Exercise-trained Animals Research Articles

Aerobic exercise and resistance exercise alleviate skeletal muscle atrophy through IGF-1/IGF-1R-PI3K/Akt pathway in mice with myocardial infarction.

Myocardial infarction (MI)-induced heart failure (HF) is commonly accompanied with profound effects on skeletal muscle. With the process of MI-induced HF, perturbations in skeletal muscle contribute to muscle atrophy. Exercise is viewed as a feasible strategy to prevent muscle atrophy. The aims of this study were to investigate whether exercise could alleviate MI-induced skeletal muscle atrophy via insulin-like growth factor 1 (IGF-1) pathway in mice. Male C57/BL6 mice were used to establish the MI model and were divided into three groups: sedentary MI group (MI), MI with aerobic exercise group, and MI with resistance exercise group; sham-operated group was used as control. Exercise-trained animals were subjected to 4 wk of aerobic exercise (AE) or resistance exercise (RE). Cardiac function, muscle weight, myofiber size, levels of IGF-1 signaling and proteins related to myogenesis, protein synthesis, and degradation and apoptosis in gastrocnemius muscle were detected. H2O2-treated C2C12 cells were intervened with recombinant human IGF-1, IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, and PI3K inhibitor LY294002 to explore the mechanism. Exercises upregulated the IGF-1/IGF-1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling; increased the expressions of Pax7, myogenic regulatory factors (MRFs), and protein synthesis; and reduced protein degradation and cell apoptosis in MI mice. In vitro, IGF-1 upregulated the levels of Pax7, MRFs, mTOR, and P70S6K; reduced MuRF1 and MAFbx; and inhibited cell apoptosis via IGF-1R-PI3K/Akt pathway. AE and RE, safely and effectively, alleviate skeletal muscle atrophy by regulating the levels of myogenesis, protein degradation, and cell apoptosis in mice with MI via activating IGF-1/IGF-1R-PI3K/Akt signaling pathway.

Oxidative Stress, Inflammation, and Activators of Mitochondrial Biogenesis: Tempol Targets in the Diaphragm Muscle of Exercise Trained-mdx Mice.

The mdx mouse phenotype aggravated by chronic exercise on a treadmill makes this murine model more reliable for the study of muscular dystrophy. Thus, to better assess the Tempol effect on dystrophic pathways, the analyses in this study were performed in the blood samples and diaphragm muscle from treadmill trained adult (7–11-weeks old) mdx animals. The mdx mice were divided into three groups: mdxSed, sedentary controls (n = 28); mdxEx, exercise-trained animals (n = 28); and mdxEx+T, exercise-trained animals with the Tempol treatment (n = 28). The results demonstrated that the Tempol treatment promoted muscle strength gain, prevented muscle damage, reduced the inflammatory process, oxidative stress, and angiogenesis regulator, and up regulated the activators of mitochondrial biogenesis. The main new findings of this study are that Tempol reduced the NF-κB and increased the PGC1-α and PPARδ levels in the exercise-trained-mdx mice, which are probably related to the ability of this antioxidant to scavenge excessive ROS. These results reinforce the use of Tempol as a potential therapeutic strategy in DMD.

Intermittent Fasting Attenuates Exercise Training-Induced Cardiac Remodeling.

