title: ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction.
abstract: Heart failure is associated with alterations in cardiac and skeletal muscle energy metabolism resulting in a generalized myopathy. We investigated the molecular and cellular effects of angiotensin-converting enzyme inhibition (ACEi) on skeletal muscle metabolism in infarcted animals. Myocardial infarction (MI) was obtained by left descending coronary artery ligation. Sham, MI, and MI-treated rats (perindopril, 2 mg.kg(-1).day(-1) given 7 days after MI) were studied 1 and 4 mo after surgery. Oxygen consumption of white gastrocnemius (Gas) muscle was studied in saponin-permeabilized fibers, using the main substrates of mitochondrial respiration. mRNA expression of nuclear factors (PGC-1alpha, NRF-2alpha, and mtTFA), involved in the transcription of mitochondrial proteins, and of MCIP1, a marker of calcineurin activation, were also determined. Echocardiographic left ventricular fractional shortening was reduced in both MI and perindopril group after 1 and 4 mo, whereas systemic blood pressure was reduced by 16% only in the MI group after 4 mo. The capacity of Gas to oxidize glutamate-malate, glycerol-triphosphate, or pyruvate (-30%, P < 0.01; -32%, P < 0.05; -33%, P < 0.01, respectively), was greatly decreased. Furthermore, PGC-1alpha (-54%), NRF-2alpha (-45%), and MCIP1 (-84%) gene expression were significantly downregulated. ACEi improved survival, left ventricular function, and blood pressure. Perindopril protected also totally the Gas mitochondrial function and preserved the mRNAs concentration of the mitochondrial transcriptional factors. Moreover, PGC-1alpha correlated with Gas oxidative capacity (r = 0.48), mitochondrial cytochrome-c oxidase (r = 0.65), citrate synthase (r = 0.45) activities, and MCIP1 expression (r = 0.44). Thus ACEi totally prevented MI-induced alterations of skeletal muscle mitochondrial function and protein expression, halting the development of this metabolic myopathy.
authors.affiliation: Département de Physiologie, Faculté de Médecine, 11, rue Humann, 67000 Strasbourg, France. Zolljoffrey@yahoo.com
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
authors.forename: Laurent
authors.initials: L
authors.lastname: Monassier
authors.forename: Anne
authors.initials: A
authors.lastname: Garnier
authors.forename: Benoit
authors.initials: B
authors.lastname: N'Guessan
authors.forename: Bertrand
authors.initials: B
authors.lastname: Mettauer
authors.forename: Vladimir
authors.initials: V
authors.lastname: Veksler
authors.forename: François
authors.initials: F
authors.lastname: Piquard
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.forename: Bernard
authors.initials: B
authors.lastname: Geny
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology*; D009203:Myocardial Infarction / Q000503:physiopathology*; D010101:Oxygen Consumption / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D020913:Perindopril / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D051268:GA-Binding Protein Transcription Factor; C495649:Gabpa protein, rat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C489030:Tfam protein, rat; D014157:Transcription Factors; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril