Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness*

Powers, Scott K.; Hudson, Matthew B.; Nelson, W. Bradley; Talbert, Erin E.; Min, Kisuk; Szeto, Hazel H.; Kavazis, Andreas N.; Smuder, Ashley J.

doi:10.1097/ccm.0b013e3182190b62

Cited by 216 publications

(314 citation statements)

References 36 publications

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“…Importantly, two independent studies have confirmed that prolonged MV also results in mitochondrial damage in the human diaphragm (80,106). Finally, treatment of animals with a mitochondrialtargeted antioxidant prevents the MV-induced activation of several proteolytic systems and prevents VIDD (82). Together, these findings indicate that ventilator-induced mitochondrial ROS emission is a required upstream signal for protease activation in the diaphragm during prolonged MV.…”

Section: R468supporting

confidence: 51%

“…However, because the rat and human diaphragm are anatomically alike and contain a similar fiber type composition (76,81), the rat has become the most commonly used animal model to study MV-induced changes in diaphragm fiber size and function. Several studies reveal that as few as 12 h of controlled MV results in a 10 -15% reduction in the cross-sectional area of all rat diaphragm fiber types (i.e., type I, type IIa, and type IIx/b) (67,69,82,103). This MV-induced rat diaphragmatic fiber atrophy increases as a function of time and approaches a 30% reduction in fiber cross-sectional area following 18 -24 h of prolonged MV (33,100,117).…”

Section: Mv-induced Diaphragm Atrophymentioning

confidence: 99%

“…Whether this increased 20S proteasome activity is due to allosteric upregulation of protease activity or increased expression of key subunits of the 20S proteasome is unknown. Also, MV-induced ROS production in skeletal muscle has been shown to activate calpain (82,117). The specific mechanism(s) responsible for this ROS-mediated activation of calpain has not been studied but is potentially linked to ROS-mediated increases in cytosolic free calcium (37,88).…”

Section: R468mentioning

confidence: 99%

“…For example, as few as 12 h of MV results in a large increase in ROS emission from rat diaphragm mitochondria during both state 3 and state 4 respiration (50,82). This increase in mitochondrial ROS production is associated with increased lipid peroxidation and protein oxidation within mitochondria (50).…”

Section: R468mentioning

confidence: 99%

“…MECHANICAL VENTILATION AND DIAPHRAGM chondrion (30,69,82,111,116). For example, as few as 12 h of MV results in a large increase in ROS emission from rat diaphragm mitochondria during both state 3 and state 4 respiration (50,82).…”

Section: R468mentioning

confidence: 99%

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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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Section: R468supporting

confidence: 51%

Section: Mv-induced Diaphragm Atrophymentioning

confidence: 99%

Section: R468mentioning

confidence: 99%

Section: R468mentioning

confidence: 99%

Section: R468mentioning

confidence: 99%

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Ventilator-induced diaphragm dysfunction: cause and effect

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Wiggs

Sollanek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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151

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Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H₂O₂ emission during impaired oxidative phosphorylation

