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Dysregulation of mitochondrial dynamics and the muscle transcriptome in ICU patients suffering from sepsis induced multiple organ failure

Fredriksson, Katarina ; Tjäder, Inga ; Keller, Pernille ; Petrovic, Natasa ; Ahlman, Bo ; Schéele, Camilla ; Wernerman, Jan ; Timmons, James A ; Rooyackers, Olav Bozza, Patricia

PloS one, 2008-11, Vol.3 (11), p.e3686-e3686 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Dysregulation of mitochondrial dynamics and the muscle transcriptome in ICU patients suffering from sepsis induced multiple organ failure
Autor: Fredriksson, Katarina ; Tjäder, Inga ; Keller, Pernille ; Petrovic, Natasa ; Ahlman, Bo ; Schéele, Camilla ; Wernerman, Jan ; Timmons, James A ; Rooyackers, Olav
Bozza, Patricia
Assuntos: Age ; Aged ; Analysis ; Anesthesiology ; Animal models ; Biologi ; Biology ; Biopsy ; Biosynthesis ; Care and treatment ; Critical Care and Emergency Medicine ; Critical Care and Emergency Medicine/Sepsis and Multiple Organ Failure ; Damage detection ; Diabetes ; Disruption ; Energy balance ; Enzymes ; Female ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation ; Gene regulation ; Genes ; Genetic transcription ; Genetics and Genomics ; Genetics and Genomics/Bioinformatics ; Genetics and Genomics/Comparative Genomics ; Genetics and Genomics/Disease Models ; Genetics and Genomics/Functional Genomics ; Genetics and Genomics/Gene Expression ; Genetics and Genomics/Genomics ; Genetics and Genomics/Physiogenomics ; Genomics ; Genotype & phenotype ; Homeostasis ; Hospital patients ; Humans ; Infectious Diseases ; Inflammation ; Insulin ; Intensive care ; Intensive Care Units ; Laboratories ; Liver cancer ; Male ; Medicin och hälsovetenskap ; Metabolism ; MicroRNAs ; MicroRNAs - genetics ; MicroRNAs - metabolism ; Middle Aged ; miRNA ; Mitochondria ; Mitochondria, Muscle - genetics ; Mitochondria, Muscle - metabolism ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - metabolism ; Mortality ; Multiple organ dysfunction syndrome ; Multiple organ failure ; Multiple Organ Failure - etiology ; Multiple Organ Failure - genetics ; Multiple Organ Failure - metabolism ; Muscle fatigue ; Muscle function ; Muscle, Skeletal - metabolism ; Muscles ; Musculoskeletal system ; NATURAL SCIENCES ; NATURVETENSKAP ; Nutrition/Malnutrition ; Oxidative Phosphorylation ; Oxidative stress ; Patients ; Phenotyping ; Physiology/Genomics ; Post-transcription ; Protein biosynthesis ; Protein synthesis ; Proteins ; Proteolysis ; Ribonucleic acid ; RNA ; Rodents ; Sepsis ; Sepsis - complications ; Sepsis - genetics ; Sepsis - metabolism ; Signal transduction ; Signaling ; Skeletal muscle ; Therapeutic applications ; Transcription
É parte de: PloS one, 2008-11, Vol.3 (11), p.e3686-e3686
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Conceived and designed the experiments: KF IT JW OR. Performed the experiments: KF IT PK NP BA CS JW JAT. Analyzed the data: KF IT PK NP CS JW JAT OR. Contributed reagents/materials/analysis tools: NP BA JW JAT OR. Wrote the paper: KF IT PK NP BA CS JW JAT OR.
Descrição: Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patient's protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients impairing cellular energy balance, which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments and the molecular consequences. Utilising biopsy material from seventeen patients and ten age-matched controls we demonstrate that neither mitochondrial in vivo protein synthesis nor expression of mitochondrial genes are compromised. Indeed, there was partial activation of the mitochondrial biogenesis pathway involving NRF2alpha/GABP and its target genes TFAM, TFB1M and TFB2M yet clearly this failed to maintain mitochondrial function. We therefore utilised transcript profiling and pathway analysis of ICU patient skeletal muscle to generate insight into the molecular defects driving loss of muscle function and metabolic homeostasis. Gene ontology analysis of Affymetrix analysis demonstrated substantial loss of muscle specific genes, a global oxidative stress response related to most probably cytokine signalling, altered insulin related signalling and a substantial overlap between patients and muscle wasting/inflammatory animal models. MicroRNA 21 processing appeared defective suggesting that post-transcriptional protein synthesis regulation is altered by disruption of tissue microRNA expression. Finally, we were able to demonstrate that the phenotype of skeletal muscle in ICU patients is not merely one of inactivity, it appears to be an actively remodelling tissue, influenced by several mediators, all of which may be open to manipulation with the aim to improve clinical outcome. This first combined protein and transcriptome based analysis of human skeletal muscle obtained from septic patients demonstrated that losses of mitochondria and muscle mass are accompanied by sustained protein synthesis (anabolic process) while dysregulation of transcription programmes appears to fail to compensate for increased damage and proteolysis. Our analysis identified both validated and novel clinically tractable targets to manipulate these failing processes and pursuit of these could lead to new potential treatments.
Editor: United States: Public Library of Science
Idioma: Inglês

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Dysregulation of mitochondrial dynamics and the muscle transcriptome in ICU patients suffering from sepsis induced multiple organ failure

Fredriksson, Katarina ; Tjäder, Inga ; Keller, Pernille ; Petrovic, Natasa ; Ahlman, Bo ; Schéele, Camilla ; Wernerman, Jan ; Timmons, James A ; Rooyackers, Olav Bozza, Patricia

United States: Public Library of Science

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