underlying biology of respiratory disease, and highlights current and future translation and clinical research questions.

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“…Mitochondrion is critical in energy metabolism and playing key roles in biochemical synthesis, redox control and apoptosis. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in many human diseases [ 36 – 39 ]. Recent understanding showed mitochondrion dysfunction and oxidative stress are usually co-existing in toxicant induced cell toxicity, and maybe a prevention method in cell toxicity [ 40 ].…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Cell toxicity mechanism and biomarker

Zhang

2018

Clinical & Translational Med

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Cell toxicity may result in organ dysfunction and cause severe health problem. Recent studies revealed many toxicants may induced the over production of Nitric oxide, reactive oxygen species and the subsequent oxidative stress, cause cell toxicity. Mitochondrion dysfunction maybe the subsequent consequence of oxidative stress and has been recognized as another contributing factor in cell toxicity. Besides, oxidative products induced by some toxicants may also produce the compounds that damage cell DNA, leading to toxicity. Especially, the significance of nanoparticle induced cell toxicity was disclosed recently and attract more concern. The mechanism mainly includes inflammation, oxidative stress and DNA damage. On the other side, some biomarkers of cell toxicity including autophagy, cytokines, miRNA has been identified. The understanding of these phenomenon may enable us to clarify the cell toxicity mechanism then contribute to cell toxicity protection, disease treatment and drug side effect prevention.

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Diaphragm Atrophy and Weakness in the Absence of Mitochondrial Dysfunction in the Critically Ill

Cited by 62 publications

References 57 publications

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

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

COVID-19 and Respiratory System Disorders

Cell toxicity mechanism and biomarker

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