Endurance exercise attenuates cardiotoxicity induced by androgen deprivation and doxorubicin.

Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX-induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague-Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg·(kg body mass)(-1)·d(-1) by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (-21% and -27%), maximal rate of pressure development (-29% and -32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective.

Therapeutic Application of Dendrobium fimbriatum Hook for Retinopathy Caused by Ultraviolet Radiation and Chemotherapy Using ARPE-19 Cells and Mouse Retina.

Retinopathy caused by ultraviolet radiation and cancer chemotherapy has increased dramatically in humans due to rapid environmental and social changes. Therefore, it is very important to develop therapeutic strategies to effectively alleviate retinopathy. In China, people often choose dendrobium to improve their eyesight. In this study, we explored how Dendrobium fimbriatum extract (DFE) protects ARPE-19 cells and mouse retinal tissue from damage of ultraviolet (UV) radiation and chemotherapy. We evaluated the antioxidant capacity of DFE using the 1,1-diphenyl-2-trinitophenylhydrazine (DPPH) assay. The protective effects of DEF from UV- and oxaliplatin (OXA)-induced damage were examined in ARPE-19 cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and immunofluorescence (IF) stains, and in mouse retinal tissue using immunohistochemistry (IHC) stains. Our results show that DFE has excellent antioxidant capacity. The ARPE-19 cell viability was decreased and the F-actin cytoskeleton structure was damaged by UV radiation and OXA chemotherapy, but both were alleviated after the DFE treatment. Furthermore, DFE treatment can alleviate OXA chemotherapy-induced reduced expressions of rhodopsin and SOD2 and increased expressions of TNF-α and caspase 3 in mouse retinal tissue. Thus, we suggest that DFE can act as suitable treatment for retinopathy through reducing oxidative stress, inflammation, and apoptosis.

Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat.

PURPOSE: Doxorubicin (DOX) is an effective antineoplastic agent with well-characterized cardiotoxic effects. Although exercise has been shown to protect against DOX cardiotoxicity, a clear and concise mechanism to explain its cardioprotective effects is lacking. The purpose of this study was to determine if exercise training reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity. METHODS: Sprague-Dawley rats were randomly assigned to 1 of 3 primary experimental groups: sedentary (n = 77), wheel running (n = 65), or treadmill (n = 65). Animals in wheel running and treadmill groups completed 10 weeks of exercise before DOX treatment. DOX was administered 24 hours after the last training session as a bolus intraperitoneal injection at 10 mg/kg. Subgroups of rats from each primary group were killed at 1, 3, 5, 7, and 9 days after DOX exposure to assess cardiac function and DOX accumulation. RESULTS: Ten weeks of exercise preconditioning reduced myocardial DOX accumulation, and this reduction in accumulation was associated with preserved cardiac function. CONCLUSIONS: These data suggest that the cardioprotective effects of exercise against DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.

Voluntary wheel running in growing rats does not protect against doxorubicin-induced osteopenia.

There is growing concern regarding the long-term negative side effects of chemotherapy in childhood cancer survivors. Doxorubicin (DOX) is commonly used in the treatment of childhood cancers and has been shown to be both cardiotoxic and osteotoxic. It is unclear whether exercise can attenuate the negative skeletal effects of this chemotherapy. Rat pups were treated with saline or DOX. Animals remained sedentary or voluntarily exercised. After 10 weeks, femoral bone mineral content and bone mineral density were measured using dual-energy x-ray absorptiometry. Cortical and cancellous bone architecture was then evaluated by microcomputed tomography. DOX had a profound negative effect on all measures of bone mass and cortical and cancellous bone architecture. Treatment with DOX resulted in shorter femora and lower femoral bone mineral content and bone mineral density, lower cross-sectional volume, cortical volume, marrow volume, cortical thickness, and principal (IMAX, IMIN) and polar (IPOLAR) moments of inertia in the femur diaphysis, and lower cancellous bone volume/tissue volume, trabecular number, and trabecular thickness in the distal femur metaphysis. Exercise failed to protect bones from the damaging effects of DOX. Other modalities may be necessary to mitigate the deleterious skeletal effects that occur in juveniles undergoing treatment with anthracyclines.

Therapeutic Effects of Plant Extracts of Anoectochilus roxburghii on Side Effects of Chemotherapy in BALB/c Breast Cancer Mice.

