Mechanical Ventilation Depresses Protein Synthesis in the Rat Diaphragm

Shanely, R. Andrew; Gammeren, Darin Van; DeRuisseau, Keith C.; Zergeroğlu, Ali Murat; McKenzie, Michael J.; Yarasheski, Kevin E.; Powers, Scott K.

doi:10.1164/rccm.200304-575oc

Cited by 126 publications

(123 citation statements)

References 42 publications

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“…This notion is supported by the observations that new nuclei are incorporated into locomotor skeletal muscle fibers during growth and that nuclei are lost during atrophy (12,14,16). Although it is known that controlled MV decreases protein synthesis and induces proteolysis and myofiber atrophy across all fiber types (6,17,18), it is unknown whether the myonuclear domain of diaphragm myofibers is altered during the fiber atrophy associated with MV.Regulation of myonuclear loss in skeletal muscle could occur through extrinsic death receptor and intrinsic (sarcoplasmic reticulum and mitochondrial) mediated pathways (19). Caspase (cysteine-dependent, aspartate-directed protease) activation results in protein cleavage and functions in intrinsic and extrinsic pathways of apoptosis.…”

mentioning

confidence: 86%

Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation–induced Atrophy

McClung

Kavazis

DeRuisseau

et al. 2007

Am J Respir Crit Care Med

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162

178

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Rationale: Unloading the diaphragm via mechanical ventilation (MV) results in rapid diaphragmatic fiber atrophy. It is unknown whether the myonuclear domain (cytoplasmic myofiber volume/ myonucleus) of diaphragm myofibers is altered during MV. Objective: We tested the hypothesis that MV-induced diaphragmatic atrophy is associated with a loss of myonuclei via a caspase-3-mediated, apoptotic-like mechanism resulting in a constant myonuclear domain. Methods: To test this postulate, Sprague-Dawley rats were randomly assigned to a control group or to experimental groups exposed to 6 or 12 h of MV with or without administration of a caspase-3 inhibitor. Measurements and Main Results:After 12 h of MV, type I and type IIa diaphragm myofiber areas were decreased by 17 and 23%, respectively, and caspase-3 inhibition attenuated this decrease. Diaphragmatic myonuclear content decreased after 12 h of MV and resulted in the maintenance of a constant myonuclear domain in all fiber types. Both 6 and 12 h of MV resulted in caspase-3-dependent increases in apoptotic markers in the diaphragm (e.g., number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive nuclei and DNA fragmentation). Caspase-3-dependent increases in apoptotic markers occurred after 6 h of MV, before the onset of myofiber atrophy. Conclusions: Collectively, these data support the hypothesis that the myonuclear domain of diaphragm myofibers is maintained during prolonged MV and that caspase-3-mediated myonuclear apoptosis contributes to this process. Keywords: muscle atrophy; respiratory muscle; apoptosis; ventilatory weaning Mechanical ventilation (MV) is a clinical intervention for patients who are unable to maintain adequate alveolar ventilation. Recent evidence reveals that controlled MV results in a swift progression of diaphragmatic atrophy and weakness (1-6). It seems that this diaphragmatic atrophy and weakness contributes to difficulty in weaning patients from the ventilator (7). The mechanism(s) responsible for the rapid onset of diaphragmatic atrophy and weakness are not fully understood. Therefore, delineating these mechanisms is a prerequisite for the development of therapeutic strategies to circumvent weaning difficulties. Although mechanical ventilation-induced diaphragm inactivity results in fiber atrophy, it is unknown if prolonged mechanical ventilation is associated with alterations in myonuclear domain via apoptotic mechanisms. What This Study Adds to the FieldOur results reveal that inhibiting caspase-3 activation and myonuclear loss during mechanical ventilation attenuates diaphragmatic muscle atrophy.Mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction is characterized by oxidative stress and stress-related gene expression in myofibers that occurs within a matter of hours (7,8). In addition to myofibrillar protein loss, extracellular matrix expansion, and metabolic enzyme alterations (9-11), prolonged disuse of skeletal muscle results in the selective loss of myonuclei (12-16). Myonu...

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mentioning

confidence: 86%

Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation–induced Atrophy

McClung

Kavazis

DeRuisseau

et al. 2007

Am J Respir Crit Care Med

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162

178

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“…85). Furthermore, prolonged full support MV results in a depression of protein synthesis in the diaphragm (99). Collectively, this MV-induced increase in proteolysis coupled with depressed protein synthesis results in the net loss of protein and diaphragm fiber atrophy.…”

Section: Mechanisms Responsible For Ventilator-induced Diaphragmatic mentioning

confidence: 98%

“…However, animal studies show that full support MV promotes a rapid decline in protein synthesis in the rat diaphragm (32,99 rapidly within the first 6 h of full support MV and remains depressed during the next 12 h of MV (99). Only one investigation has explored the influence of partial support MV on rat diaphragm protein synthesis.…”