ResumoFundamento A influência de intervenções não farmacológicas como restrição calórica e exercício físico sobre a saúde e prevenção de enfermidades cardíacas tem sido documentada em estudos clínicos e experimentais.Objetivo Analisar a influência da combinação entre dieta intermitente e exercício físico sobre a capacidade funcional, metabolismo glicêmico e remodelação cardíaca.Métodos Foram utilizados 60 ratos Wistar machos distribuídos em quatro grupos: Controle (C), Exercício Físico (EF), Dieta Intermitente (DI) e Exercício Físico e Dieta Intermitente (EDI). Durante 12 semanas, enquanto C e EF foram tratados diariamente com dieta comercial padrão ad libitum, DI e EDI receberam dieta similar em dias alternados com dias de jejum. Os grupos EF e EDI foram submetidos a protocolo de corrida em esteira rolante. Posteriormente, foram analisadas capacidade funcional, comportamento nutricional e metabolismo glicêmico. Além da morfologia do coração, a expressão proteica das proteínas extracellular signal-regulated kinase (ERK) e c-Jun N-terminal kinase (JNK) no coração foi avaliada por Western-blot. A análise dos resultados foi feita por meio de Two-Way ANOVA e teste de Student-Newman-Keuls. O nível de significância considerado foi de 5%.Resultados O exercício físico aumentou a capacidade funcional nos grupos EF e EDI, e acarretou fibrose cardíaca. A combinação entre dieta intermitente e exercício físico resultou em menor área sob a curva de glicemia e menores medidas de área e interstício cardíaco no EDI em relação ao EF. A expressão de proteínas ERK e JNK foi similar entre os grupos (p>0,05).Conclusões Dieta intermitente se associa com melhor tolerância glicêmica e atenua o processo de remodelação cardíaca decorrente do exercício físico. (Arq Bras Cardiol. 2020; 115(2):184-193)

Exercise Training Results in Lower Amyloid Plaque Load and Greater Cognitive Function in an Intensity Dependent Manner in the Tg2576 Mouse Model of Alzheimer's Disease.

Three months of exercise training (ET) decreases soluble Aβ40 and Aβ42 levels in an intensity dependent manner early in life in Tg2576 mice (Moore et al., 2016). Here, we examined the effects of 12 months of low- and high- intensity exercise training on cognitive function and amyloid plaque load in the cortex and hippocampus of 15-month-old Tg2576 mice. Low- (LOW) and high- (HI) intensity ET animals ran at speeds of 15 m/min on a level treadmill and 32 m/min at a 10% grade, respectively, for 60 min/day, five days/week, from 3 to 15 months of age. Sedentary mice (SED) were placed on a level, non-moving, treadmill for the same duration. ET mice demonstrated a significantly lower amyloid plaque load in the cortex and hippocampus that was intensity dependent. Improvement in cognitive function, assessed by Morris Water Maze and Novel Object Recognition tests, was greater in the HI group compared to the LOW and SED groups. LOW mice performed better in the initial latency to the platform location during the probe trial of the Morris Water Maze (MWM) test than SED, but not in any other aspect of MWM or the Novel Object Recognition test. The results of this study indicate that exercise training decreases amyloid plaque load in an intensity dependent manner and that high-intensity exercise training improves cognitive function relative to SED mice, but the intensity of the LOW group was below the threshold to demonstrate robust improvement in cognitive function in Tg2576 mice.

Exercise Training Prevents Doxorubicin-induced Mitochondrial Dysfunction of the Liver.

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of a broad spectrum of cancers. However, clinical use of DOX is limited by irreversible and dose-dependent hepatotoxicity. The liver is the primary organ responsible for the clearance of antineoplastic agents, and evidence indicates that hepatotoxicity occurs as a result of impaired mitochondrial efficiency during DOX metabolism. In this regard, exercise training is sufficient to improve mitochondrial function and protect against DOX-induced cytotoxicity. Therefore, the purpose of this study was to determine whether short-term exercise preconditioning is sufficient to protect against DOX-induced liver mitochondrionopathy. Female Sprague-Dawley rats (4-6 months old) were randomly assigned to one of four groups: 1) sedentary, treated with saline; 2) sedentary, treated with DOX; 3) exercise trained, treated with saline; and 4) exercise trained, treated with DOX. Exercise-trained animals underwent 5 d of treadmill running habituation followed by 10 d of running for 60 min·d (30 m·min; 0% grade). After the last training bout, exercise-trained and sedentary animals were injected with either DOX (20 mg·kg i.p.) or saline. Two days after drug treatment, the liver was removed and mitochondria were isolated. DOX treatment induced mitochondrial dysfunction of the liver in sedentary animals because of alterations in mitochondrial oxidative capacity, biogenesis, degradation, and protein acetylation. Furthermore, exercise preconditioning protected against DOX-mediated liver mitochondrionopathy, which was associated with the maintenance of mitochondrial oxidative capacity and protein acetylation. These findings demonstrate that endurance exercise training protects against DOX-induced liver mitochondrial dysfunction, which was attributed to modifications in organelle oxidative capacity and mitochondrial protein acetylation.

