Swimming Exercise Attenuates Dox-Induced Cardiotoxicity by Modulating Apoptosis and DRP1/PGC1α/ miR-23a Dependent Pathway in Rat Heart Tissue

1819 Purpose: Previously we reported that electrical stimulation of the rat epitrochlearis muscle in vitro increases peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA expression (Biochem Biophys Res Commun. 296: 350–4, 2002), suggesting that the stimuli evoked in the recruited muscle directly enhance PGC-1α expression during exercise. However, several factors, which are known to emerge during exercise (ex. β-adrenergic receptor stimulation), may possibly induce skeletal muscle PGC-1α expression. Therefore, for the purpose of confirming the relationship between the muscle recruitments during exercises and PGC-1α protein expression in skeletal muscle, we observed changes in muscle glycogen concentration and PGC-1α protein content after different modes of exercise (swimming vs. running) in which different muscles are recruited and in which the humoral effects might be virtually similar. Methods: Male Sprague-Dawley rats (5–6-wk-old, body weight: 150–170 g) were randomly assigned to low-intensity prolonged swimming exercise (SE), lowintensity running exercise (RE), and age-matched sedentary control group. Rats in the SE and RE group swam without a load and ran on the treadmill at a speed of 13 m/min, respectively, in two 3-h sessions separated by 45 min of rest. Epitrochlearis, triceps, soleus, plantaris, and red- and white-gastrocnemius muscles were dissected out immediately after and 6-h after the SE and RE for measurements of muscle glycogen concentration and PGC-1α protein expression, respectively. Results: Muscle glycogen concentrations in rat epitrochlearis, triceps and red-gastrocnemius muscles significantly decreased after SE, while RE significantly reduced muscle glycogen concentrations in the soleus, plantaris, and red-gastrocnemius muscles. Irrespectively of exercise mode, approximately 60–100 % increase in PGC-1α protein expression were observed exclusively in the muscles in which glycogen concentrations significantly decreased after the SE and RE. Conclusion: The present investigation demonstrated that acute bouts of low-intensity prolonged swimming and running exercise increased the PGC-1α protein content in the rat skeletal muscles that were recruited during each exercise.

