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Skeletal muscle transcriptome in ICU patient suffering from sepsis induced multiple organ failure - GSE13205

Purpose

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 resulting in decreased cellular energy which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments. Methodology/Principle Findings 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 NRF2?/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. Conclusions/Significance 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.

Hypothesis

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Experimental Design

13 septic samples, 8 controls

Experimental Variables

Sepsis induced multiple organ failure (2021 ICD-10-CM code* = A41)

Controls

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Methods

Data presented in the paper was quality controlled using the Microarray Suite software (MAS 5.0). All array data were normalized through implementations of the MAS5 algorithm, to a global scaling intensity of 100. Probesets declared absent by MAS5 across all chips were removed from further analysis.

Additional Information

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE13205

Microarray
Affymetrix HG-U133_Plus_2
21 Samples Loaded: 21
Human (Homo sapiens)
vastus lateralis
Sepsis induced multiple organ failure
Total RNA was isolated from muscle samples using TRIzol (Invitrogen, Stockholm, Sweden) and quantified using a Nano-drop spectrophotometer.
Sample Set Spreadsheet
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Samples Preview
Sample ID !Sample Title Age Gender Grouping
GSM333436 Muscle septic k49 60 male, Age:60 Septic Patient
GSM333437 Muscle septic k50 46 male, Age:46 Septic Patient
GSM333438 Muscle septic k53 77 male, Age:77 Septic Patient
GSM333439 Muscle septic k54 56 female, Age:56 Septic Patient
GSM333440 Muscle septic k55 77 male, Age:77 Septic Patient
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sampleset4000218_sampleannotations_GSE13205.csv
Sample Set Spreadsheet
sampleset4000218_sampleannotations_v1.csv
Sample Set Spreadsheet
sampleset4000218_sampleannotations_v1.csv
Sample Set Spreadsheet
Log2 Transformed
Raw Signal
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Sample ID !Sample Title Age Gender Grouping
GSM333436
Muscle septic k49
60
male, Age:60
Septic Patient
GSM333437
Muscle septic k50
46
male, Age:46
Septic Patient
GSM333438
Muscle septic k53
77
male, Age:77
Septic Patient
GSM333439
Muscle septic k54
56
female, Age:56
Septic Patient
GSM333440
Muscle septic k55
77
male, Age:77
Septic Patient
GSM333441
Muscle septic k56
69
female, Age:69
Septic Patient
GSM333442
Muscle septic k57
77
male, Age:77
Septic Patient
GSM333443
Muscle septic k59
74
male, Age:74
Septic Patient
GSM333444
Muscle septic k60
67
female, Age:67
Septic Patient
GSM333445
Muscle septic k61
77
male, Age:77
Septic Patient
GSM333446
Muscle septic k62
48
male, Age:48
Septic Patient
GSM333447
Muscle septic k63
71
female, Age:71
Septic Patient
GSM333448
Muscle septic k64
25
female, Age:25
Septic Patient
GSM333449
Muscle control k65
70
male, Age:70
Control Subject
GSM333450
Muscle control k66
76
male, Age:76
Control Subject
GSM333451
Muscle control k67
76
male, Age:76
Control Subject
GSM333452
Muscle control k68
72
female, Age:72
Control Subject
GSM333453
Muscle control k69
60
male, Age:60
Control Subject
GSM333454
Muscle control k70
76
male, Age:76
Control Subject
GSM333455
Muscle control k71
71
male, Age:71
Control Subject
GSM333456
Muscle control k72
70
male, Age:70
Control Subject

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