PO-157 Effect of exercise training on mitochondrial content after ischemia in the cerebral cortex of rat

Objective To investigate the effect exercise training on mitochondrial content after ischemia in the cerebral cortex, and the balance between mitochondrial biogenesis and mitophagy in this process.
 Methods Male Sprague-Dawley rats were randomly divided into 4 groups (n = 8): Sham operation group (SH), Sham operation and training group (ST), ischemia control group (IC), ischemia and training group (IT). The ischemia model rats were subjected to right middle cerebral artery occlusion which was produced by the intraluminal suture technique. The rats in the sham group underwent the same procedure except for the occlusion of the middle cerebral artery. Fourteen days after operation, the exercise training animals were exercised on a motor-driven rodent treadmill at a speed of 10 m/min, 5% grade for 30 min/day, 5 days/week for 4 weeks. Mitochondrial membrane potent was determined using JC-1. ATP synthesis capacity was determined using a bioluminescence technique. The protein expression of VDAC-1, COXIV, PGC-1α, Tfam, PINK1 and Parkin in cerebral cortex were detected by Western-blotting.
 Results Compared with SH group, ischemia attenuated mitochondrial membrane potential, ATP synthesis capacity, and the expression of VDAC-1, COXIV, PGC-1α, Tfam in cerebral cortex (P<0.05~0.01). Furthermore, ischemia increased the expression of PINK1 and Parkin (P<0.05~0.01). Compared with IC group, exercise training elevated mitochondrial membrane potential, ATP synthesis capacity, and the expression of VDAC-1, COXIV, PGC-1α, Tfam, PINK1, Parkin in IT group (P<0.05~0.01).
 Conclusions A combination of reduced mitochondrial biogenesis and increased mitophage seems to be responsible for the decrease in mitochondrial content after ischemia. Exercise training after ischemia elevated mitochondrial content and function in cerebral cortex, which may be mediated by appropriately increase and co-regulation of mitochondrial biogenesis and mitophage.

Interval exercise training increases LIF expression and prevents myocardial infarction-induced skeletal muscle atrophy in rats

AimsMyocardial infarction (MI) is commonly associated with body weight loss and skeletal muscle atrophy. Studies have shown that exercise training could give beneficial effects on skeletal muscle growth. Leukemia inhibitory factor (LIF) is a key regulator of muscle growth and regeneration. The aim of this study was to investigate the effects of interval exercise training (IET) on the expression of LIF and the MI-induced skeletal muscle atrophy. Main methodsMale Sprague-Dawley rats were used to establish the MI model by ligation of the left anterior descending coronary artery. Infarcted Rats were divided into two groups: sedentary MI group (MI) and MI with interval exercise group (ME), and compared to sham-operated group (Sham). Exercise-trained animals were subjected to eight weeks of IET. Cardiac function, collagen volume fraction, expression of LIF and its receptor LIFR, myofiber size, apoptosis and proliferation in gastrocnemius muscle were analyzed. Key findingsIET increased heart functional performance and was accompanied with reversing cardiac pathological remodeling. Moreover, IET increased the expression of LIF and LIFR, activated signal transducer and activator of transcription (STAT3), reduced apoptosis and promoted proliferation in gastrocnemius muscle compared with the MI group. In addition, there was a significant negative correlation between skeletal muscle atrophy and LIF expression which was stimulated by IET in infarcted rats. SignificanceIET reverses MI-induced cardiac dysfunction and skeletal muscle atrophy. In addition, IET up-regulates the expression of muscle LIF/LIFR and activates the STAT3.