Background and Aim of Work Doxorubicin (DOX) is one of the most commonly used effective anticancer drugs, through its inhibition of topoisomerase II, DNA replication and repair. In addition, DOX leads to generation of semiquinone free radicals and oxygen free radicals which attack DNA and oxidize DNA bases. However, the clinical use of doxorubicin is limited by its adverse effects such as cardiotoxicity, which is acute and occurs within 2-3 days of its administration. Recently, the potential health benefits of Astaxanthin were investigated, however, the protective effect of astaxanthin supplementation on cardiac dysfunction induced by Doxorubicin is not clearly investigated. The aim of the present study is directed to investigate the possible role of astaxanthin (xanthophyll carotenoid) in protection against DOX- induced cardiac toxicity, and to elucidate the underlying mechanism(s). Materials and Methods Animals used were 47 adult male albino rats, which were randomly allocated into four groups. Control group(C): received 0.1ml/100gm BW i.p. saline injections for 7 successive days. DOX-treated group: received 0.1ml/100gm BW i.p. saline injections for 7 successive days, followed by a single i.p. injection of DOX, 20 mg/kg i.p. on the 7th day. ATX-treated group: received 40mg/kg/day BW i.p. ATX injections for 7 successive days. ATX+DOX treated group: received 40mg/kg/day BW i.p. ATX injections for 7 successive days, followed by a single i.p. injection of DOX, 20 mg/kg i.p. on the 7th day. At the end of the study, the overnight fasted rats were subjected to final arterial blood pressure measurement. Rats were then weighed and anaesthetized with 40 mg/kg B.W i.p. thiopental sodium. Then, ECG was recorded, blood samples were collected from abdominal aorta and centrifuged. The resulting plasma was used for measurement of plasma cardiac Troponin I (cTnI) and plasma Cytochrome C. The heart was subjected to In vitro study of isolated hearts perfused in langendorff preparation. Hearts and ventricles were weighed. The left ventricle was then stored at -80οC for later determination of cardiac tissue iron. Statistical Analysis was made using 1-way ANOVA for difference between means of different groups. Ethics Committee The study protocol was approved by the Research Ethical Committee of Faculty o fMedicine Ain Shams University (Reference No. FWA00017585). Results The systolic blood pressure was increased significantly in the DOX treated group compared to the control group. All of the systolic, diastolic and mean arterial blood pressures were significantly decreased in the ATX +DOX treated group compared to the DOX treated group. Heart rate was significantly increased in the ATX +DOX treated group compared to the control group, and compared to the DOX treated group. PT and PT/LVW were significantly increased in the ATX +DOX group compared to both of the DOX group and the control group. In addition, PT and PT/LVW were significantly increased in the ATX-treated group compared to the DOX group. The TPT was prolonged in the DOX group compared to the control group and this prolongation was statistically significant in pre-ischemia and 5 minutes after reperfusion of the isolated hearts, and was significantly shortened in the ATX-treated group and ATX +DOX group compared to the DOX. Also, TPT was significantly shortened in the ATX-treated and in the in the ATX +DOX groups compared to the control group. HRT was significantly prolonged in the DOX group compared to the control group. However, HRT was significantly shortened in the ATX-treated and ATX +DOX groups compared to the DOX group, and in the ATX +DOX group compared to the control group. The MFR and MFR/LVW were significantly decreased in the DOX group compared to the control group. However, the MFR was significantly increased in each of the ATX-treated group and ATX +DOX group when each was compared to the DOX group. Moreover, MFR was significantly increased in the ATX +DOX group compared to the control group. Each of plasma cardiac Troponin, plasma Cytochrome C and Cardiac Tissue Iron were significantly increased in the DOX group compared to the control group, and all were significantly decreased in the ATX-treated group when compared to DOX group, and in the ATX +DOX group when compared to the DOX group. No significant changes were detected in body weight, heart weights and ECG parameters between the different studied groups. Conclusion Doxorubicin produces acute cardiotoxic effects and impairs systolic and diastolic cardiac functions, which is due to increased oxidative stress, mitochondrial instability and iron accumulation in the cardiac tissue. Astaxanthin exerts a major cardioprotective activities against DOXinduced cardiotoxicity, probably due to its major antioxidant and iron chelation properties.

Effects of short-term swimming exercise on bone mineral density, geometry, and microstructural properties in sham and ovariectomized rats

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. limited studies has been done on the effects of calorie restriction (CR) and aerobic exercise (AE) on mitochondrial biogenesis (PGC1α, NRF2) and dynamics (MFN2, DRP1) in NAFLD rats. In this present, the changes on PGC1α, NRF2, MFN2 and DRP1 Proteins expression after 12 weeks of CR and AE intervention in the NAFLD rat model were evaluated. Methods: 40 rats were used, with 32 of them being induced to develop NAFLD through an 8-week high-fat diet. These rats were then divided into five groups: control (ate fatty food), sham (ate normal food), CR, AE, and CA (CR & AE). The CA and CR groups received 60% of their daily diet, while the AE and CA groups participated in treadmill aerobic exercise sessions five times a week for 12 weeks. After the intervention period, protein expression levels were measured in all groups. Data analysis utilized one-way ANOVA with a significance level set at P<0.05. Results: As shown by the findings, there are significant differences in the expression of proteins between the groups. In PGC1α, NRF2, MFN2 proteins, CA group showed higher protein expression than CR group (respectively P=0.045, P=0.028, P=0.025). However, it presented a significant reduction in DRP1 protein. (P=0.015), and there was no significant difference between CA and AE in expression of PGC1α, NRf2, MFN2 and DRP1 proteins (P=0.995, P=0.44, P=0.635, P=0.076). Conclusion: The results showed that AE combined with CR is able to improve NAFLD.

