caa a22 4500 605543771 CHVBK 20210128100928.0 cr unu---uuuuu 210128e20150501xx s 000 0 eng 10.1007/s00109-014-1244-0 doi (NATIONALLICENCE)springer-10.1007/s00109-014-1244-0 Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension [Elektronische Daten] [Simon Malenfant, François Potus, Frédéric Fournier, Sandra Breuils-Bonnet, Aude Pflieger, Sylvie Bourassa, Ève Tremblay, Benjamin Nehmé, Arnaud Droit, Sébastien Bonnet, Steeve Provencher] Exercise limitation comes from a close interaction between cardiovascular and skeletal muscle impairments. To better understand the implication of possible peripheral oxidative metabolism dysfunction, we studied the proteomic signature of skeletal muscle in pulmonary arterial hypertension (PAH). Eight idiopathic PAH patients and eight matched healthy sedentary subjects were evaluated for exercise capacity, skeletal muscle proteomic profile, metabolism, and mitochondrial function. Skeletal muscle proteins were extracted, and fractioned peptides were tagged using an iTRAQ protocol. Proteomic analyses have documented a total of 9 downregulated proteins in PAH skeletal muscles and 10 upregulated proteins compared to healthy subjects. Most of the downregulated proteins were related to mitochondrial structure and function. Focusing on skeletal muscle metabolism and mitochondrial health, PAH patients presented a decreased expression of oxidative enzymes (pyruvate dehydrogenase, p < 0.01) and an increased expression of glycolytic enzymes (lactate dehydrogenase activity, p < 0.05). These findings were supported by abnormal mitochondrial morphology on electronic microscopy, lower citrate synthase activity (p < 0.01) and lower expression of the transcription factor A of the mitochondria (p < 0.05), confirming a more glycolytic metabolism in PAH skeletal muscles. We provide evidences that impaired mitochondrial and metabolic functions found in the lungs and the right ventricle are also present in skeletal muscles of patients. Key message: • Proteomic and metabolic analysis show abnormal oxidative metabolism in PAH skeletal muscle. • EM of PAH patients reveals abnormal mitochondrial structure and distribution. • Abnormal mitochondrial health and function contribute to exercise impairments of PAH. • PAH may be considered a vascular affliction of heart and lungs with major impact on peripheral muscles. Springer-Verlag Berlin Heidelberg, 2014 Pulmonary hypertension nationallicence Skeletal muscle nationallicence Mitochondrial metabolism nationallicence Proteomic nationallicence Exercise capacity nationallicence Malenfant Simon Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut Potus François Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut Fournier Frédéric Proteomics Center and Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, QC, Canada aut Breuils-Bonnet Sandra Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut Pflieger Aude Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut Bourassa Sylvie Proteomics Center and Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, QC, Canada aut Tremblay Ève Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut Nehmé Benjamin Proteomics Center and Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, QC, Canada aut Droit Arnaud Proteomics Center and Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, QC, Canada aut Bonnet Sébastien Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut Provencher Steeve Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/5(2015-05-01), 573-584 0946-2716 93:5<573 2015 93 109 https://doi.org/10.1007/s00109-014-1244-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-014-1244-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Malenfant Simon Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut NATIONALLICENCE 700 1- Potus François Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut NATIONALLICENCE 700 1- Fournier Frédéric Proteomics Center and Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, QC, Canada aut NATIONALLICENCE 700 1- Breuils-Bonnet Sandra Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut NATIONALLICENCE 700 1- Pflieger Aude Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut NATIONALLICENCE 700 1- Bourassa Sylvie Proteomics Center and Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, QC, Canada aut NATIONALLICENCE 700 1- Tremblay Ève Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut NATIONALLICENCE 700 1- Nehmé Benjamin Proteomics Center and Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, QC, Canada aut NATIONALLICENCE 700 1- Droit Arnaud Proteomics Center and Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, QC, Canada aut NATIONALLICENCE 700 1- Bonnet Sébastien Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut NATIONALLICENCE 700 1- Provencher Steeve Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, QC, Canada aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/5(2015-05-01), 573-584 0946-2716 93:5<573 2015 93 109