Abstract
BackgroundMitochondrial damage occurs in the acute phase of critical illness, followed by activation of mitochondrial biogenesis in survivors. It has been hypothesized that bioenergetics failure of skeletal muscle may contribute to the development of ICU-acquired weakness. The aim of the present study was to determine whether mitochondrial dysfunction persists until protracted phase of critical illness.MethodsIn this single-centre controlled-cohort ex vivo proof-of-concept pilot study, we obtained vastus lateralis biopsies from ventilated patients with ICU-acquired weakness (n = 8) and from age and sex-matched metabolically healthy controls (n = 8). Mitochondrial functional indices were measured in cytosolic context by high-resolution respirometry in tissue homogenates, activities of respiratory complexes by spectrophotometry and individual functional capacities were correlated with concentrations of electron transport chain key subunits from respiratory complexes II, III, IV and V measured by western blot.ResultsThe ability of aerobic ATP synthesis (OXPHOS) was reduced to ~54 % in ICU patients (p<0.01), in correlation with the depletion of complexes III (~38 % of control, p = 0.02) and IV (~26 % of controls, p<0.01) and without signs of mitochondrial uncoupling. When mitochondrial functional indices were adjusted to citrate synthase activity, OXPHOS and the activity of complexes I and IV were not different, whilst the activities of complexes II and III were increased in ICU patients 3-fold (p<0.01) respectively 2-fold (p<0.01).ConclusionsCompared to healthy controls, in ICU patients we have demonstrated a ~50 % reduction of the ability of skeletal muscle to synthetize ATP in mitochondria. We found a depletion of complex III and IV concentrations and relative increases in functional capacities of complex II and glycerol-3-phosphate dehydrogenase/complex III.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1160-x) contains supplementary material, which is available to authorized users.
Highlights
Mitochondrial damage occurs in the acute phase of critical illness, followed by activation of mitochondrial biogenesis in survivors
Relative content of mitochondrial proteins In length of stay in intensive care (ICU) patients compared to controls, there was a significant reduction of core 2 subunit of complex III and COX2 subunit of complex IV
Global indices of mitochondrial function in skeletal muscle homogenates (Protocol 1) In the skeletal muscle of patients with protracted critical illness (ICU) compared to control subjects, there was a reduction in citrate synthase (CS) activity per muscle wet weight (median 0.25 (IQR 0.16–0.28) vs 0.34 (IQR 0.28–0.43) nkat/mg Ww, p = 0.03)
Summary
Mitochondrial damage occurs in the acute phase of critical illness, followed by activation of mitochondrial biogenesis in survivors. Generalized inflammation and multi-organ failure in the acute phase of critical illness are accompanied by impairment of mitochondrial morphology [1] and function of skeletal muscle [2,3,4,5] and other organs [6, 7]. It appears that the inability to meet cellular ATP demand is caused by a global depletion of functional mitochondria, as the reduction of respiratory complex content [4] or activities [3] is proportional to Little is known about mitochondrial function in patients who do survive the acute phase of disease, but fail to wean from mechanical ventilation and enter a protracted phase of critical illness. We hypothesized that bioenergetics failure would be present in the skeletal muscle of patients with weaning failure and ICUacquired weakness as a result of mitochondrial uncoupling and/or depletion. We performed muscle biopsies in such patients, measured concentrations and activities of Jiroutková et al Critical Care (2015) 19:448 key proteins of the respiratory chain and assessed mitochondrial function in the cytosolic context by highresolution respirometry in fresh skeletal muscle homogenates [8]
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