Abstract 458: Moderate Exercise Training Attenuates Isoproterenol-Induced Myocardial Injury by Activating Nrf2-Signaling

Background: Nuclear erythroid-2 like factor-2 (Nrf2), a master transcriptional regulator of antioxidants, is critical to maintain cellular redox homeostasis. We recently reported that exercise training activates Nrf2/antioxidant signaling in the heart. Isoproterenol (ISO) mediated structural, and functional changes in the heart involve oxidative stress. Here, we tested a hypothesis that moderate exercise training will protect the myocardium from isoproterenol-induced injury by augmenting Nrf2-dependent antioxidant defense system. Methods: Age- and sex-matched WT (C57/BL6) mice (6-8 months old) were subjected to moderate exercise training (MET) on a treadmill for 6 weeks (60 min/day; 10m/min; 0% grade). Randomly assigned untrained (UNT) and trained (MET) animals were intraperitoneally injected (at the start of 6 th week) with 50 mg of isoproterenol/kg.bw./day for 7 consecutive days. MET was continued during ISO administration and the animals (UNT + PBS, UNT + ISO; MET + ISO) underwent echocardiography analysis. Heart tissues were collected for histopathology, Nrf2-ARE promoter binding assay (Active-motif TransAM kit), antioxidant gene (qPCR) and protein (Immunoblotting) levels, and glutathione redox status. Results: ISO administration significantly reduced the Nrf2 promoter activity (p<0.05) and downregulated the expression of cardiac antioxidant genes ( Gclc, Nqo1, Cat, Gsr and Gst-μ ) in UNT mice. Further, increased oxidative stress with severe myocardial injury was evident in UNT+ISO when compared to UNT mice receiving PBS under basal condition. Interestingly, MET stabilized the Nrf2-promoter activity and promoted the expression of Nrf2-dependent antioxidant genes and proteins animals receiving ISO, and thereby attenuated the oxidative stress-induced myocardial damage. Echocardiography analysis showed impaired systolic/diastolic ventricular volumes coupled with decreased cardiac output in UNT+ISO mice, but this was normalized in exercise-trained animals. Conclusion: Thus moderate exercise training conferred protection against ISO-induced myocardial injury by augmentation of Nrf2-antioxidant signaling and attenuation of redox perturbations.

Exercise training activates neuregulin 1/ErbB signaling and promotes cardiac repair in a rat myocardial infarction model

AimsExercise training (ET) has a cardioprotective effect and can alter the molecular response to myocardial infarction (MI). The Neuregulin 1 (NRG1)/ErbB signaling plays a critical role in cardiac repair and regeneration in the failing heart. We sought to investigate whether ET following MI could activate the NRG1/ErbB signaling and promote cardiac repair and regeneration. Main methodsMale Sprague-Dawley rats were used to establish the MI model. Exercise-trained animals were subjected to four weeks of exercise (16m/min, 50min/d, 5d/wk) following the surgery. AG1478 was used as an inhibitor of ErbB (1mg/kg body weight, administered i.v. every other day during the process of training). NRG1/ErbB signaling activation, cardiomyocyte (CM) proliferation and apoptosis were evaluated. Key findingsIn the exercise-trained rats, NRG1 expression was up-regulated and ErbB/PI3K/Akt signaling was activated compared with the MI group. In addition, ET preserved heart function accompanied with increased numbers of BrdU+ CMs, PCNA+ CMs and c-kit+ cells, and reduced apoptosis level in the MI rats. In contrast, blocking ErbB signaling by AG1478 attenuated the ET-induced cardiac repair and regeneration. SignificanceET up-regulates NRG1 expression and activates ErbB2, ErbB4 and PI3K/Akt signal transduction to promote cardiac repair through endogenous regeneration. Activation of ErbB may be an underlying mechanism for the ET-induced cardiac repair and regeneration following MI.

Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptor.

