title: Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension.
abstract: 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.
  
  
  CONCLUSIONS
  • 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.
authors.affiliation: Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, Québec City, QC, G1V 4G5, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Malenfant
authors.forename: François
authors.initials: F
authors.lastname: Potus
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fournier
authors.forename: Sandra
authors.initials: S
authors.lastname: Breuils-Bonnet
authors.forename: Aude
authors.initials: A
authors.lastname: Pflieger
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bourassa
authors.forename: Ève
authors.initials: È
authors.lastname: Tremblay
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nehmé
authors.forename: Arnaud
authors.initials: A
authors.lastname: Droit
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
mesh_terms: D000328:Adult; D001706:Biopsy; D016000:Cluster Analysis; D017079:Exercise Tolerance; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020543:Proteome; D040901:Proteomics / Q000379:methods
chemical_list: D020543:Proteome