Diaphragm Fiber Strength Is Reduced in Critically Ill Patients and Restored by a Troponin Activator

Hooijman, Pleuni E.; Beishuizen, Albertus; Waard, Monique C. de; Man, Frances S. de; Vermeijden, Wytze J.; Steenvoorde, Pascal; Bouwman, R. Arthur; Lommen, Wies; Hees, Hieronymus W. H. van; Heunks, Leo; Dickhoff, Chris; Peet, Donald L. van der; Girbes, Armand R. J.; Jasper, Jeff R.; Malik, Fady I.; Stienen, G. J. M.; Hartemink, Koen J.; Paul, Marinus A.; Ottenheijm, Coen A.C.

doi:10.1164/rccm.201312-2260le

Cited by 44 publications

(68 citation statements)

References 16 publications

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“…We found both type I and type II myofibers in the diaphragm atrophy in ALI mice, consistent with a recent report of diaphragmatic biopsies in critically ill humans (47). Therapeutic exercise in ALI mice attenuated type II myofiber atrophy in the limb muscle and diaphragm but did not improve type I myofiber atrophy in the diaphragm.…”

Section: Discussionsupporting

confidence: 93%

Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting

et al. 2015

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Early mobilization of critically ill patients with the acute respiratory distress syndrome (ARDS) has emerged as a therapeutic strategy that improves patient outcomes, such as the duration of mechanical ventilation and muscle strength. Despite the apparent efficacy of early mobility programs, their use in clinical practice is limited outside of specialized centers and clinical trials. To evaluate the mechanisms underlying mobility therapy, we exercised acute lung injury (ALI) mice for 2 days after the instillation of lipopolysaccharides into their lungs. We found that a short duration of moderate intensity exercise in ALI mice attenuated muscle ring finger 1 (MuRF1)–mediated atrophy of the limb and respiratory muscles and improved limb muscle force generation. Exercise also limited the influx of neutrophils into the alveolar space through modulation of a coordinated systemic neutrophil chemokine response. Granulocyte colony-stimulating factor (G-CSF) concentrations were systemically reduced by exercise in ALI mice, and in vivo blockade of the G-CSF receptor recapitulated the lung exercise phenotype in ALI mice. Additionally, plasma G-CSF concentrations in humans with acute respiratory failure (ARF) undergoing early mobility therapy showed greater decrements over time compared to control ARF patients. Together, these data provide a mechanism whereby early mobility therapy attenuates muscle wasting and limits ongoing alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans.

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Section: Discussionsupporting

confidence: 93%

Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting

et al. 2015

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“…Additionally, we evaluated critical components of the ubiquitin-proteasome pathway, and performed proof-of-concept studies in muscle-specific ring finger protein-1 (MuRF-1) knockout (KO) mice to evaluate the role of this pathway in the development of contractile weakness during MV. Some of the present findings were published as pilot data in a letter (29).…”

mentioning

confidence: 66%

“…Consequently, it is unknown whether these findings translate to critically ill patients. Establishing whether in critically ill patients the individual diaphragm muscle fibers exhibit contractile weakness is of utmost importance, because this provides rationale for treatment strategies that specifically improve the contractility of diaphragm fibers to facilitate weaning (27)(28)(29).…”

mentioning

confidence: 99%

Diaphragm Muscle Fiber Weakness and Ubiquitin–Proteasome Activation in Critically Ill Patients

Hooijman

Beishuizen²,

Witt³

et al. 2015

Am J Respir Crit Care Med

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172

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Rationale: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.Objectives: We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm.Methods: We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation.Measurements and Main Results: Both slow-and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.Conclusions: These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.

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“…While it is recognised that exercise training can improve muscle function and exercise capacity in PAH patients [5], its tolerability is limited in severely haemodynamically impaired PAH patients [6]. Calcium sensitisers, which specifically target sarcomeric function by improving submaximal force generation and reduced [Ca 2+ ] pumping by the sarco/endoplasmic reticulum Ca 2+ ATPase [14,15], might be a pharmacological therapeutic option to improve muscle function in this patient population.…”

Section: Quadriceps Muscle Fibre Dysfunction In Patients With Pulmonamentioning

confidence: 99%

Quadriceps muscle fibre dysfunction in patients with pulmonary arterial hypertension

et al. 2015

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Diaphragm Fiber Strength Is Reduced in Critically Ill Patients and Restored by a Troponin Activator

Cited by 44 publications

References 16 publications

Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting

Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting

Diaphragm Muscle Fiber Weakness and Ubiquitin–Proteasome Activation in Critically Ill Patients

Quadriceps muscle fibre dysfunction in patients with pulmonary arterial hypertension

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