Journal of Applied Physiology AJP: Heart and Circulatory Physiology
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J Appl Physiol (April 13, 2006). doi:10.1152/japplphysiol.01486.2005
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Submitted on November 23, 2005
Accepted on March 31, 2006

ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction

Joffrey Zoll1*, Laurent Monassier1, Anne Garnier1, Benoit N'Guessan1, Bertrand Mettauer1, Vladimir Veksler1, Francois Piquard1, Renee Ventura-Clapier1, and Bernard Geny1

1 Physiologie, Faculte de Medecine, Strasbourg, France; Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, INSERM U715, Strasbourg, France; Cardiologie Cellulaire et Moleculaire, INSERM U769, Paris, France

* To whom correspondence should be addressed. E-mail: zolljoffrey{at}yahoo.com.

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, 2mg/kg/day given seven days after MI) were studied one and four months 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{alpha}, NRF2{alpha} 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 PE group after 1 and 4 months, while systemic blood pressure was reduced by 16% only in the MI group after 4 months. 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{alpha} (-54%), NRF2{alpha} (-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{alpha} 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.




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