title: Skeletal muscle mitochondrial dysfunction precedes right ventricular impairment in experimental pulmonary hypertension.
abstract: We assessed the time courses of mitochondrial biogenesis factors and respiration in the right ventricle (RV), gastrocnemius (GAS), and left ventricle (LV) in a model of pulmonary-hypertensive rats. Monocrotaline (MT) rats and controls were studied 2 and 4 weeks after injection. Compensated and decompensated heart failure stages were defined according to obvious congestion signs. mRNA expression and protein level of peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α), citrate synthase (CS) mRNA and activity, and mitochondrial respiration were investigated. In addition, mRNA expression of sirtuin1, nuclear respiratory factor 1, and mitochondrial transcription factor A were studied. As early as 2 weeks, the expression of the studied genes was decreased in the MT GAS. At 4 weeks, the MT GAS and MT RV showed decreased mRNA levels whatever the stage of disease, but PGC-1α protein and CS activity were significantly reduced only at the decompensated stage. The functional result was a significant fall in mitochondrial respiration at the decompensated stage in the RV and GAS. The mRNA expression and mitochondrial respiration were not significantly modified in the MT LV. MT rats demonstrated an early decrease in expression of genes involved in mitochondrial biogenesis in a skeletal muscle, whereas reduced protein expression, and the resulting mitochondrial respiratory dysfunction appeared only in rats with overt heart failure, in the GAS and RV. Dissociations between mRNA and protein levels at the compensated stage deserve to be further studied.
authors.affiliation: Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Centre Hospitalier Universitaire Strasbourg, Nouvel Hôpital Civil, 1, Place de l'Hôpital, 67091 Strasbourg, France. Irina.Enache@chru-strasbourg.fr
authors.forename: Irina
authors.initials: I
authors.lastname: Enache
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Charles
authors.forename: Jamal
authors.initials: J
authors.lastname: Bouitbir
authors.forename: Fabrice
authors.initials: F
authors.lastname: Favret
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Monique
authors.initials: M
authors.lastname: Oswald-Mammosser
authors.forename: Bernard
authors.initials: B
authors.lastname: Geny
authors.forename: Anne
authors.initials: A
authors.lastname: Charloux
mesh_terms: D000818:Animals; D002950:Citrate (si)-Synthase / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D006352:Heart Ventricles / Q000201:enzymology / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism*; D016686:Monocrotaline; D018482:Muscle, Skeletal / Q000473:pathology; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*
chemical_list: D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; C489030:Tfam protein, rat; D014157:Transcription Factors; D016686:Monocrotaline; D002950:Citrate (si)-Synthase; C488368:Sirt1 protein, rat; D056564:Sirtuin 1