Breast cancer is the most common cancer in women, and chemotherapy is an effective treatment. However, chemotherapy often causes adverse side effects such as cardiotoxicity, myelosuppression, immunodeficiency, and osteoporosis. Our study focused on the alleviating effects of Anoectochilus roxburghii extracts (AREs) on the adverse side effects of chemotherapy in mice with breast cancer. We individually evaluated the antioxidant capacity and cytotoxicity of the AREs using DPPH and MTT assays. We also examined the effects of the AREs on intracellular F-actin, reactive oxygen species (ROS), and the mitochondrial membrane potential (MMP) of 4T1 cancer cells before and after doxorubicin (DOX) treatment. Our results showed that ARE treatment enhanced the effects of DOX chemotherapy by promoting cell morphology damage, oxidative stress, and ROS generation, as well as by reducing MMP in the 4T1 breast cancer cells. By using BALB/c mice with breast cancer with DOX treatment, our results showed that the DOX treatment reduced body weight, blood pressure, and heart rate and induced myelosuppression, immunodeficiency, cardiotoxicity, and osteoporosis. After oral ARE treatment of BALB/c mice with breast cancer, the chemotherapeutic effects of DOX were enhanced, and the adverse side effects of DOX chemotherapy were alleviated. Based on the above results, we suggest that AREs can be used as an adjuvant reliever to DOX chemotherapy in BALB/c mice with breast cancer.

Exercise training mitigates anthracycline-induced chronic cardiotoxicity in a juvenile rat model.

BACKGROUND: Childhood cancer survivors are at greater risk of cardiovascular complications once they reach adulthood. Anthracyclines may be a major contributor to these delayed-onset complications, yet their use continues because of favorable clinical outcomes. Exercise has been shown to protect against anthracycline cardiotoxicity, yet it is unclear whether exercise can protect against delayed-onset cardiotoxicity when treatment is initiated in childhood. The aim of the present study was to determine if exercise training provides cardioprotection in a juvenile rat model of delayed-onset anthracycline cardiotoxicity. PROCEDURE: At 25 days of age, male Sprague-Dawley rat pups were subjected to a treatment regimen with the anthracycline doxorubicin (DOX). Pups received DOX at 2 mg/kg on 7 consecutive days (cumulative dose 14 mg/kg) or saline as a control. At the time DOX treatment began, pups remained sedentary or were allowed to voluntarily exercise. Ten weeks after the initiation of exercise, cardiac function was assessed both in vivo and ex vivo. RESULTS: DOX treatment stunted normal growth and significantly impaired cardiac function. While voluntary exercise did not offset changes in the growth curve, it did provide significant cardioprotection against DOX-induced cardiotoxicity. CONCLUSIONS: Exercise training, initiated at the time treatment begins, can protect against delayed-onset anthracycline-induced cardiotoxicity in adult rats that were treated with anthracyclines as juveniles.

Chinese Herbal Medicine, Guilu Erxian Glue, as Alternative Medicine for Adverse Side Effects of Chemotherapy in Doxorubicin-Treated Cell and Mouse Models.

Doxorubicin (DOX), a chemotherapeutic drug, often causes many adverse side effects in patients with cancer, such as weight loss, motor disability, blood circulation defects, myelosuppression, myocardial injury, joint degeneration, and bone loss. The Chinese herbal medicine Guilu Erxian Glue (GEG) has been used in the prevention and treatment of osteoarthritis and osteoporosis for hundreds of years, with considerably fewer side effects. We expected that GEG could serve as a protective and beneficial alternative treatment for DOX-induced adverse side effects. In this study, we evaluated whether GEG can alleviate DOX-induced weight loss, motor disability, abnormal blood circulation, myelosuppression, myocardial injury, joint degeneration, and bone loss by using chemotherapy models of synoviocyte cell line HIG-82 and mice. Moreover, we examined the antioxidant capacity of GEG by using DPPH (1,1-diphenyl-2-picrylhydrazyl) free-radical scavenging. Our results revealed that GEG treatment can significantly enhance DPPH free-radical scavenging and reduce DOX-induced cytotoxicity in synoviocyte HIG-82 cells. In addition, GEG treatment for 2 weeks can significantly relieve weight loss, enhance exhaustive exercise capacity, improve blood circulation, alleviate myocardial oxidative stress and inflammation, and strengthen the tibias of DOX-treated mice. Thus, we suggest that GEG treatment can be a protective and alternative therapy for alleviating chemotherapy-related side effects such as weight loss, motor disability, blood circulation defects, and bone loss.

