Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice

Dolinsky, Vernon W.; Rogan, Kyle J.; Sung, Miranda M.; Zordoky, Beshay N.; Haykowsky, Mark J.; Young, Martin E.; Jones, Lee W.; Dyck, Jason R.B.

doi:10.1152/ajpendo.00044.2013

Cited by 110 publications

(136 citation statements)

References 51 publications

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“…The pivotal role played by mitochondrial dysfunction in doxorubicin cardiotoxicity is, furthermore, revealed by the fact that activation of mitochondrial function or biogenesis by various agents, such as frataxin overexpression, exercise training or resveratrol, are sufficient to protect against doxorubicin cardiotoxicity and cardiac dysfunction. 45,46 In the present study, doxorubicin cardiotoxicity was observed only in males and was accompanied by early mitochondrial dysfunction again emphasizing the role of mitochondrial dysfunction in doxorubicin cardiotoxicity and further suggesting a possible role in sex differences.…”

Section: Discussionsupporting

confidence: 62%

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Moulin

Piquereau

Matéo

et al. 2015

Circ: Heart Failure

110

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Background— Cardiovascular diseases are the major cause of mortality among both men and women with a lower incidence in women before menopause. The clinical use of doxorubicin, widely used as an antineoplastic agent, is markedly hampered by severe cardiotoxicity. Even if there is a significant sex difference in incidence of cardiovascular disease at the adult stage, it is not known whether a difference in doxorubicin-related cardiotoxicity between men and women also exists. The objective of this work was to explore the cardiac side effects of doxorubicin in adult rats and decipher whether signaling pathways involved in cardiac toxicity differ between sexes. Methods and Results— After 7 weeks of doxorubicin (2 mg/kg per week), males developed major signs of cardiomyopathy with cardiac atrophy, reduced left ventricular ejection fraction and 50% mortality. In contrast, no female died and their left ventricular ejection fraction was only moderately affected. Surprisingly, neither global oxidation levels nor the antioxidant response nor the apoptosis signaling pathways were altered by doxorubicin. However, the level of total adenosine monophosphate–activated protein kinase was severely decreased only in males. Moreover, markers of mitochondrial biogenesis and cardiolipin content were strongly reduced only in males. To analyze the onset of the pathology, maximal oxygen consumption rate of left ventricular permeabilized fibers after 4 weeks of treatment was reduced only in doxorubicin-treated males. Conclusions— Altogether, these results clearly evidence sex differences in doxorubicin toxicity. Cardiac mitochondrial dysfunction and adenosine monophosphate–activated protein kinase seem as critical sites of sex differences in cardiotoxicity as evidenced by significant statistical interactions between sex and treatment effects.

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Section: Discussionsupporting

confidence: 62%

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Moulin

Piquereau

Matéo

et al. 2015

Circ: Heart Failure

110

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“…36,39 However, it is not known whether resveratrol can be used to treat established pressure-overload-induced HF and prevent or reverse cardiac and vascular remodeling induced by HF. Using the TAC mouse model, we made several key findings starting with resveratrol treatment significantly improving median survival of mice with HF.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Treatment of Mice With Pressure-Overload–Induced Heart Failure Improves Diastolic Function and Cardiac Energy Metabolism

Sung

Das

Levasseur³

et al. 2015

Circ: Heart Failure

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Background— Although resveratrol has multiple beneficial cardiovascular effects, whether resveratrol can be used for the treatment and management of heart failure (HF) remains unclear. In the current study, we determined whether resveratrol treatment of mice with established HF could lessen the detrimental phenotype associated with pressure-overload–induced HF and identified physiological and molecular mechanisms contributing to this. Methods and Results— C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks post surgery, a cohort of mice with established HF (% ejection fraction <45) was administered resveratrol (≈320 mg/kg per day). Despite a lack of improvement in ejection fraction, resveratrol treatment significantly increased median survival of mice with HF, lessened cardiac fibrosis, reduced gene expression of several disease markers for hypertrophy and extracellular matrix remodeling that were upregulated in HF, promoted beneficial remodeling, and improved diastolic function. Resveratrol treatment of mice with established HF also restored the levels of mitochondrial oxidative phosphorylation complexes, restored cardiac AMP-activated protein kinase activation, and improved myocardial insulin sensitivity to promote glucose metabolism and significantly improved myocardial energetic status. Finally, noncardiac symptoms of HF, such as peripheral insulin sensitivity, vascular function, and physical activity, were improved with resveratrol treatment. Conclusions— Resveratrol treatment of mice with established HF lessens the severity of the HF phenotype by lessening cardiac fibrosis, improving molecular and structural remodeling of the heart, and enhancing diastolic function, vascular function, and energy metabolism.

