Mitochondrial Dysfunction and Lipid Accumulation in the Human Diaphragm during Mechanical Ventilation (original) (raw)
Related papers
Critical Care Medicine, 2011
BACKGROUND-Mechanical ventilation (MV) is a life-saving intervention used to provide adequate pulmonary ventilation in patients suffering from respiratory failure. However, prolonged MV is associated with significant diaphragmatic weakness resulting from both myofiber atrophy and contractile dysfunction. Although several signaling pathways contribute to diaphragm weakness during MV, it is established that oxidative stress is required for diaphragmatic weakness to occur. Therefore, identifying the site(s) of MV-induced reactive oxygen species (ROS) production in the diaphragm is important. OBJECTIVE-These experiments tested the hypothesis that elevated mitochondrial ROS emission is required for MV-induced oxidative stress, atrophy, and contractile dysfunction in the diaphragm. DESIGN-Cause and effect was determined by preventing MV-induced mitochondrial ROS emission in the diaphragm of rats using a novel mitochondrial-targeted antioxidant (SS-31). MEASUREMENTS AND MAIN RESULTS-Compared to mechanically ventilated animals treated with saline, animals treated with SS-31 were protected against MV-induced mitochondrial dysfunction, oxidative stress, and protease activation in the diaphragm. Importantly, treatment of animals with the mitochondrial antioxidant also protected the diaphragm against MV-induced myofiber atrophy and contractile dysfunction. CONCLUSIONS-These results reveal that prevention of MV-induced increases in diaphragmatic mitochondrial ROS emission protects the diaphragm MV-induced diaphragmatic weakness. This important new finding indicates that mitochondria are a primary source of ROS production in the diaphragm during prolonged MV. These results could lead to the development of a therapeutic intervention to impede MV-induced diaphragmatic weakness.
PLOS ONE, 2015
Mechanical ventilation (MV) is a life-saving intervention in patients in respiratory failure. Unfortunately, prolonged MV results in the rapid development of diaphragm atrophy and weakness. MV-induced diaphragmatic weakness is significant because inspiratory muscle dysfunction is a risk factor for problematic weaning from MV. Therefore, developing a clinical intervention to prevent MV-induced diaphragm atrophy is important. In this regard, MVinduced diaphragmatic atrophy occurs due to both increased proteolysis and decreased protein synthesis. While efforts to impede MV-induced increased proteolysis in the diaphragm are well-documented, only one study has investigated methods of preserving diaphragmatic protein synthesis during prolonged MV. Therefore, we evaluated the efficacy of two therapeutic interventions that, conceptually, have the potential to sustain protein synthesis in the rat diaphragm during prolonged MV. Specifically, these experiments were designed to: 1) determine if partial-support MV will protect against the decrease in diaphragmatic protein synthesis that occurs during prolonged full-support MV; and 2) establish if treatment with a mitochondrial-targeted antioxidant will maintain diaphragm protein synthesis during full-support MV. Compared to spontaneously breathing animals, full support MV resulted in a significant decline in diaphragmatic protein synthesis during 12 hours of MV. In contrast, diaphragm protein synthesis rates were maintained during partial support MV at levels comparable to spontaneous breathing animals. Further, treatment of animals with a mitochondrial-targeted antioxidant prevented oxidative stress during full support MV and maintained diaphragm protein synthesis at the level of spontaneous breathing animals. We conclude that treatment with mitochondrial-targeted antioxidants or the use of partial-support MV are potential strategies to preserve diaphragm protein synthesis during prolonged MV.
American Journal of Respiratory and Critical Care Medicine, 2002
Prolonged mechanical ventilation (MV) results in reduced diaphrag-Further, experiments performed in our laboratory have conmatic maximal force production and diaphragmatic atrophy. To firmed that as few as 18 hours of MV results in diaphragmatic investigate the mechanisms responsible for MV-induced diaphragcontractile dysfunction (4) and atrophy (our unpublished obmatic atrophy, we tested the hypothesis that controlled MV results servations). The mechanism(s) responsible for this atrophy in oxidation of diaphragmatic proteins and increased diaphragare unknown and are the focus of the experiments described matic proteolysis due to elevated protease activity. Further, we in this article. postulated that MV would result in atrophy of all diaphragmatic Experiments investigating disuse locomotor skeletal musmuscle fiber types. Mechanically ventilated animals were anesthecle atrophy (e.g., hindlimb unloading) indicate that whereas tized, tracheostomized, and ventilated with 21% O 2 for 18 hours. all muscle fibers atrophy during prolonged periods of un-MV resulted in a decrease (p Ͻ 0.05) in diaphragmatic myofibrillar loading, slow (i.e., Type I) muscle fibers are particularly susprotein and the cross-sectional area of all muscle fiber types (i.e., ceptible to this type of atrophy (reviewed by Roy and cowork-I, IIa, IId/x, and IIb). Further, MV promoted an increase (p Ͻ 0.05) ers [5]). In contrast, diaphragmatic inactivity induced by in diaphragmatic protein degradation along with elevated (p Ͻ either unilateral denervation or tetrodotoxin blockade of 0.05) calpain and 20S proteasome activity. Finally, MV was also nerve impulses results in atrophy of Type IIx and IIb fibers associated with a rise (p Ͻ 0.05) in both protein oxidation and and hypertrophy of Type I and IIa fibers (6-8). At present, lipid peroxidation. These data support the hypothesis that MV is it is unclear which diaphragmatic fiber types are subject to associated with atrophy of all diaphragmatic fiber types, increased atrophy during MV. It is also well known that locomotor diaphragmatic protease activity, and augmented diaphragmatic oxmuscle atrophy due to reduced use is associated with an idative stress.
Mechanical Ventilation Triggers Abnormal Mitochondrial Dynamics and Morphology in the Diaphragm
Journal of applied physiology (Bethesda, Md. : 1985), 2015
The diaphragm is a unique skeletal muscle designed to be rhythmically active throughout life, such that its sustained inactivation by the medical intervention of mechanical ventilation (MV) represents an unanticipated physiological state in evolutionary terms. Within a short period after initiating MV, the diaphragm develops muscle atrophy, damage and diminished strength, and many of these features appear to arise from mitochondrial dysfunction. Notably, in response to metabolic perturbations, mitochondria fuse, divide and interact with neighboring organelles to remodel their shape and functional properties - a process collectively known as mitochondrial dynamics. Using a quantitative electron microscopy approach, here we show that diaphragm contractile inactivity induced by 6 hours of MV in mice leads to fragmentation of intermyofibrillar (IMF) but not subsarcolemmal (SS) mitochondria. Furthermore, physical interactions between adjacent organellar membranes were less abundant in IM...
MECHANICAL VENTILATION-INDUCED OXIDATIVE STRESS IN THE DIAPHRAGM
2003
Prolonged mechanical ventilation (MV) results in oxidative damage in the diaphragm; however, it is unclear if this MV-induced oxidative injury occurs rapidly or develops slowly over time. Further, it is unknown if both soluble (cytosolic) and insoluble (myofibrillar) proteins are equally susceptible to oxidation during MV. These experiments tested two hypotheses: 1) MV-induced oxidative injury in the diaphragm occurs within the first 6 hours after the initiation of MV; and 2) MV is associated with oxidative modification of both soluble and insoluble proteins. Adult Sprague-Dawley rats were randomly divided into one of seven experimental groups: 1) control (n=8); 2) 3 hours MV (n=8); 3) 6 hours MV (n=6); 4) 18 hours MV (n=8); 5) 3 hours anesthesiaspontaneous breathing (n= 8); 6) 6 hours anesthesia-spontaneous breathing (n=6); and 7) 18 hours anesthesia-spontaneous breathing (n=8). Markers of oxidative injury in the diaphragm included the measurement of reactive (protein) carbonyl derivatives (RCD), and total lipid hydroperoxides. Three hours of MV did not result in oxidative injury in the diaphragm. In contrast, both 6 and 18 hours of MV promoted oxidative injury in the diaphragm as indicated by increases in both protein RCD and lipid hydroperoxides. Electrophoretic separation of soluble and insoluble proteins indicated that the MVinduced accumulation of RCD was limited to insoluble proteins with molecular weights around 200, 120, 80 and 40 kDa. We conclude that MV results in a rapid onset of oxidative injury in the diaphragm and that insoluble proteins are primary targets of MVinduced protein oxidation. Mechanical ventilation-induced oxidative stress in the diaphragm
Oxidative stress is an important mediator of diaphragm muscle atrophy and contractile dysfunction during prolonged periods of controlled mechanical ventilation (MV). To date, specific details related to the impact of MV on diaphragmatic redox status remain unknown. To fill this void, we tested the hypothesis that MV-induced diaphragmatic oxidative stress is the consequence of both an elevation in intracellular oxidant production in conjunction with a decrease in the antioxidant buffering capacity.