Chinese Herbal Medicine Alleviates Thyroidectomy-Induced Cardiopulmonary Exercise Dysfunction in Rats.

Hypothyroidism frequently causes cardiopulmonary dysfunction, such as heart failure and respiratory and metabolic deficiencies. This study investigated the effects of Chinese herbal formula B307 on thyroidectomy-induced cardiopulmonary exercise dysfunction in rats. Twenty male rats were equally divided into four groups: negative control with sham treatment, positive control with oral B307 treatment only, thyroidectomy treatment only, and thyroidectomy with B307 posttreatment groups. The feeding dose of B307 was 50 mg/kg per day for 14 days. We examined and then compared the thyroid-stimulating hormone (TSH), free triiodothyronine (T3), free thyroxine (T4), and reactive oxygen species (ROS) from the blood of these four groups. Also, we compared the body weight, neck subcutaneous blood flow, cardiac ejection function, cardiopulmonary exercise function of oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory quotient (RQ = VCO2/VO2) among the four groups. Our results indicated that thyroidectomized rats had significantly decreased body weight, neck subcutaneous blood flow, cardiac ejection function, serum T3 and T4, and VO2 and VCO2, but had significantly increased ROS and TSH levels and RQ values compared with sham rats (P < 0.01-0.05). In addition, thyroidectomized rats receiving oral B307 treatment had significantly increased body weight, neck subcutaneous blood flow, cardiac ejection function, and VO2, but significantly decreased ROS and TSH levels and VCO2 and RQ values compared with thyroidectomized rats (P < 0.01-0.05). We suggest that the B307 could be a protective and beneficial alternative treatment for thyroidectomy-induced cardiopulmonary exercise dysfunction.

Oral treatment with the Chinese herbal supplements B307 enhances muscle endurance of ICR mice after exhaustive swimming via suppressing fatigue, oxidative stress, and inflammation.

Exhaustive exercise may damage muscles due to oxidative stress and inflammation and cause muscle fatigue and soreness. The study investigated the effects of Chinese herbal supplements (CHS) B307 on muscle endurance after exhaustive swimming (ES). Thirty-two male ICR mice were randomly divided into 4 groups: Sham + ES, pretreatment of CHS B307 + ES (Pre + ES), post-treatment of CHS B307 + ES (Post + ES), and dual treatment of CHS B307 + ES (Dual + ES). All mice were subjected to ES in the form of a forced swimming test. Then, we compared ES time (EST) as the index of muscular endurance. Also, we examined the fatigue, oxidative stress, inflammation, and damage in the muscle tissue among these groups by using immunohistochemistry (IHC), chemiluminescence, and biochemical analysis. Our results revealed that those mice of Pre + ES and Dual + ES groups had remarkably better EST than those mice of Sham + ES and Post + ES groups. Those mice with oral treatment of CHS B307(Pre + ES, Post + ES, and Dual + ES groups) showed significantly reduced leukocyte counts in the urine, and reduced levels of reactive oxygen species (ROS), neutrophils, and lactic acid in the blood than those mice of Sham + ES. In addition, those mice with oral treatment of CHS B307 (Pre + ES, Post + ES, and Dual + ES groups) showed significant alleviation of oxidative stress, inflammation, and damage in the muscle tissue than those mice of Sham + ES. Thus, we suggested that CHS B307 can be a functional sports supplement because it can enhance muscle endurance after exhaustive swimming via suppressing fatigue, oxidative stress, and inflammation.

Chinese Veterinary Medicine B307 Promotes Cardiac Performance and Skeletal Muscle Contraction via Enhancing Intracellular Calcium Levels and Neural Electrical Activity in Animal and Cell Models.

