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miR-542 promotes mitochondrial dysfunction and SMAD activity and is raised in ICU Acquired Weakness

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Title: miR-542 promotes mitochondrial dysfunction and SMAD activity and is raised in ICU Acquired Weakness
Authors: Farre garros
Paul, R
Connolly, M
Lewis, A
Natanek, SA
Garfield, BE
BLoch, S
Mouly, V
Griffiths, M
Polkey, MI
Kemp, P
Item Type: Journal Article
Abstract: Rationale: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases but the mechanisms by which this occurs are unclear. Objectives: We aimed to identify miRNAs that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. Methods: miR-542-3p/-5p were quantified in the quadriceps of patients with COPD and intensive care unit acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and TGF-β signaling in vitro and in vivo. Measurements and main results: miR-542-3p/5p were elevated in patients with COPD but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10, and reduced 12S rRNA expression suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1 and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation suggesting that miR-542-5p increased TGF-β signaling. In mice, miR-542 over-expression caused muscle wasting, reduced mitochondrial function, 12S rRNA expression and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased TGF-β signaling. In patients undergoing aortic surgery, pre-operative levels of miR-542-3p/5p were positively correlated with muscle loss following surgery. Conclusion; Elevated miR-542-3p/5p may cause muscle atrophy in ICU patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.
Issue Date: 15-Aug-2017
Date of Acceptance: 11-Aug-2017
URI: http://hdl.handle.net/10044/1/50413
DOI: https://dx.doi.org/10.1164/rccm.201701-0101OC
ISSN: 1073-449X
Publisher: American Thoracic Society
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Volume: 196
Issue: 11
Copyright Statement: Copyright © 2017 by the American Thoracic Society
Sponsor/Funder: Medical Research Council (MRC)
National Institute for Health Research
Royal Brompton & Harefield NHS Foundation Trust
British Heart Foundation
Rosetrees Trust
Funder's Grant Number: G1001362
BRU 6279
na
FS/14/71/31038
A960
Keywords: SMAD signaling
microRNA
mitochondrial function
skeletal muscle wasting
11 Medical And Health Sciences
Respiratory System
Publication Status: Published online
Appears in Collections:National Heart and Lung Institute
Airway Disease
Department of Medicine
Faculty of Medicine



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