Recent data suggest that exercise training (ExT) is beneficial in chronic heart failure (CHF) because it improves autonomic and peripheral vascular function. In this study, we hypothesized that ExT in the CHF state ameliorates the renal vasoconstrictor responses to hypoxia and that this beneficial effect is mediated by changes in α1-adrenergic receptor activation. CHF was induced in rabbits. Renal blood flow (RBF) and renal vascular conductance (RVC) responses to 6 min of 5% isocapnic hypoxia were assessed in the conscious state in sedentary (SED) and ExT rabbits with CHF with and without α1-adrenergic blockade. α1-adrenergic receptor expression in the kidney cortex was also evaluated. A significant decline in baseline RBF and RVC and an exaggerated renal vasoconstriction during acute hypoxia occurred in CHF-SED rabbits compared with the prepaced state (P < 0.05). ExT diminished the decline in baseline RBF and RVC and restored changes during hypoxia to those of the prepaced state. α1-adrenergic blockade partially prevented the decline in RBF and RVC in CHF-SED rabbits and eliminated the differences in hypoxia responses between SED and ExT animals. Unilateral renal denervation (DnX) blocked the hypoxia-induced renal vasoconstriction in CHF-SED rabbits. α1-adrenergic protein in the renal cortex of animals with CHF was increased in SED animals and normalized after ExT. These data provide evidence that the acute decline in RBF during hypoxia is caused entirely by the renal nerves but is only partially mediated by α1-adrenergic receptors. Nonetheless, α1-adrenergic receptors play an important role in the beneficial effects of ExT in the kidney.

A spectrum of exercise training reduces soluble Aβ in a dose-dependent manner in a mouse model of Alzheimer's disease

Physical activity has long been hypothesized to influence the risk and pathology of Alzheimer's disease. However, the amount of physical activity necessary for these benefits is unclear. We examined the effects of three months of low and high intensity exercise training on soluble Aβ40 and Aβ42 levels in extracellular enriched fractions from the cortex and hippocampus of young Tg2576 mice. Low (LOW) and high (HI) intensity exercise training animals ran at speeds of 15m/min on a level treadmill and 32m/min at a 10% grade, respectively for 60min per day, five days per week, from three to six months of age. Sedentary mice (SED) were placed on a level, non-moving, treadmill for the same duration. Soleus muscle citrate synthase activity increased by 39% in the LOW group relative to SED, and by 71% in the HI group relative to LOW, indicating an exercise training effect in these mice. Soluble Aβ40 concentrations decreased significantly in an exercise training dose-dependent manner in the cortex. In the hippocampus, concentrations were decreased significantly in the HI group relative to LOW and SED. Soluble Aβ42 levels also decreased significantly in an exercise training dose-dependent manner in both the cortex and hippocampus. Five proteins involved in Aβ clearance (neprilysin, IDE, MMP9, LRP1 and HSP70) were elevated by exercise training with its intensity playing a role in each case. Our data demonstrate that exercise training reduces extracellular soluble Aβ in the brains of Tg2576 mice in a dose-dependent manner through an up-regulation of Aβ clearance.

Exercise Enhances the Behavioral Responses to Acute Stress in an Animal Model of PTSD.

This study examined the effects of endurance exercise on the behavioral response to stress and patterns of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and δ-opioid receptor (phospho-DOR) expression in the hippocampus. Animals ran on a treadmill at 15 m·min, 5 min·d gradually increasing to 20 min·d, 5 d·wk for 6 wk. After training, one group of animals was exposed to a predator scent stress (PSS) protocol for 10 min. Outcome measurements included behavior in an elevated plus-maze (EPM) and acoustic startle response (ASR) 7 d after exposure to stress. Immunohistochemical technique was used to detect the expression of the BDNF, NPY, and phospho-DOR in the hippocampus 8 d after exposure. Sedentary animals exposed to PSS were observed to have a greater incidence of extreme behavior responses including higher anxiety, less total activity in the EPM, and greater amplitude in the ASR than unexposed and/or trained animals. Exercise-trained animals exposed to PSS developed a resiliency to the stress, reflected by significantly greater total activity in the EPM, reduced anxiety, and reduced ASR compared to the sedentary, exposed animals. Exercise in the absence of stress significantly elevated the expression of BDNF and phospho-DOR, whereas exposure to PSS resulted in a significant decline in the expression of NPY, BDNF, and phospho-DOR. Trained animals that were exposed maintained expression of BDNF, NPY, and phospho-DOR in most subregions of the hippocampus. Results indicated that endurance training provided a mechanism to promote resilience and/or recovery from stress. In addition, exercise increased expression of BDNF, NPY, and DOR signaling in the hippocampus that was associated with the greater resiliency seen in the trained animals.