The study mainly investigated the effects of Chinese veterinary medicine B307 in cardiac and motor functions in animal models of pigeons and mice. Related cellular mechanisms were also studied in the neuroblastoma cell model of SH-SY5Y. Cardiac functions of pigeons and mice were examined by using moorFLPI Laser color Doppler imager and M-mode echocardiography, and motor functions were examined by using muscle electrical stimulation and force recording in the isolated breast muscle. Intracellular calcium levels and electrical activity of SH-SY5Y cells were examined by using Fura 2-AM fluorescence and MED64 system separately. Our results in vivo found that those pigeons under oral B307 treatment obviously enhanced subcutaneous microcirculation and contractile force and prolonged fatigue time in their breast muscles. Those mice under oral B307 treatment obviously elevated ejection fraction and cardiac output in their hearts. Our results in vitro showed that those SH-SY5Y cells under B307 treatment obviously increased intracellular calcium mobilization and electrical activities. These results revealed that improvement of cardiac and motor functions under B307 treatments may be caused by increasing electrical activities and intracellular calcium levels in neuromuscular cells and a similar mechanism may also occur in muscle cells. Thus, we suggested that B307 can be a functional Chinese veterinary medicine for flying pigeons.

Anandamide preserves cardiac function and geometry in an acute doxorubicin cardiotoxicity rat model.

We investigated the use of the endocannabinoid anandamide as a means of cardioprotection against doxorubicin-induced cardiac dysfunction. Male rats received doxorubicin with or without anandamide pretreatment. Cardiac function was assessed in vivo using transthoracic echocardiography and ex vivo using the isolated working heart 5 days posttreatment. Doxorubicin administration without anandamide pretreatment resulted in a decline in fractional shortening (P < .05) and left ventricular wall thickness when compared to controls (P < .05). Ex vivo cardiac function analysis revealed a reduction in left ventricular developed pressure in hearts from animals receiving doxorubicin without anandamide pretreatment when compared to controls (P < .05). Left ventricles from animals receiving anandamide pretreatment before doxorubicin administration did not exhibit depressed fractional shortening, ventricular wall thickness, or developed pressure when compared to controls (P > .05). These results suggest that a potential therapy for doxorubicin-induced cardiotoxicity involves targeting the endogenous cannabinoid system.

Exercise preconditioning protects against doxorubicin-induced cardiac dysfunction.

UNLABELLED: The clinical use of the chemotherapeutic drug doxorubicin (DOX) is limited due to a dose-dependent cardiotoxicity. Evidence is mounting that exercise protects against DOX-related cardiac dysfunction, and as such, it may be possible that prior endurance training promotes defense against DOX cardiotoxicity. PURPOSE: To examine the effects of exercise preconditioning on acute DOX-induced cardiotoxicity, and to determine whether any observed cardioprotection was associated with myosin heavy chain (MHC) isoform alterations. METHODS: Male Sprague-Dawley rats trained on a motorized treadmill, had access to voluntary running wheels, or remained sedentary for 10 wk prior to being injected with either saline or 10 mg.kg(-1) DOX. Left ventricular function was then assessed in vivo using transthoracic echocardiography and ex vivo using the isolated working heart at 5 and 10 d after injection. Additionally, left ventricular MHC isoform expression was analyzed as a possible mechanism to explain exercise-induced cardioprotection. RESULTS: DOX treatment promoted significant in vivo and ex vivo cardiac dysfunction at 5 and 10 d after injection in sedentary animals, and this dysfunction was associated with an upregulation of the beta-MHC isoform. Exercise preconditioning protected against DOX-induced cardiac dysfunction at 5 and 10 d after injection by attenuating beta-MHC upregulation. CONCLUSION: Endurance training prior to DOX treatment protects against acute DOX cardiotoxicity for up to 10 d, and this protection can potentially be explained by a preservation of MHC isoform distribution.

Effects of voluntary wheel running on goserelin acetate-induced bone degeneration.

A common treatment option for many breast and prostate cancer patients is the use of a luteinizing hormone-releasing hormone agonist such as goserelin acetate (GA) which reduces sex hormone levels. This treatment, however, is associated with bone degeneration, and exercise has been suggested as a means of preventing this side effect. Little is known about the effects of low intensity, low volume exercise on GA-induced bone loss. The purpose of this study, therefore, was to investigate the effects of voluntary wheel running on bone architecture in growing male (M) and female (F) rats receiving GA treatment. Rats received an 8-week GA treatment or placebo (CON) and were either housed in cages equipped with voluntary running wheels (WR) or remained sedentary (SED) in standard cages throughout the experimental period. Following treatments, tibiae were excised and analyzed for cortical bone (cross-sectional volume, cortical volume, marrow volume, cortical thickness) and cancellous bone (bone volume/total volume, trabecular number, trabecular thickness, trabecular spacing) using micro-computed tomography. Treatment with GA resulted in a significant reduction in running wheel distances in both sexes throughout the study period (P<0.05). GA treatment had no effect on cortical bone architecture in neither sex (P>0.05). Cancellous bone degeneration, however, was observed in M and F SED+GA (P<0.05). No significant differences were observed in M WR+GA animals in bone volume/total volume, trabecular number and trabecular spacing when compared to M SED+CON (P>0.05). In F WR+GA, trabecular thickness did not differ from that of F SED+CON (P>0.05), and trabecular spacing was found to be significantly lower than F SED+GA (P<0.05). The current report indicates that 8 weeks of GA treatment promotes cancellous bone degeneration, and voluntary wheel running provides no clear osteoprotection in growing male and female rats.

Short-term exercise training attenuates acute doxorubicin cardiotoxicity.

Doxorubicin (DOX) is a potent and widely used antineoplastic agent. Despite the efficacy of DOX, its clinical use is limited by a dose-dependent cardiotoxicity. Chronic exercise training has been shown to protect against DOX-induced cardiotoxicity. It is less clear whether short-term exercise can attenuate DOX-induced dysfunction. The purposes of this study were to determine if short-term wheel running and treadmill exercise training can attenuate the cardiac dysfunction that accompanies DOX treatment and to investigate possible mechanisms that may be involved with any protective effects of exercise. Male Sprague-Dawley rats engaged in a short-term 5-day voluntary wheel running (WR) or treadmill exercise (TM) regimen. Following the exercise preconditioning period, animals received either 10 or 15 mg/kg of DOX or an equivalent volume of saline (SAL). Five days after DOX/SAL exposure, cardiac function was examined. Western immunoblotting was used to quantify left ventricular sarcoendoplasmic reticulum calcium-ATPase 2a (SERCA2a) protein expression. Exercise preconditioning attenuated in vivo and ex vivo cardiac dysfunction observed with DOX treatment alone. Specifically, short-term treadmill exercise (TM + DOX10, 56 ± 4%; TM + DOX15, 48 ± 5%) and voluntary wheel running (WR + DOX10, 51 ± 5%; WR + DOX15, 45 ± 3%) consistently preserved fractional shortening when compared to sedentary (SED) animals treated with DOX (SED + DOX10, 48 ± 4%; SED + DOX15, 39 ± 6%). Likewise, both exercise protocols preserved left ventricular developed pressure (TM + DOX10, 115 ± 6 mmHg; TM + DOX15, 85 ± 5 mmHg; WR + DOX10, 92 ± 12 mmHg; WR + DOX15, 91 ± 8 mmHg) when compared to SED animals treated with DOX (SED + DOX10, 79 ± 6 mmHg; SED + DOX15, 69 ± 7 mmHg). SERCA2a expression was also preserved in TM + DOX and WR + DOX. These findings suggest that short-term exercise prior to DOX treatment may be a valuable adjuvant therapy to offset acute cardiotoxicities and that maintaining calcium handling in cardiomyocytes may be responsible, in part, for the preservation in cardiac function.

Oral treatment with the herbal formula B307 alleviates cardiac toxicity in doxorubicin-treated mice via suppressing oxidative stress, inflammation, and apoptosis.