Effects of Acute Bouts of Swimming Exercise on AMPKα2 Expression in Mouse Skeletal Muscle

Oxidative damage and proinflammatory cytokines are involved in exhaustive exercise-induced fatigue. This study aimed to investigate the effects of bee venom, a natural toxin, on fatigue and tissue damage in rats that underwent forced swimming exercise. Rats were divided into four groups: control, swimming exercise (SE), bee venom (BV) and swimming exercise + bee venom (SE + BV). SE and SE + BV groups were subjected to forced swimming (load of 7% body weight) for 5days. BV and SE + BV groups were injected with 1mg/kg BV subcutaneously. Swimming time, blood lactate and TNF-α levels, MDA and GSH levels in liver and gastrocnemius muscle were evaluated. Swimming time was shorter in SE + BV group than SE group. There was no difference in lactate levels between SE and SE + BV groups. MDA and GSH levels were increased in SE, BV and SE + BV groups. TNF-α levels were increased in BV group compared to control and SE groups. Our study demonstrated that BV administration before exhaustive exercise in rats did not provide anti-fatigue effect. Additionally, BV did not show anti-inflammatory activity and had different effects on antioxidant capacity at tissue level. Further research might explore the effects of different doses and durations of BV on exhaustive exercise.

Muscle dysfunction is a common complication and an important prognostic factor in chronic obstructive pulmonary disease (COPD). As therapeutic strategies are still needed to treat this complication, gaining more insight into the process that leads to skeletal muscle decline in COPD appears to be an important issue. This review focuses on mitochondrial involvement in limb skeletal muscle alterations (decreased muscle mass, strength, endurance and power and increased fatigue) in COPD. Mitochondria are the main source of energy for the cells; they are involved in production of reactive oxygen species and activate an important pathway that leads to apoptosis. In COPD patients, skeletal muscles are characterized by decreased mitochondrial density and biogenesis, impaired activity and coupling of mitochondrial respiratory chain complexes, increased mitochondrial production of reactive oxygen species and, possibly, increased apoptosis. Of particular interest, a sedentary lifestyle, hypoxia, hypercapnia, tobacco smoking, corticosteroid therapy and, possibly, inflammation participate in this mitochondrial dysfunction, which is accessible to conventional therapies, such as exercise and tobacco cessation, as well as, potentially, to more innovative approaches, such as antioxidant treatment and supplementation with polyunsaturated fatty acids.

Doxorubicin (DOX), the anthracycline chemotherapeutic agent, is widely used for the treatment of various cancers. However, its clinical application is compromised by dose-dependent and fatal cardiotoxicity. This study is aimed at investigating the cardioprotective effects of Qishen granule (QSG) and the specific mechanism by which QSG alleviates DOX-induced cardiotoxicity (DIC) and providing an alternative for the treatment of DIC. We first evaluated the cardioprotective effects of QSG in a DIC mouse model, and the obtained results showed that QSG significantly protected against DOX-induced myocardial structural and functional damage, mitochondrial oxidative damage, and apoptosis. Subsequently, after a comprehensive understanding of the specific roles and recent developments of p53-mediated mitochondrial quality control mechanisms in DIC, we investigated whether QSG acted on MDM2 to regulate the activity of p53 and downstream mitophagy and mitochondrial biogenesis. The in vivo results showed that DOX inhibited mitochondrial biogenesis and blocked mitophagy in the mouse myocardium, while QSG reversed these effects. Mechanistically, we combined nutlin-3, which inhibits the binding of p53 and MDM2, with DOX and QSG and evaluated their influence on mitophagy and mitochondrial biogenesis in H9C2 cardiomyocytes. The obtained results showed that both DOX and nutlin-3 substantially inhibited mitophagy and mitochondrial biogenesis and induced mitochondrial oxidative damage and apoptosis, which could be partially recovered by QSG. Importantly, the immunoprecipitation results showed that QSG promoted the binding of MDM2 to p53, thus decreasing the level of p53 protein and the binding of p53 to Parkin. Collectively, QSG could promote the degradation of p53 by enhancing the binding of MDM2 to the p53 protein, resulting in the reduced binding of p53 to the Parkin protein, thus improving Parkin-mediated mitophagy. Increased degradation of p53 protein by QSG simultaneously enhanced mitochondrial biogenesis mediated by PGC-1α. Ultimately, QSG relieved DOX-induced mitochondrial oxidative damage and apoptosis by coordinating mitophagy and mitochondrial biogenesis.

