Roser Farre Garros1, Richard Paul1,2, Martin Connolly1, Amy Lewis1, Benjamin E Garfield1, S Amanda Natanek1, Susannah Bloch1,2, Vincent Mouly3, Mark J Griffiths4, Michael I Polkey2, Paul R Kemp1. 1. 1 Molecular Medicine Section and. 2. 2 National Institute for Health Research Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, United Kingdom; and. 3. 3 Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Paris, France. 4. 4 Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College, South Kensington Campus, London, United Kingdom.
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: To identify microRNAs (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: miRNA-542-3p/5p (miR-542-3p/5p) were quantified in the quadriceps of patients with chronic obstructive pulmonary disease and intensive care unit-acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and transforming growth factor-β signaling in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: miR-542-3p/5p were elevated in patients with chronic obstructive pulmonary disease but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10 and reduced 12S ribosomal RNA (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 transforming growth factor-β signaling. In mice, miR-542 overexpression caused muscle wasting, and 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 transforming growth factor-β signaling. In patients undergoing aortic surgery, preoperative levels of miR-542-3p/5p were positively correlated with muscle loss after surgery. CONCLUSIONS: Elevated miR-542-3p/5p may cause muscle atrophy in intensive care unit patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.
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: To identify microRNAs (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: miRNA-542-3p/5p (miR-542-3p/5p) were quantified in the quadriceps of patients with chronic obstructive pulmonary disease and intensive care unit-acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and transforming growth factor-β signaling in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: miR-542-3p/5p were elevated in patients with chronic obstructive pulmonary disease but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10 and reduced 12S ribosomal RNA (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 transforming growth factor-β signaling. In mice, miR-542 overexpression caused muscle wasting, and 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 transforming growth factor-β signaling. In patients undergoing aortic surgery, preoperative levels of miR-542-3p/5p were positively correlated with muscle loss after surgery. CONCLUSIONS: Elevated miR-542-3p/5p may cause muscle atrophy in intensive care unit patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.
Authors: R Faraonio; P Salerno; F Passaro; C Sedia; A Iaccio; R Bellelli; T C Nappi; M Comegna; S Romano; G Salvatore; M Santoro; F Cimino Journal: Cell Death Differ Date: 2011-11-04 Impact factor: 15.828
Authors: Naeem A Ali; James M O'Brien; Stephen P Hoffmann; Gary Phillips; Allan Garland; James C W Finley; Khalid Almoosa; Rana Hejal; Karen M Wolf; Stanley Lemeshow; Alfred F Connors; Clay B Marsh Journal: Am J Respir Crit Care Med Date: 2008-05-29 Impact factor: 21.405
Authors: David Brealey; Michael Brand; Iain Hargreaves; Simon Heales; John Land; Ryszard Smolenski; Nathan A Davies; Chris E Cooper; Mervyn Singer Journal: Lancet Date: 2002-07-20 Impact factor: 79.321
Authors: Samantha A Natanek; Harry R Gosker; Ilse G M Slot; Gemma S Marsh; Nicholas S Hopkinson; William D-C Man; Ruth Tal-Singer; John Moxham; Paul R Kemp; Annemie M W J Schols; Michael I Polkey Journal: Muscle Nerve Date: 2013-08-27 Impact factor: 3.217
Authors: Kateřina Jiroutková; Adéla Krajčová; Jakub Ziak; Michal Fric; Petr Waldauf; Valér Džupa; Jan Gojda; Vlasta Němcova-Fürstová; Jan Kovář; Moustafa Elkalaf; Jan Trnka; František Duška Journal: Crit Care Date: 2015-12-24 Impact factor: 9.097
Authors: Roser Farre-Garros; Jen Y Lee; S Amanda Natanek; Martin Connolly; Avan A Sayer; Harnish Patel; Cyrus Cooper; Michael I Polkey; Paul R Kemp Journal: J Appl Physiol (1985) Date: 2019-01-24
Authors: Martin Connolly; Benjamin E Garfield; Alexi Crosby; Nick W Morrell; Stephen J Wort; Paul R Kemp Journal: PLoS One Date: 2020-02-28 Impact factor: 3.240
Authors: Martin Connolly; Richard Paul; Roser Farre-Garros; Samantha A Natanek; Susannah Bloch; Jen Lee; Jose P Lorenzo; Harnish Patel; Cyrus Cooper; Avan A Sayer; Stephen J Wort; Mark Griffiths; Michael I Polkey; Paul R Kemp Journal: J Cachexia Sarcopenia Muscle Date: 2017-12-07 Impact factor: 12.910
Authors: Joerg C Schefold; Anna S Messmer; Stefanie Wenger; Lionel Müller; Stephan von Haehling; Wolfram Doehner; Jamie S McPhee; Michaela Fux; Kai M Rösler; Olivier Scheidegger; Radu Olariu; Werner Z'Graggen; Serge Rezzi; Dominik Grathwohl; Tobias Konz; Jukka Takala; Bernard Cuenoud; Stephan M Jakob Journal: Medicine (Baltimore) Date: 2019-01 Impact factor: 1.889