ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction

• Published in: Journal of applied physiology (1985) Vol. 101; no. 2; pp. 385 - 391
• Main Authors: Zoll, Joffrey, Monassier, Laurent, Garnier, Anne, N'Guessan, Benoit, Mettauer, Bertrand, Veksler, Vladimir, Piquard, Francois, Ventura-Clapier, Renee, Geny, Bernard
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Am Physiological Soc 01.08.2006; American Physiological Society
• Subjects: ACE inhibitors; Anatomy & physiology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Biological and medical sciences; Blood pressure; Blood Pressure - physiology; Cardiology and cardiovascular system; Fundamental and applied biological sciences. Psychology; GA-Binding Protein Transcription Factor - genetics; Heart attacks; Human health and pathology; Life Sciences; Male; Metabolism; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - physiology; Mitochondrial DNA; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiopathology; Musculoskeletal system; Myocardial infarction; Myocardial Infarction - physiopathology; Oxygen consumption; Oxygen Consumption - physiology; Peptidyl-Dipeptidase A - physiology; Perindopril - pharmacology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Wistar; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; Transcription Factors - genetics; Ventricular Dysfunction, Left - physiopathology; Myocardial infarction; Enzyme; Cardiovascular disease; angiotensin-converting enzyme inhibition; Striated muscle; Myocardial disease; Peptidases; Vertebrata; Mitochondria; rehabilitation; Mammalia; Peptidyl-dipeptidase A; Dysfunction; Heart disease; Hydrolases; Peptidyl-dipeptidases; Inhibition
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.01486.2005

1 Service de Physiologie et d'Explorations Fonctionnelles, EA 3072 and 2 Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, INSERM U715, Hôpitaux Universitaires de Strasbourg, Faculté de Médecine, Strasbourg; and 3 Cardiologie Cellulaire et Moléculaire U769 INSERM, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France Submitted 28 November 2005 ; accepted in final form 31 March 2006 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-1 , NRF-2 , 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-1 (–54%), NRF-2 (–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-1 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. rehabilitation; mitochondria; angiotensin-converting enzyme inhibition Address for reprint requests and other correspondence: J. Zoll, Département de Physiologie, Faculté de Médecine, 11, rue Humann, 67000 Strasbourg, France (e-mail: Zolljoffrey{at}yahoo.com )