Diaphragm Atrophy and Weakness in the Absence of Mitochondrial Dysfunction in the Critically Ill
American Journal of Respiratory and Critical Care Medicine, 2017
Rationale: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency and increases morbidity, duration of hospital stay, and health care costs. The mechanisms underlying diaphragm weakness are unknown, but might include mitochondrial dysfunction and oxidative stress. Objectives: We hypothesized that weakness of diaphragm muscle fibers in critically ill patients is accompanied by impaired mitochondrial function and structure, and by increased markers of oxidative stress. Methods: To test these hypotheses, we studied contractile force, mitochondrial function, and mitochondrial structure in diaphragm muscle fibers. Fibers were isolated from diaphragm biopsies of 36 mechanically ventilated critically ill patients and compared with those isolated from biopsies of 27 patients with suspected early-stage lung malignancy (control subjects). Measurements and Main Results: Diaphragm muscle fibers from critically ill patients displayed significant atrophy and contractile weakness, but lacked impaired mitochondrial respiration and increased levels of oxidative stress markers. Mitochondrial energy status and morphology were not altered, despite a lower content of fusion proteins. Conclusions: Critically ill patients have manifest diaphragm muscle fiber atrophy and weakness in the absence of mitochondrial dysfunction and oxidative stress. Thus, mitochondrial dysfunction and oxidative stress do not play a causative role in the development of atrophy and contractile weakness of the diaphragm in critically ill patients.
Redox regulation of diaphragm proteolysis during mechanical ventilation
AJP: Regulatory, Integrative and Comparative Physiology, 2008
Prevention of oxidative stress via antioxidants attenuates diaphragm myofiber atrophy associated with mechanical ventilation (MV). However, the specific redox sensitive mechanisms responsible for this remain unknown. We tested the hypothesis that regulation of skeletal muscle proteolytic activity is a critical site of redox action during MV. Sprague-Dawley rats were assigned to five experimental groups: 1) control (Con): 2) 6-hours of MV (6hr MV); 3) 6-hours of MV with infusion of the antioxidant, Trolox (6hr MVT), 4) 18-hours of MV (18hr MV); and 5) 18-hours MV with Trolox (18hr MVT). Trolox did not attenuate MV induced increases in diaphragmatic levels of ubiquitin-protein conjugation, poly-ubiquitin mRNA, and gene expression of proteasomal subunits (20S proteasome -subunit 7, 14kDa-E2, and proteasome-activating complex PA28).
Journal of Applied Physiology, 2008
Whidden MA, McClung JM, Falk DJ, Hudson MB, Smuder AJ, Nelson WB, Powers SK. Xanthine oxidase contributes to mechanical ventilation-induced diaphragmatic oxidative stress and contractile dysfunction. spiratory muscle weakness resulting from both diaphragmatic contractile dysfunction and atrophy has been hypothesized to contribute to the weaning difficulties associated with prolonged mechanical ventilation (MV). While it is clear that oxidative injury contributes to MV-induced diaphragmatic weakness, the source(s) of oxidants in the diaphragm during MV remain unknown. These experiments tested the hypothesis that xanthine oxidase (XO) contributes to MV-induced oxidant production in the rat diaphragm and that oxypurinol, a XO inhibitor, would attenuate MV-induced diaphragmatic oxidative stress, contractile dysfunction, and atrophy. Adult female Sprague-Dawley rats were randomly assigned to one of six experimental groups: 1) control, 2) control with oxypurinol, 3) 12 h of MV, 4) 12 h of MV with oxypurinol, 5) 18 h of MV, or 6) 18 h of MV with oxypurinol. XO activity was significantly elevated in the diaphragm after MV, and oxypurinol administration inhibited this activity and provided protection against MV-induced oxidative stress and contractile dysfunction. Specifically, oxypurinol treatment partially attenuated both protein oxidation and lipid peroxidation in the diaphragm during MV. Further, XO inhibition retarded MV-induced diaphragmatic contractile dysfunction at stimulation frequencies Ͼ60 Hz. Collectively, these results suggest that oxidant production by XO contributes to MV-induced oxidative injury and contractile dysfunction in the diaphragm. Nonetheless, the failure of XO inhibition to completely prevent MV-induced diaphragmatic oxidative damage suggests that other sources of oxidant production are active in the diaphragm during prolonged MV.