Role of intrinsic aerobic capacity and ventilator-induced diaphragm dysfunction.

Prolonged mechanical ventilation (MV) leads to rapid diaphragmatic atrophy and contractile dysfunction, which is collectively termed "ventilator-induced diaphragm dysfunction" (VIDD). Interestingly, endurance exercise training prior to MV has been shown to protect against VIDD. Further, recent evidence reveals that sedentary animals selectively bred to possess a high aerobic capacity possess a similar skeletal muscle phenotype to muscles from endurance trained animals. Therefore, we tested the hypothesis that animals with a high intrinsic aerobic capacity would naturally be afforded protection against VIDD. To this end, animals were selectively bred over 33 generations to create two divergent strains, differing in aerobic capacity: high-capacity runners (HCR) and low-capacity runners (LCR). Both groups of animals were subjected to 12 h of MV and compared with nonventilated control animals within the same strains. As expected, contrasted to LCR animals, the diaphragm muscle from the HCR animals contained higher levels of oxidative enzymes (e.g., citrate synthase) and antioxidant enzymes (e.g., superoxide dismutase and catalase). Nonetheless, compared with nonventilated controls, prolonged MV resulted in significant diaphragmatic atrophy and impaired diaphragm contractile function in both the HCR and LCR animals, and the magnitude of VIDD did not differ between strains. In conclusion, these data demonstrate that possession of a high intrinsic aerobic capacity alone does not afford protection against VIDD. Importantly, these results suggest that endurance exercise training differentially alters the diaphragm phenotype to resist VIDD. Interestingly, levels of heat shock protein 72 did not differ between strains, thus potentially representing an important area of difference between animals with intrinsically high aerobic capacity and exercise-trained animals.

Comparison of Nigella sativa- and Exercise-Induced Models of Cardiac Hypertrophy: Structural and Electrophysiological Features

Exercise training is employed as supplementary therapeutic intervention for heart failure, due to its ability to induce physiological cardiac hypertrophy. In parallel, supplementation with Nigella sativa (N. sativa) was found to enhance myocardial function and induce cardiac hypertrophy. In this study, we aim to compare the morphological and electrophysiological changes associated with these patterns of cardiac hypertrophy and the possible changes upon administration of N. sativa to exercise-trained animals. Fifty-six adult Wistar rats were divided into: control, Nigella-treated (N), exercise-trained (E), and Nigella-treated-exercise-trained (NE) rats. Daily 800mg/kg N. sativa was administered orally to N and NE. E and NE ran on treadmill, 2h/day. At the end of 8weeks ECG, body weight (BW), heart weight (HW), and left ventricular weight (LVW) were recorded. Hematoxylin and Eosin and periodic acid-Schiff sections were prepared to study the histology of left ventricles and to measure diameter of cardiomyocytes (Cdia). HW/BW, LVW/BW, and mean Cdia were significantly higher in all experimental animals compared to the controls. Histology showed normal cardiomyocytes with no fibrosis. ECG showed significantly lower heart rates, higher QRS amplitude, and ventricular specific potential in NE group compared to control group. Supplementation of N. sativa demonstrated a synergistic effect with exercise training as Nigella-exercise-induced cardiac hypertrophy had lower heart rate and well-matched electrical activity of the heart to its mass. Therefore, this model of cardiac hypertrophy might be introduced as a new therapeutic strategy for treatment for heart failure with superior advantages to exercise training.

Commentaries on Viewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?

Commentaries on Viewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?

