Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness

Vanhorebeek, Ilse; Ellger, Bjoern; Vos, Rita De; Boussemaere, Magaly; Debaveye, Yves; Perre, Sarah Vander; Rabbani, Naila; Thornalley, Paul J.; Berghe, Greet Van den

doi:10.1097/ccm.0b013e31819cec17

Cited by 67 publications

(47 citation statements)

References 50 publications

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“…It also improved the activity of several mitochondrial respiratory chain enzymes. Mitochondrial protection in liver, kidney, and myocardium was attributed to glucose control rather than direct insulin effects, as shown in critically ill rabbits (726,729). Intriguingly, the intervention had no impact on the mitochondria in skeletal muscle of critically ill patients or rabbits (725,726).…”

Section: F Glucose Toxicity During Critical Illnessmentioning

confidence: 90%

“…Mitochondrial protection in liver, kidney, and myocardium was attributed to glucose control rather than direct insulin effects, as shown in critically ill rabbits (726,729). Intriguingly, the intervention had no impact on the mitochondria in skeletal muscle of critically ill patients or rabbits (725,726). Nevertheless, it attenuated iNOS expression in muscle and prevented excessive NO production (184,725).…”

Section: F Glucose Toxicity During Critical Illnessmentioning

confidence: 93%

“…The intervention protected the endothelium in patients where lowering of adhesion molecules prevented organ failure and death (393). In critically ill rabbits, glycemic control improved endothelium-mediated relaxation of aortic rings, but had no effect on tissue perfusion and oxygen delivery to different organs, including skeletal muscle (183,726,729). Strict glycemic control with insulin protected against severe mitochondrial morphological abnormalities seen in liver from hyperglycemic critically ill patients (725).…”

Section: F Glucose Toxicity During Critical Illnessmentioning

confidence: 99%

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The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

329

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Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca 2ϩ dysregulation is present through altered Ca 2ϩ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

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Section: F Glucose Toxicity During Critical Illnessmentioning

confidence: 90%

Section: F Glucose Toxicity During Critical Illnessmentioning

confidence: 93%

Section: F Glucose Toxicity During Critical Illnessmentioning

confidence: 99%

See 1 more Smart Citation

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

329

View full text Add to dashboard Cite

show abstract

“…These include bacteriostatic antibiotics (45)(46)(47), catecholamines (48), corticosteroids (49), thyroid analogs (50), and nutrition (51). Similarly, complications of critical illness, including hyperglycemia (51), immobility, and mechanical ventilation (52), may compromise mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

Survival in Critical Illness Is Associated with Early Activation of Mitochondrial Biogenesis

Carré¹,

Orban²,

Re³

et al. 2010

Am J Respir Crit Care Med

367

286

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Rationale: We previously reported outcome-associated decreases in muscle energetic status and mitochondrial dysfunction in septic patients with multiorgan failure. We postulate that survivors have a greater ability to maintain or recover normal mitochondrial functionality. Objectives: To determine whether mitochondrial biogenesis, the process promoting mitochondrial capacity, is affected in critically ill patients. Methods: Muscle biopsies were taken from 16 critically ill patients recently admitted to intensive care (average 1-2 d) and from 10 healthy, age-matched patients undergoing elective hip surgery. Measurements and Main Results: Survival, mitochondrial morphology, mitochondrial protein content and enzyme activity, mitochondrial biogenesis factor mRNA, microarray analysis, and phosphorylated (energy) metabolites were determined. Ten of 16 critically ill patients survived intensive care. Mitochondrial size increased with worsening outcome, suggestive of swelling. Respiratory protein subunits and transcripts were depleted in critically ill patients and to a greater extent in nonsurvivors. The mRNA content of peroxisome proliferator-activated receptor g coactivator 1-a (transcriptional coactivator of mitochondrial biogenesis) was only elevated in survivors, as was the mitochondrial oxidative stress protein manganese superoxide dismutase. Eventual survivors demonstrated elevated muscle ATP and a decreased phosphocreatine/ATP ratio. Conclusions: Eventual survivors responded early to critical illness with mitochondrial biogenesis and antioxidant defense responses. These responses may partially counteract mitochondrial protein depletion, helping to maintain functionality and energetic status. Impaired responses, as suggested in nonsurvivors, could increase susceptibility to mitochondrial damage and cellular energetic failure or impede the ability to recover normal function. Clinical trial registered with clinical trials.gov (NCT00187824).

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“…However, evidence of morphological changes of mitochondria in hepatocytes has drawn much attention. Increased level of fragmented mitochondria was related to reduced fuel oxidation and increased oxidative stress in hepatocytes from diabetic rats [7]. Moreover, hypertrophic mitochondria with increased number of irregular cristae and reduced matrix electron density were observed in liver of critically ill diabetic patients [8].…”

Section: Introductionmentioning

confidence: 91%

Mitochondrial fusion/fission process involved in the improvement of catalpol on high glucose-induced hepatic mitochondrial dysfunction

Zhang

et al. 2015

ABBS

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Catalpol, an iridoid glycoside, has been shown to exert hypoglycemic effect by rescuing mitochondrial function, but the detailed mechanism remains unclear yet. In this study, the effect and mechanism of catalpol on the hepatic mitochondria under diabetic conditions were further examined. Oral administration of catalpol significantly reduced the blood glucose, triglyceride, and cholesterol levels in high-fat diet-and streptozotocin-induced diabetic mice. Additionally, catalpol attenuated the decrease in liver mitochondrial ATP content resulting from diabetes. Furthermore, the number of mitochondria possessing a long size was increased in catalpol-treated mice. Interestingly, the catalpol-induced recovery of mitochondrial function was associated with decreased fission protein 1 and dynamin-related protein 1 expression as well as increased mitofusin 1 expression in the liver. In HepG2 cells, catalpol alleviated the decrease of ATP content and mitochondrial membrane potential, and the increase of reactive oxygen species formation induced by high glucose. MitoTracker Green stain shows that the tubular feature of mitochondria was maintained when cells were treated with catalpol. Catalpol also decreased fission protein 1 and dynamin-related protein 1 expression and increased mitofusin 1 expression in HepG2 cells. The present results suggest that catalpol can ameliorate hepatic mitochondrial dysfunction under a diabetic state, and this may be related to its regulation of mitochondrial fusion and fission events.

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Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness

Abstract: In a rabbit model of critical illness, HG evokes cellular glucose overload in liver and myocardium inducing mitochondrial dysfunction, which explained the HG-induced organ damage. Maintenance of normoglycemia, but not HI, protects against such mitochondrial and organ damage.

Cited by 67 publications

References 50 publications

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Survival in Critical Illness Is Associated with Early Activation of Mitochondrial Biogenesis

Mitochondrial fusion/fission process involved in the improvement of catalpol on high glucose-induced hepatic mitochondrial dysfunction

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