Section: Mv-induced Decreases In Protein Diaphragmatic Synthesismentioning

confidence: 99%

Ventilator-induced diaphragm dysfunction: cause and effect

Powers

Wiggs

Sollanek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Powers SK, Wiggs MP, Sollanek KJ, Smuder AJ. Ventilator-induced diaphragm dysfunction: cause and effect. Am J Physiol Regul Integr Comp Physiol 305: R464 -R477, 2013. First published July 10, 2013 doi:10.1152/ajpregu.00231.2013 is used clinically to maintain gas exchange in patients that require assistance in maintaining adequate alveolar ventilation. Common indications for MV include respiratory failure, heart failure, drug overdose, and surgery. Although MV can be a life-saving intervention for patients suffering from respiratory failure, prolonged MV can promote diaphragmatic atrophy and contractile dysfunction, which is referred to as ventilator-induced diaphragm dysfunction (VIDD). This is significant because VIDD is thought to contribute to problems in weaning patients from the ventilator. Extended time on the ventilator increases health care costs and greatly increases patient morbidity and mortality. Research reveals that only 18 -24 h of MV is sufficient to develop VIDD in both laboratory animals and humans. Studies using animal models reveal that MV-induced diaphragmatic atrophy occurs due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, autophagy, and the ubiquitin-proteasome system as key proteases that participate in MV-induced diaphragmatic proteolysis. The challenge for the future is to define the MV-induced signaling pathways that promote the loss of diaphragm protein and depress diaphragm contractility. Indeed, forthcoming studies that delineate the signaling mechanisms responsible for VIDD will provide the knowledge necessary for the development of a pharmacological approach that can prevent VIDD and reduce the incidence of weaning problems. respiratory muscle; atrophy; mechanical ventilation; weaning; muscle wasting MECHANICAL VENTILATION (MV) is used clinically to achieve sufficient pulmonary gas exchange in patients unable to sustain adequate alveolar ventilation on their own. Common indications for MV include respiratory failure due to chronic obstructive pulmonary disease, status asthmaticus, and/or heart failure. In addition, MV is often an essential intervention in patients suffering from acute drug overdose, neuromuscular diseases, sepsis, and during surgery along with postsurgical recovery.The number of patients receiving prolonged MV in the United States exceeds more than 300,000 each year in the intensive care unit (ICU) (20). Although MV can be a lifesaving measure, prolonged MV results in the rapid development of diaphragmatic weakness due to both atrophy and contractile dysfunction. This detrimental impact of prolonged MV on the diaphragm has been termed ventilator-induced diaphragmatic dysfunction (VIDD) and VIDD is predicted to be a major contributor to problems in weaning patients from the ventilator (26, 114). Although previous reports describing the impact of prolonged MV on the diaphragm have appeared in the literature, advances in our understanding of the mechanisms responsible for VIDD h...

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“…In general, disuse atrophy can be a result of decreased protein synthesis 40 , increased proteolysis 41 , or both. Only in 6 hours of CMV, rats underwent an in vivo reduction in the protein synthesis rate of all muscle proteins by 30% and in the myosin heavy chain protein rate by 65%, both persisting during 18 hours of CMV 42 . In addition, 24 hours of CMV suppressed the levels of IGF-1 (insulin-growth factor) mRNA, which stimulates protein synthesis 3 .…”

Section: Muscle Atrophymentioning

confidence: 97%

“…This trauma has been implicated in the origin of VIDD 12,42 , particularly during sarcomere injury 36,37 and during decreased force-generating capacity of diaphragm 8,11 .…”

Section: Muscle Atrophymentioning

confidence: 99%

Effects of controlled and pressure support mechanical ventilation on rat diaphragm muscle

Oliveira

Costa²,

Assis

et al. 2012

Acta Cir. Bras.

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PURPOSE:The objective of this study was to analyze the effects of Pressure Controlled Ventilation mode (PCV-C) and PSV mode in diaphragm muscle of rats. METHODS: Wistar rats (n=18) were randomly assigned to the control group or to receive 6 hours of PCV and PSV. After this period, animals were euthanized and their diaphragms were excised, frozen in liquid nitrogen and stored in at -80º C for further histomorphometric analysis. RESULTS: Results showed a 15% decrease in cross-sectional area of muscle fibers on the PCV-C group when compared to the control group (p<0.001) and by 10% when compared to the PSV group (p<0.05). Minor diameter was decreased in PCV-C group by 9% when compared with the control group (p<0.001) and by 6% when compared to the PSV group (p<0.05). When myonuclear area was analyzed, a 16% decrease was observed in the PCV-C group when compared to the PSV group (p<0.05). No significant difference between the groups was observed in myonuclear perimeter (p>0.05). CONCLUSION: Short-term controlled mechanical ventilation seems to lead to muscular atrophy in diaphragm fibers. The PSV mode may attenuate the effects of VIDD. Key words: Anatomy & Histology. Diaphragm. Tracheostomy. Rats, Wistar. RESUMO OBJETIVO:Avaliar os efeitos do modo ventilatório controlado por pressão controlada (PCV-C) e do modo PSV sobre o músculo diafragma de ratos. MÉTODOS: Ratos (n = 18) da linhagem Wistar foram distribuídos no grupo controle (RE) ou para receber AVM por 6 horas no modo PCV-C e no modo PSV. Após esse período, os animais foram eutanasiados, o diafragma retirado e encaminhado para a análise histológica e morfométrica. RESULTADOS: Os resultados revelaram uma redução da área das fibras musculares de 15% no grupo PCV-C em comparação ao controle (p<0,001) e de 10% quando comparado ao grupo PSV (p<0,05). Já com relação ao diâmetro menor observou-se uma redução de 9% do grupo PCV-C em comparação ao controle (p<0,001) e de 6% em relação ao grupo PSV (p<0,05). Quando avaliada a área dos mionúcleos, notou-se uma redução de 16% desse parâmetro no grupo PCV-C, comparado ao PSV (p<0,05). Não houve diferença significativa no perímetro dos mionúcleos entre os grupos estudados (p>0,05). CONCLUSÃO: O grupo PCV-C apresentou atrofia muscular em um período curto de ventilação mecânica. O modo PSV parece atenuar os efeitos da DDIV.

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Mechanical Ventilation Depresses Protein Synthesis in the Rat Diaphragm

Cited by 126 publications

References 42 publications

Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation–induced Atrophy

Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation–induced Atrophy

Ventilator-induced diaphragm dysfunction: cause and effect

Effects of controlled and pressure support mechanical ventilation on rat diaphragm muscle

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