Swimming exercise leads to a nonpathological, physiological left ventricular hypertrophy. However, the potential molecular mechanisms are unknown. We investigated the role of microRNAs (miRNA) regulating the cardiac signal cascades were studied in exercised rats. Female Wistar rats were assigned into two groups: (1) sedentary control (SC), (2) swimming exercise (SE). The rats in the SE group completed a 1-h swimming exercise, 5times/week/8-week with 5% body overload. miRNA, phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3α), phosphatase and tensin homolog (PTEN) and tuberous sclerosis complex 2 (TSC2) gene expression analysis were performed by real-time PCR in heart muscle. Moreover, we assessed cardiac protein expression of ERK1/2, PI3K/AKT/mTOR, PTEN and TSC2. Cardiac phospho(ser473)-AKT and phospho(Ser2448)-mTOR were, respectively, increased by 46 and 38% in the SE group when compared with SC group. miRNAs-21, 144, and 145 were, respectively, up-regulated in the SE group (152%, 128, and 101% relative increases), but miRNA-124 was decreased by 38%. In SE group, PIK3α (targeted by miRNA-124) gene expression increased by 213%, and Pten (targeted by miRNAs-21 and 144), and TSC2 (targeted by miRNA-145) were, respectively, decreased by 51 and 55%. In addition, the swimming exercise increased protein levels of PIK3α (36%) and phospho(Thr1462)-TSC2 (48%), while it decreased PTEN (37%) and TSC2 (22%), which induced activation of PI3K/AKT/mTOR signaling pathway. These findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, changing the expression of specific miRNAs targeting the PIK3/AKT/mTOR signaling pathway and its negative regulators.

Introduction: Cardiac sympathovagal imbalance is a common pathologic finding in patients receiving doxorubicin (DOX), and is considered as a cardiovascular risk factor. Growing evidence demonstrates that cardiac autonomic modulation by vagus nerve stimulation (VNS) exerted cardioprotection in both myocardial ischemia/reperfusion injury and heart failure models. However, the cardioprotection of VNS in DOX-induced cardiotoxicity has never been investigated. Hypothesis: Increased cardiac parasympathetic activity by VNS attenuates the sympathovagal imbalance and mitochondrial dysfunction , thereby improving left ventricular (LV) function. Methods: Rats were divided into a sham group and a VNS group. Two weeks after cervical VNS implantation, all rats were subdivided into 3 groups: control (CON), DOX-treated group (3 mg/kg/day, ip, 6 doses) without VNS (DOX+Sham: DS), and DOX-treated group with VNS (DOX+VNS: DV). VNS was activated simultaneously with the first dose of DOX (20 Hz, 500 μs pulse width, 0.5-0.75 mA, turn ON 14 s and turn OFF 48 s (23% duty cycle), and was maintained for 30 days. At the end of the study protocol, cardiac biochemical and functional analyses were evaluated. Results: DOX treatment increased cardiac mitochondrial ROS production, mitochondrial depolarization, and mitochondrial swelling, leading to left ventricular systolic (%LVFS) and diastolic (E/A ratio) dysfunctions (Fig 1). Moreover, LF/HF ratio was increased in DOX-treated rats, indicating cardiac autonomic imbalance (Fig 1F). Interestingly, VNS could effectively protect the Dox-treated heart by alleviating all of those impaired parameters (Fig 1). Conclusions: VNS protects against DOX-induced cardiotoxicity by improving cardiac mitochondrial function and attenuating cardiac autonomic dysfunctions, leading to improved LV function. Thus, enhancing parasympathetic activity by VNS could be a novel therapeutic approach to prevent DOX-induced cardiotoxicity.