Exercise training prior to myocardial infarction attenuates cardiac deterioration and cardiomyocyte dysfunction in rats

OBJECTIVES:The present study was performed to investigate 1) whether aerobic exercise training prior to myocardial infarction would prevent cardiac dysfunction and structural deterioration and 2) whether the potential cardiac benefits of aerobic exercise training would be associated with preserved morphological and contractile properties of cardiomyocytes in post-infarct remodeled myocardium.METHODS:Male Wistar rats underwent an aerobic exercise training protocol for eight weeks. The rats were then assigned to sham surgery (SHAM), sedentary lifestyle and myocardial infarction or exercise training and myocardial infarction groups and were evaluated 15 days after the surgery. Left ventricular tissue was analyzed histologically, and the contractile function of isolated myocytes was measured. Student's t-test was used to analyze infarct size and ventricular wall thickness, and the other parameters were analyzed by the Kruskal-Wallis test followed by Dunn's test or a one-way analysis of variance followed by Tukey's test (p<0.05).RESULTS:Myocardial infarctions in exercise-trained animals resulted in a smaller myocardial infarction extension, a thicker infarcted wall and less collagen accumulation as compared to myocardial infarctions in sedentary animals. Myocardial infarction-induced left ventricular dilation and cardiac dysfunction, as evaluated by +dP/dt and -dP/dt, were both prevented by previous aerobic exercise training. Moreover, aerobic exercise training preserved cardiac myocyte shortening, improved the maximum shortening and relengthening velocities in infarcted hearts and enhanced responsiveness to calcium.CONCLUSION:Previous aerobic exercise training attenuated the cardiac dysfunction and structural deterioration promoted by myocardial infarction, and such benefits were associated with preserved cardiomyocyte morphological and contractile properties.

Exercise-induced morphine insensitivity is accompanied with a decrease in specific G-protein subunits gene expression in rats

Numerous studies have shown a decreased analgesic potency of morphine in exercise trained animals. Since G-protein subunits have a critical role in opioid effects at the cellular level and the exact mechanism(s) of exercise-induced morphine insensitivity has not been fully clarified, the present study was designed to determine the changes in the levels of Gαi and Gβ proteins gene expression involved in this phenomenon. All experiments were carried out on male Wistar rats. Nociceptive thermal threshold was determined by the tail-flick method. Physical training was performed using treadmill apparatus. Semiquantitative RT-PCR and Western blot techniques were used to estimate Gai and Gβ mRNA and protein levels, respectively and normalized to an internal standard (β-actin).The antinociceptive effect of intrathecal morphine (5, 10 and 15μg) was significantly suppressed in trained rats. Following physical training, a significant decrease in the mRNA and protein levels of Gαi (P<0.001 and P<0.05 respectively) and Gβ (P<0.01 and P<0.001 respectively) were observed in the dorsal portion of the lumbar spinal cord.In conclusion, our results reveal that the expression patterns of the opioid receptor signaling elements change in exercise training animals. This may be, at least partly, responsible for exercise-induced morphine insensitivity.

Abstract 19552: Exercise-Induced Changes in Mechanotransduction Improve Myocardial Function in a Porcine Model of Chronic Occlusion

Introduction: Exercise training has been shown to improve cardiac dysfunction both in patients and animal models of coronary artery disease; however, the underlying cellular and molecular mechanisms have not been completely understood. Transmembrane integrins that connect the extracellular matrix (ECM) and intracellular cytoskeleton are important for mechanotransduction in cardiomyocytes. Hypothesis: The binding probability and adhesion force between integrins-ECM, and their subsequent signaling that is cell stiffness will be increased in the myocytes from exercise-trained animals when compared to the sedentary group. Methods: Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of adult female Yucatan pigs. Twenty-two weeks postoperatively, myocardium was isolated from non-occluded and collateral-dependent regions of sedentary and exercise trained (treadmill run; 5 days/wk for 14 wks) pigs. We used atomic force microscopy for measuring cell stiffness and adhesion force between integrin and fibronectin (FN) in pig cardiomyocytes. In addition, integrins and FN expression were determined. Results: While exercise-trained pigs showed an increase in β1 integrin expression, β3 integrin expression was detected at an increased level in the sedentary myocardium. An increase in the amount of total FN and its fragments were found in the myocardium from collateral-dependent regions of exercise-trained and sedentary pigs when compared to the non-occluded myocardium regions. The peak bond rupture force of FN-integrin (46.4±0.3 pN vs 34.8±0.2 pN), the probability of adhesion (72% vs 54%) and cell stiffness (67.9±4.7 kPa vs 29.0±1.8 kPa) were significantly increased (p&lt;0.05; n=10) in myocytes from exercise-trained pigs when compared to sedentary hearts, which were prevented by function blocking α5 and αv integrin antibodies, respectively. Conclusion: Our data demonstrate that the differences seen in adhesion force, probability and stiffness between the sedentary and exercise-trained myocytes are due to interactions of FN to different integrins, e.g., αvβ3 in sedentary and α5β1 in exercise-trained cells, suggesting potential importance of mechanotransduction pathway for therapeutic development.