Hughes

Turnbull

Rebalka

et al. 2019

J cachexia sarcopenia muscle

120

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Background Muscle wasting and weakness in Duchenne muscular dystrophy (DMD) causes severe locomotor limitations and early death due in part to respiratory muscle failure. Given that current clinical practice focuses on treating secondary complications in this genetic disease, there is a clear need to identify additional contributions in the aetiology of this myopathy for knowledge‐guided therapy development. Here, we address the unresolved question of whether the complex impairments observed in DMD are linked to elevated mitochondrial H 2 O 2 emission in conjunction with impaired oxidative phosphorylation. This study performed a systematic evaluation of the nature and degree of mitochondrial‐derived H 2 O 2 emission and mitochondrial oxidative dysfunction in a mouse model of DMD by designing in vitro bioenergetic assessments that attempt to mimic in vivo conditions known to be critical for the regulation of mitochondrial bioenergetics. Methods Mitochondrial bioenergetics were compared with functional and histopathological indices of myopathy early in DMD (4 weeks) in D2.B10‐DMD mdx /2J mice (D2. mdx )—a model that demonstrates severe muscle weakness. Adenosine diphosphate's (ADP's) central effect of attenuating H 2 O 2 emission while stimulating respiration was compared under two models of mitochondrial‐cytoplasmic phosphate exchange (creatine independent and dependent) in muscles that stained positive for membrane damage (diaphragm, quadriceps, and white gastrocnemius). Results Pathway‐specific analyses revealed that Complex I‐supported maximal H 2 O 2 emission was elevated concurrent with a reduced ability of ADP to attenuate emission during respiration in all three muscles (mH 2 O 2 : +17 to +197% in D2. mdx vs. wild type). This was associated with an impaired ability of ADP to stimulate respiration at sub‐maximal and maximal kinetics (−17 to −72% in D2. mdx vs. wild type), as well as a loss of creatine‐dependent mitochondrial phosphate shuttling in diaphragm and quadriceps. These changes largely occurred independent of mitochondrial density or abundance of respiratory chain complexes, except for quadriceps. This muscle was also the only one exhibiting decreased calcium retention capacity, which indicates increased sensitivity to calcium‐induced permeability transition pore opening. Increased H 2 O 2 emission was accompanied by a compensatory increase in total glutathione, while oxidative stress markers were unchanged. Mitochondrial b...

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Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation

Smuder

Morton

Hall

et al. 2019

J cachexia sarcopenia muscle

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Background Mechanical ventilation (MV) is a life‐saving measure for patients in respiratory failure. However, prolonged MV results in significant diaphragm atrophy and contractile dysfunction, a condition referred to as ventilator‐induced diaphragm dysfunction (VIDD). While there are currently no clinically approved countermeasures to prevent VIDD, increased expression of heat shock protein 72 (HSP72) has been demonstrated to attenuate inactivity‐induced muscle wasting. HSP72 elicits cytoprotection via inhibition of NF‐κB and FoxO transcriptional activity, which contribute to VIDD. In addition, exercise‐induced prevention of VIDD is characterized by an increase in the concentration of HSP72 in the diaphragm. Therefore, we tested the hypothesis that increased HSP72 expression is required for the exercise‐induced prevention of VIDD. We also determined whether increasing the abundance of HSP72 in the diaphragm, independent of exercise, is sufficient to prevent VIDD. Methods Cause and effect was determined by inhibiting the endurance exercise‐induced increase in HSP72 in the diaphragm of exercise trained animals exposed to prolonged MV via administration of an antisense oligonucleotide targeting HSP72. Additional experiments were performed to determine if increasing HSP72 in the diaphragm via genetic (rAAV‐HSP72) or pharmacological (BGP‐15) overexpression is sufficient to prevent VIDD. Results Our results demonstrate that the exercise‐induced increase in HSP72 protein abundance is required for the protective effects of exercise against VIDD. Moreover, both rAAV‐HSP72 and BGP‐15‐induced overexpression of HSP72 were sufficient to prevent VIDD. In addition, modification of HSP72 in the diaphragm is inversely related to the expression of NF‐κB and FoxO target genes. Conclusions HSP72 overexpression in the diaphragm is an effective intervention to prevent MV‐induced oxidative stress and the transcriptional activity of NF‐κB and FoxO. Therefore, overexpression of HSP72 in the diaphragm is a potential therapeutic target to protect against VIDD.

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Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness*

Cited by 216 publications

References 36 publications

Ventilator-induced diaphragm dysfunction: cause and effect

Ventilator-induced diaphragm dysfunction: cause and effect

Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H₂O₂ emission during impaired oxidative phosphorylation

Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation

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Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness*

Cited by 216 publications

References 36 publications

Ventilator-induced diaphragm dysfunction: cause and effect

Ventilator-induced diaphragm dysfunction: cause and effect

Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H2O2 emission during impaired oxidative phosphorylation

Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation

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Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H₂O₂ emission during impaired oxidative phosphorylation