OBJECTIVE: This study aimed to investigate whether the herbal formula B307 could alleviate doxorubicin (DOX)-induced acute cardiotoxicity. If so, we further unraveled possible molecular mechanisms of cardiac protection under treatment with the herbal formula B307. METHODS: Before the animal experiment, we examined relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307. To test whether oral treatment with the herbal formula B307 could alleviate cardiotoxicity, equal volumes of B307 (50 mg/kg) or saline (sham treatment) were administered to 20-week-old male mice once daily for 14 consecutive days. Then, DOX (10 mg/kg; ip) was administered to male mice under B307 and sham treatments at 22-23 weeks of age. Cardiac functions in these mice were assessed via echocardiography at 23-24 weeks of age. Then, expressions of oxidative stress, inflammation, and apoptosis-related proteins were examined in the heart tissue by immunohistochemistry and Western blotting at 24-25 weeks of age. Apart from this, mortality rate and body weight were measured during the experiment. RESULTS: In vitro, the relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307 had shown no obvious change at doses of 10-160 ng/mL. Furthermore, the relative viabilities of Huh7 cancer cells were significantly reduced under DOX treatment but showed no significant change under DOX only and DOX plus B307 treatment. In vivo, the mortality rate, body weight, and cardiac function of DOX-treated mice were obviously improved under oral treatment with the herbal formula B307. Furthermore, cardiac expressions of endothelial nitric oxide synthase, superoxide dismutase 2, and B-cell lymphoma 2 were significantly enhanced, but tumor necrosis factor alpha, NFKB1 (p50 and its precursor, p105), neurotrophin-3, Bcl-2-associated X protein, calpain, caspase 12, caspase 9, and caspase 3 were significantly suppressed in DOX-treated mice under oral treatment with the herbal formula B307. CONCLUSION: Our results revealed that oral treatment with the herbal formula B307 may provide cardioprotection in DOX-treated mice via suppressing oxidative stress, inflammation, and apoptosis in heart tissue. We believe that the herbal formula B307 may be developed as a potential alternative treatment for cancer patients under DOX treatment.

Switching to a low-fat diet attenuates the intensified doxorubicin cardiotoxicity associated with high-fat feeding.

PURPOSE: A high-fat diet has been shown to exacerbate the cardiotoxicity associated with the chemotherapy drug doxorubicin (DOX); however, it is unknown whether switching from a high-fat diet to a low-fat diet can attenuate the intensified DOX cardiotoxicity. The purpose of this study was to investigate the effects of a low-fat diet on DOX-induced cardiotoxicity in rats previously fed a high-fat diet. METHODS: Male rats were randomly assigned to consume a Western diet or a low-fat diet for 6 weeks. Western diet-fed rats were then further randomized to switch to the low-fat diet (WD-LF) or continue with the Western diet (WD). One week later, WD-LF and WD received 1 mg/kg DOX per day for 10 consecutive days and continued with their diets (WD-LF + DOX, WD + DOX). LF was further randomized to receive 1 mg/kg DOX per day for 10 consecutive days (LF + DOX) or saline injections as a control (LF + SAL). Four weeks following the first injection, cardiac function was analyzed, and left ventricles were analyzed for cardiotoxicity indices. RESULTS: When compared to LF + SAL and LF + DOX, WD + DOX exhibited an enhanced cardiotoxicity as evidenced by reduced septal wall thickness, fractional shortening, and sarco-endoplasmic reticulum Ca(2+) ATPase expression as well as increased left ventricular cavity dimensions, lipid peroxidation, and ß-myosin heavy-chain expression. This exacerbated cardiotoxicity was not observed in WD-LF + DOX. CONCLUSIONS: Switching to a low-fat diet 1 week prior to, during, and following DOX treatment attenuated the exacerbated cardiotoxicity observed in the previously Western diet-fed rats.

Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity.

The use of exercise to minimize doxorubicin (DOX)-induced cardiotoxicity is gaining attention. However, very few clinically relevant reports exist investigating the effects of exercise performed during and following DOX treatments. The purpose of this study, therefore, was to examine the effects of voluntary wheel running during and following DOX treatment using two models of late-onset DOX cardiotoxicity in the rat. Female Sprague-Dawley rats received either DOX or saline injections using one of two separate treatment regimens. These regimens involved either daily or weekly DOX injections with cumulative doses for both protocols totaling 15 mg/kg. Daily DOX injections were 1 mg/kg and lasted for 15 consecutive days while weekly DOX injections were 2.5 mg/kg and lasted for six consecutive weeks with control animals receiving matched saline injection regimens. Immediately following the initial DOX/saline injection, animals were randomly housed in cages with voluntary running wheels or standard rat cages throughout DOX/saline treatments and continued until reaching 10 weeks. Cardiac function was then assessed using echocardiography and an isolated working heart model, and myosin heavy chain (MHC) isoform distribution was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When compared wth controls, daily DOX treatment resulted in reduced running wheel distances at weeks 2-10 (P < 0.05), and weekly DOX treatment resulted in reduced running wheel distances at weeks 2, 6 and 10 (P < 0.05). Nonetheless, wheel running during and following daily and weekly DOX dosing protected against DOX-induced cardiotoxicity by preserving maximal mitral and aortic blood flow velocities, left ventricular developed pressure and MHC isoform expression. In conclusion, the overall reduced volume of activity during and following daily and weekly DOX treatments attenuated DOX-induced cardiac dysfunction suggesting that low-volume endurance training may be an effective rehabilitative approach in minimizing DOX cardiotoxicity in cancer patients.

