Changes in the cardiac oxidative metabolism induced by PGC-1{alpha}: Response of different physical training protocols in infarction-induced rats Ricardo A. Pinho ⁎, Cleber A. Pinho, Camila B. Tromm, Bruna G. Pozzi, Daniela R. Souza, Luciano A. Silva, Talita Tuon, Claudio T. Souza Laboratory of Physiology and Biochemistry of Exercise, Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, Criciúma, Santa Catarina, Brazil article info Article history: Received 8 April 2013 Received in revised form 7 May 2013 Accepted 30 June 2013 Available online 21 July 2013 Keywords: Exercise Acute myocardium infarction Metabolism PGC-1α Exercise has been discussed as a mechanism of preconditioning and cardioprotection in several studies, and many of them have been focused on indexes of ischemic injury, oxidative stress, and hypertrophy besides cell death [1]. Previous reports of our group indicate that physical exercise may modulate the oxidative parameters in a healthy myocardium [2] and post-infarction [3,4]. The proposed mechanisms to explain the cardioprotective effects of exercise include alterations in coronary circulation, reduced oxidative stress, and functional changes at the protein level of oxidative metabolism. Due to the high energy demand of the heart, particularly after to Acute Myocardium Infarction (AMI), a decline in mitochondrial function occurs [5] and probably, this is the major metabolic alteration of post-infarction. Among the mitochondrial proteins, the mitochondrial transcriptional regulator peroxisome-proliferator-activated receptor gamma coactivator-1α (PGC-1α) plays a key role in regulating genes involved in the myocardial fuel metabolism [5] and cardiac function, and it is the major regulator of mitochondrial biogenesis induced by exercise [6]. Although experi- mental data in skeletal muscle have shown the mechanisms involved in exercise-induced mitochondrial biogenesis, less information is available about the heart. It was believed that physical exercise can contribute to the mitochondrial regulation and can be crucial in the recovery of patients with myocardial infarction. However, controversy remains around the best model of exercise (type, frequency intensity, and duration of exercise) that can promote significant changes on the cardiac oxidative metabolism post-infarction. Interval training or intermittent training (IT) has been proposed to be more effective than the sessions of continuous exercise for improving exercise capacity. In contrast with the continuous training (CT) protocol, the patient is asked to alternate short bouts of moderate–high intensity exercise, with a longer recovery phase, performed at low or no workload [7]. Thus, in this letter the focus is exclusively on the ability of exercise to improve the oxidative metabolism by increasing the content of PGC-1α and to confer protection to the heart. Thirty-six 2-month-old male Wistar rats were used and all procedures were conducted and approved by the local ethics committee. The size sample was determined based on results of previous studies in animals trained with AMI [4,8] and was considered a significance level of 5% and power of 80%. After 30 days of AMI, according to a procedure previously described and adapted by Tavares and colleagues [8], the animals (infarcted and sham) were submitted to a CT or to an IT protocol in water, five days a week for six weeks. The CT was conducted for a 60- minute period, while the IT comprised of 10 series lasting for 5 min that were performed at 1-minute intervals along a 60-minute period as described in a previous study [4]. Forty-eight hours after the last training session, all animals were killed by decapitation, and left ventricle (LV) portion was surgically removed and homogenized immediately in extraction buffer for the analysis of PGC-1α, carnitine palmitoyltrans- ferase (CPT1), phosphofructokinase (PFK), cytochrome c oxidase (cit c), and succinate dehydrogenase (SDH) by western blotting assay or specific buffer for the analyses of electron transport chain (ETC) complexes. The blot data were shown as representative bands and were expressed as number of alterations when compared to control, and ETC results were shown as nmol/min/mg protein. A p value less than .05 was considered to be significant. This study investigated two exercise protocols on ventricular oxidative parameters in rats post-infarction, and the results showed that significant improvement occurred in the myocardium oxidative status in rats challenged with AMI after different training routines. Unlike skeletal muscle, training adaptations to the heart following swim pool protocols were not normally characterized by improved oxidative metabolism, and low-intensity exercise, but our results showed that after AMI, both training models increased significantly complex I and IV (Table 1), PGC1-α (Fig. 1a), PFK (Fig. 1b), cytochrome c oxidase (Fig. 1e) levels, and only CT groups increased CPT1 level (Fig. 1c) while the SDH levels (Fig. 1d) were not altered by training in infracted animals. The effect of both exercise models observed on PGC-1α may be the factor that is responsible for the results obtained from this study, because, according to Rowe et al. [5], more than 70% of the subunits of respiratory chain complexes are induced by PGC-1α, enzymes of the Krebs cycle, and all key enzymes in fatty acid β-oxidation, including carnitine palmitoyltransferase system, and enzymes that mediate metabolism of glycolysis as PFK. The PGC-1α is enriched in tissues with high oxidative capacity and are rapidly induced under conditions with increased energy demand, as exercise, however in heart failure, the efficiency of ATP production declines [9] and the main reason is due to the decline in the expression of numerous nuclear genes encoding for mitochondrial proteins possibly by the dysregulation of PGC-1 coactivators [10,11]. Li and colleagues suggest in their recent work [6] that endurance training induces mitochondrial biogenesis in mouse skeletal muscle but not in the normal LV, probably due the absence of SIRT1-dependent PGC-1α deacetylation in LV of male IL-6 -/- (IL-6 KO) mice. On the other hand, in the infracted heart, the physical training seems to mediate the oxidative alterations in LV possibly due to the needs of the heart to increase ATP synthesis that is preceded by a large increased expression of PGC-1α. The effects obtained by both the exercise models (CT-treadmill and IT-swimming) are possibly associated with the maintenance of homeostatic energy metabolism via mitochondrial biogenesis in the heart that is promoted by endurance or aerobic training. These models of exercise induce mitochondrial biogenesis by activating PGC-1α [11], possibly as the exercise triggers a fine-tuned metabolic response and this, according to Cantó and colleagues [12] results in several post- ⁎ Corresponding author at: Laboratory of Physiology and Biochemistry of Exercise, Postgraduate Program in Health Sciences, Health Sciences Unit, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105 Bairro Universitário, 88806-000, Criciúma, SC, Brazil. Tel./fax: +55 48 3431 2773. E-mail address: pinho@unesc.net (R.A. Pinho). 4560 Letters to the Editor