0520. The role of mitochondrial dysfunction in the pathophysiology of icu-acquired weakness
© Jiroutkova et al; licensee Springer. 2014
Published: 26 September 2014
To assess whether mitochondrial dysfunction in skeletal muscle perists until protracted critical illness and whether it contributes to the development of ICU-acquired weakness.
Muscle biopsies were obtained from critically ill patients with severe ICUAW (defined as MRC score < 24 on two separate tests) and from otherwise healthy controls undergoing elective hip replacement. 50-100mg of the native sample was homogenized by a technique which perserves mitochondria in their cytosolic context . Oxygen consumption was measured by high-resolution respirometry (Oxygraph-2Km Oroboros) under two occasions: 1. homogenate enriched with substrates was sequentially treated with an ATPase inhibitor (oligomycine), an uncoupler (FCCP) and KCN. This allowed us to measure oxidative phosphorylation, respiratory chain capacity, proton leak through inner mitochondrial membrane and non-mitochondrial O2 consumption. 2. skeletal muscle homogenate enriched with abundant ADP was treated with sequential addition of substrates and inhibitors of complexes I, II, III, and IV, respectively. Integrity of outer membrane was assessed by measuring the response to addition of cytochrome c. Oxygen consumption rate was normalized to citrate-synthase activity and total protein content.
Activities of respiratory complexes [pmol/nkat]
Data as median (IQR)
Resp. chain spare capacity
p [Mann Whitney
Upregulation of complex II may represent an adaptive phenomenon as skeletal muscle during critical illness is more reliant on fatty oxidation (which feeds electrons to respiratory chain via complex II), because of insulin resistance and impaired oxidative glucose disposal.
In patients with severe ICUAW we have demonstrated increased activity of respiratory chain complexes downstream to complex I and intact global mitochondrial function. This may represent an adaptation to insulin resistance.
Supported by IGA NT 12319.
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