Echocardiographic evaluation of cardiac structure and function during exercise training in the developing Sprague-Dawley rat.

Echocardiography is a widely used evaluation tool in cardiovascular research. Although rats are a common model in such research, normal echocardiographic values for young, developing rats have not been established. Furthermore, whether exercise during the developmental phase of the lifespan affects the structure or function of the heart is unclear. Male Sprague-Dawley rat pups (21 d) were assigned randomly to a nonexercise or voluntary exercise group for 12 wk. Echocardiograms were obtained before and at weekly intervals during the 12-wk observation period. Maturation resulted in changes in many echocardiographically derived variables, whereas voluntary exercise failed to alter the development of cardiac structure or function. This study provides normal echocardiographic variables for developing male rats and provides evidence that exercise during the developmental phase of the lifespan has little effect on cardiac morphology and function as assessed by echocardiography.

Characterization of the effect of in vivo doxorubicin treatment on skeletal muscle function in the rat.

UNLABELLED: Doxorubicin (DOX)-induced muscle dysfunction may contribute to patient fatigue, but the nature of this myotoxicity remains unclear. The purpose of this study was to characterize the muscle function dose-response to DOX. A secondary purpose was to compare the degree of DOX-induced muscle dysfunction to the observed cardiac dysfunction. MATERIALS AND METHODS: Rats received DOX at 10 mg/kg (DOX1), 12.5 mg/kg (DOX2), or 15 mg/kg (DOX3). Muscle and cardiac function were assessed 5 days, post injection. RESULTS: Compared to controls, DOX2 and DOX3 soleus and DOX3 extensor digitorum longus (EDL) had lower maximal twitch force (p<0.05). Soleus fatigue rate was altered by DOX, but EDL fatigue rate was not. Additionally, fractional shortening was lower in DOX2 and DOX3 compared to controls (p<0.05). CONCLUSION: DOX impaired muscle function in a dose-dependent manner. The degree of dysfunction was greater in the soleus and was consistent with the observed cardiac dysfunction.

Exercise preconditioning provides long-term protection against early chronic doxorubicin cardiotoxicity.

Acute doxorubicin (DOX) cardiotoxicity can be attenuated by exercise preconditioning, but little is known of whether this cardioprotection continues beyond 10 days post-DOX administration. The purpose of this study was to determine the effects of exercise preconditioning on early chronic DOX-induced cardiotoxicity. Male rats were randomly assigned to sedentary, treadmill, or wheel running groups. Treadmill and wheel running animals participated in a progressive treadmill training protocol or voluntary wheel running, respectively, for 10 weeks. Following the intervention, animals were further randomized to receive either DOX (sedentary + DOX, treadmill + DOX, wheel running + DOX) or saline (sedentary + saline, treadmill + saline, wheel running + saline). All animals then remained sedentary for 4 weeks. A 22% reduction in fractional shortening was observed in left ventricles from previously sedentary animals receiving DOX when compared with sedentary + saline. This degree of decline was not observed in treadmill + DOX and wheel running + DOX. Sedentary + DOX possessed significantly depressed mitral and aortic valve blood flow velocities when compared with sedentary + saline, but these decrements were not observed in treadmill + DOX and wheel running + DOX. Ex vivo analysis revealed that left ventricular developed pressure and maximal rate of pressure development were significantly lower in sedentary + DOX when compared to sedentary + saline. Treadmill and wheel running prior to DOX treatment protected against these decrements. Exercise cardioprotection was associated with preserved myosin heavy chain but not sarcoendoplasmic reticulum Ca(2+) ATPase 2a expression. In conclusion, 10 weeks of prior exercise protected against early chronic DOX cardiotoxicity suggesting that training status may be a determining factor in the degree of late-onset cardiotoxicity experienced by cancer patients undergoing treatment with DOX.