title: Quadriceps muscle weakness and atrophy are associated with a differential epigenetic profile in advanced COPD.
abstract: Epigenetic mechanisms regulate muscle mass and function in models of muscle dysfunction and atrophy. We assessed whether quadriceps muscle weakness and atrophy are associated with a differential expression profile of epigenetic events in patients with advanced COPD (chronic obstructive pulmonary disease). In vastus lateralis (VL) of sedentary severe COPD patients (n=41), who were further subdivided into those with (n=25) and without (n=16) muscle weakness and healthy controls (n=19), expression of muscle-enriched miRNAs, histone acetyltransferases (HATs) and deacetylases (HDACs), growth and atrophy signalling markers, total protein and histone acetylation, transcription factors, small ubiquitin-related modifier (SUMO) ligases and muscle structure were explored. All subjects were clinically evaluated. Compared with controls, in VL of all COPD together and in muscle-weakness patients, expression of miR-1, miR-206 and miR-27a, levels of lysine-acetylated proteins and histones and acetylated histone 3 were increased, whereas expression of HDAC3, HDAC4, sirtuin-1 (SIRT-1), IGF-1 (insulin-like growth factor-1) were decreased, Akt (v-akt murine thymoma viral oncogene homologue 1) expression did not differ, follistatin expression was greater, whereas myostatin expression was lower, serum reponse factor (SRF) expression was increased and fibre size of fast-twitch fibres was significantly reduced. In VL of severe COPD patients with muscle weakness and atrophy, epigenetic events regulate muscle differentiation rather than proliferation and muscle growth and atrophy signalling, probably as feedback mechanisms to prevent those muscles from undergoing further atrophy. Lysine-hyperacetylation of histones may drive enhanced protein catabolism in those muscles. These findings may help design novel therapeutic strategies (enhancers of miRNAs promoting myogenesis and acetylation inhibitors) to selectively target muscle weakness and atrophy in severe COPD.
authors: *Pulmonology Department-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), C/ Dr. Aiguader, 88, Barcelona, Catalonia, E-08003 Spain.
authors: Ester
authors: E
authors: Puig-Vilanova
authors: *Pulmonology Department-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), C/ Dr. Aiguader, 88, Barcelona, Catalonia, E-08003 Spain.
authors: Juana
authors: J
authors: Martínez-Llorens
authors: *Pulmonology Department-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), C/ Dr. Aiguader, 88, Barcelona, Catalonia, E-08003 Spain.
authors: Pilar
authors: P
authors: Ausin
authors: †Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), C/ Monforte de Lemos 5, Madrid, E-28029 Spain.
authors: Josep
authors: J
authors: Roca
authors: *Pulmonology Department-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), C/ Dr. Aiguader, 88, Barcelona, Catalonia, E-08003 Spain.
authors: Joaquim
authors: J
authors: Gea
authors: *Pulmonology Department-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), C/ Dr. Aiguader, 88, Barcelona, Catalonia, E-08003 Spain.
authors: Esther
authors: E
authors: Barreiro
mesh_terms: D000886:Anthropometry / Q000379:methods; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D044127:Epigenesis, Genetic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D018908:Muscle Weakness / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000235:genetics* / Q000473:pathology; D052097:Quadriceps Muscle / Q000473:pathology / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D035683:MicroRNAs