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“…Cardiomyocytes derive as much as 90% of ATP from mitochondrial oxidative phosphorylation, and thus, are extremely sensitive to the effects of anthracyclines. In animal models, exercise has been shown to mitigate cardiotoxicity [56] in part alleviating the effects on mitochondrial function [57] . While overt toxicity may not be evident, other tissues may suffer from impairments.…”

Section: Compositionmentioning

confidence: 99%

Weight gain following breast cancer diagnosis: Implication and proposed mechanisms

Makari-Judson

Braun

Jerry

et al. 2014

WJCO

130

106

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Weight gain occurs in the majority of women following breast cancer treatment. An overview of studies describing weight gain amongst women treated with early to modern chemotherapy regimens is included. Populations at higher risk include women who are younger, closer to ideal body weight and who have been treated with chemotherapy. Weight gain ranges between 1 to 5 kg, and may be associated with change in body composition with gain in fat mass and loss in lean body mass. Women are unlikely to return to pre-diagnosis weight. Possible mechanisms including inactivity and metabolic changes are explored. Potential interventions are reviewed including exercise, dietary changes and pharmacologic agents. Although breast cancer prognosis does not appear to be significantly impacted, weight gain has negative consequences on quality of life and overall health. Future studies should explore change in body composition, metabolism and insulin resistance. Avoiding weight gain in breast cancer survivors following initial diagnosis and treatment should be encouraged.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Breast cancer; Weight gain; Exercise; Survivorship; Insulin resistance Core tip: Weight gain occurs in the majority of women following breast cancer treatment, especially those who are younger, closer to ideal body weight and who have been treated with chemotherapy. Although weight gain may be modest, changes are consistent with sarcopenic obesity. Women are unlikely to return to pre-diagnosis weight. Although the degree of weight gain does not appear to significantly alter prognosis, associated changes in metabolism and inactivity are of concern. Interventions should be promoted to avoid weight gain. INTRODUCTIONWeight gain following a diagnosis of breast cancer has been reported consistently in women treated for breast cancer, but was an unexpected finding when first described Dixon and colleagues in 1978 [1] . After subsequent reports confirmed this observation, weight gain was included as a known side effect of adjuvant chemotherapy [2] . Despite this, most women appear to be inadequately informed about this possibility, as demonstrated by one study reporting concern about treatment-associated weight gain in only 27% of survivors prior to therapy [3] . WHY IS POST-TREATMENT WEIGHT GAIN OF CONCERN?Obesity is a global issue associated with increased risk of developing post-menopausal breast cancer [4] and a worse prognosis at the time of diagnosis [5] . However, the effect of weight gain following a diagnosis of breast cancer is less well understood. While weight gain following diagnosis does not necessarily lead to obesity or its consequences, any impact on breast cancer prognosis and overall health, patient self-image, or quality of life (QoL) would be an undesirable outcome. These outcomes may be interrelated: weight gain can influence other medical conditions such as diabetes, heart disease, hypertension and hypercholesterolemia that may impact overall survival. For example, Erick...

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Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice

Cited by 110 publications

References 51 publications

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Resveratrol Treatment of Mice With Pressure-Overload–Induced Heart Failure Improves Diastolic Function and Cardiac Energy Metabolism

Weight gain following breast cancer diagnosis: Implication and proposed mechanisms

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