Clinically, the use of doxorubicin (DOX) is limited due to DOX-induced cardiotoxicity (DIC). The current study aimed to evaluate the cardioprotective effect of trehalose (TRE) against DIC in a female Swiss albino mouse model. Mice were divided into five experimental groups: Gp. I: saline control group (200 μl/mouse saline three times per week for 3 weeks day after day), Gp. II: DOX-treated group (2 mg/kg body weight three times per week for 3 weeks day after day), Gp. III: TRE group (200 μg/mouse three times per week for 3 weeks day after day), Gp. IV: DOX + TRE cotreatment group (animals were coadministered with DOX and TRE as in Gp. II and III, respectively), and Gp. V: DOX + TRE posttreatment group (animals were treated with DOX as in Gp. II followed by treatment with TRE as in Gp. III). DOX-treated mice showed significant elevation in cardiac injury biomarkers (lactate dehydrogenase, creatine kinase isoenzyme-MB, and cardiac troponin I), cardiac oxidative stress (OS) markers (malondialdehyde and myeloperoxidase), and cardiac levels of autophagy-related protein 5. Moreover, DOX significantly reduced the levels of total antioxidant capacity and activities of catalase and glutathione S-transferase. In contrast, TRE treatment of DOX-administered mice significantly improved almost all of the above-mentioned assessed parameters. Furthermore, histopathological changes of cardiac tissues observed in mice treated with TRE in combination with DOX were significantly improved as compared to DOX-treated animals. Taken together, the present study provides evidence that TRE has cardioprotective effects against DIC, which is likely mediated via suppression of OS and autophagy.

Ononin alleviates endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity by activating SIRT3

Swimming exercise reduces oxidative stress and liver damage indices of male rats exposed to electromagnetic radiation

Downregulation of Nrf2 deteriorates cognitive impairment in APP/PS1 mice by inhibiting mitochondrial biogenesis through the PPARγ/PGC1α signaling pathway.

Objective: Doxorubicin (DOX) is a type of chemotherapy drug frequently used to treat different malignancies. However, one of the most serious adverse effects of DOX usage is the potential of cardiotoxicity. Cardioprotective medications may be used to reduce cardiac damage because of DOX therapy. Glycyrrhizin (GL) is found in high amounts in the roots of the ‘Licorice’ plant from the Glycyrrhiza species. Due to its possible effects on blood pressure (BP) and cardiovascular health, GL has attracted attention concerning the heart. Oxidative stress and inflammatory process have been shown to be responsible for DOX-induced cardiotoxicity (DIC). For this reason, in consequence of its possible pharmacological benefits, such as antiinflammatory and antioxidant GL has been researched in this study. Here in, we aimed to investigate the protective effects of GL on DIC. Material and Methods: In this study, thirty-two male Wistar albino adult male rats were used. Four groups of rats were assigned at randomly: Control, DOX, GL+DOX, and GL groups. DOX was given 20 mg/kg intraperitoneally (i.p.) and 100 mg/kg GL was administered orally (p.o.) once a day for 14 days. Electrocardiography (ECG) and BP records of the rats were obtained. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels in the tissue were measured. Histopathological analyses were performed on the myocardium and descending aorta. Results: In the DOX group, mean and diastolic BP were higher than in the control group (p<0.05). In the GL+DOX group, diastolic BP was lower than in the DOX group (p<0.05). Pathological ECG changes such as ST segment changes and T negativity were observed in DOX-treated groups. MDA, SOD, CAT, and GSH levels studied in heart tissue were similar in all groups (p>0.05). GSH level in descending aorta was significantly lower in the GL+DOX group compared to the other groups (p<0.05). In the DOX group, degenerated cardiomyocyte density, interstitial edema, and severity of congestion-hemorrhage were statistically significantly increased compared to the control group (p<0.05). On the other hand, degenerated cardiomyocyte density was found to be significantly decreased in the GL+DOX group compared to the DOX group (p<0.05). In the DOX group, thinning of elastic lamellae and loss of myofibrils in muscle cells were observed in the descending aorta. Therefore, the histopathological alterations identified in the DOX group exhibited a significant statistical improvement in the GL+DOX group (p<0.05). Conclusion: Based on the study's findings, GL can regulate high blood pressure caused by DOX and also alleviate the toxic effects of DOX on both the myocardium and descending aorta.