The effect of creatine supplementation on myocardial function, mitochondrial respiration and susceptibility to ischaemia/reperfusion injury in sedentary and exercised rats

To investigate the effects of dietary creatine supplementation alone and in combination with exercise on basal cardiac function, susceptibility to ischaemia/reperfusion injury and mitochondrial oxidative function. There has been an increase in the use of creatine supplementation among sports enthusiasts, and by clinicians as a therapeutic agent in muscular and neurological diseases. The effects of creatine have been studied extensively in skeletal muscle, but not in the myocardium. Male Wistar rats were swim-trained for 8weeks, 5days per week. Hearts were excised and either freeze-clamped for biochemical analysis or perfused on the isolated heart perfusion system to assess function and ischaemia/reperfusion tolerance. Mechanical function was documented in working heart and retrograde mode. The left coronary artery was ligated and infarct size determined. Mitochondrial oxidative capacity was quantified. Aortic output recovery of hearts from the sedentary controls (CSed) was significantly higher than those from creatine-supplemented sedentary (CrSed), creatine-supplemented exercised (CrEx) as well as control exercised (CEx) groups. Ischaemic contracture of hearts from CrEx was significantly higher than that of CSed. There were no differences in infarct size and mitochondrial oxygen consumption. This study suggests that creatine supplementation has no effects on basal cardiac function but reduces myocardial tolerance to ischaemia in hearts from exercise-trained animals, by increasing the ischaemic contracture and decreasing reperfusion aortic output. Exercise training alone also significantly decreased aortic output recovery. However, the exact mechanisms for these adverse myocardial effects are unknown and need further investigation.

Exercise Protects Cardiac Mitochondria against Ischemia–Reperfusion Injury

Three to five consecutive days of endurance exercise can protect the heart against an ischemia-reperfusion (IR) insult. However, the mechanisms responsible for this exercise-mediated cardioprotection remain unknown. Given the important role that mitochondria play in IR-induced cardiac myocyte injury, we hypothesized that exercise training promotes cardioprotection, at least in part, by increasing mitochondrial antioxidants, preventing mitochondrial release of reactive oxygen species, and protecting cardiac mitochondria against IR-induced oxidative damage and functional impairment. To test our hypothesis, Sprague-Dawley rats were assigned to either sedentary (n = 16) or exercise-trained (n = 16) groups. Exercise-trained animals performed 5 d of treadmill running for 60 min·d(-1) at 30 m·s(-1). Hearts were excised from sedentary and exercised-trained animals and were either perfused for 80 min or exposed to 40 min of global ischemia followed by 45 min of reperfusion by using an ex vivo isolated working heart model. After the protocol, cardiac subsarcolemmal and intermyofibrillar mitochondria were isolated and used to determine respiratory control ratio, reactive oxygen species emission, and indices of oxidative stress and apoptosis. Our results support our hypothesis because exercise training protected both cardiac subsarcolemmal and intermyofibrillar mitochondria from IR-induced uncoupling and oxidative damage. Specifically, the levels of cardiac mitochondrial 4-hydroxynonenal-conjugated proteins were elevated in hearts from sedentary animals exposed to IR compared with cardiac mitochondria isolated from exercise-trained animals. Exercise also resulted in an increase in mitochondrial antioxidant enzymes (copper-zinc superoxide dismutase, manganese superoxide dismutase, and glutathione peroxidase) and prevented the IR-induced release of proapoptotic proteins from the mitochondria. Collectively, these novel findings reveal that exercise-induced cardioprotection is mediated, at least in part, through mitochondrial adaptations resulting in a mitochondrial phenotype that resists IR-induced damage.