Oxidative and proteolytic profiles of the right and left heart in a model of cancer-induced cardiac cachexia

Borges, Fernando H.; Marinello, Poliana Camila; Cecchini, Alessandra Lourenço; Blegniski, F.P.; Guarnier, Flávia Alessandra; Cecchini, Rúbens

doi:10.1016/j.pathophys.2014.05.003

Cited by 20 publications

(17 citation statements)

References 50 publications

(65 reference statements)

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“…Meanwhile, in the present work, nutritional supplementation with leucine led to some positive effects on the changes in QT‐c, T‐wave amplitude, and area in group LW, despite the observed reduction in the right and left ventricle walls. The reduction of the ventricular wall might not indicate an impaired contractile force, but when associated with the reduction of cardiac mass (lower weight and protein content, which was present especially in group W, rather than group LW) this change could compromise the contractile strength, reducing the heart rate and indicating cardiac failure …”

Section: Discussionsupporting

confidence: 82%

“…Here we show some ECG parameters in tumour‐bearing rats that were compromised by tumour effects (significant decrease in heart rate, alteration in the QT‐c interval, and increased area under the T‐wave curve), suggesting a higher risk of death in the tumour‐bearing group. In association with morphometric parameters, which showed an important reduction in the left ventricle wall, these changes likely suggest cardiac failure . Although the electrocardiography yields some interesting and important data, Xu and colleagues demonstrated that the cardiac damage, at the cellular level, that occurs in a cancer‐cachexia model is much more severe than suggested by electrocardiography .…”

Section: Discussionmentioning

confidence: 38%

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Nutritional leucine supplementation attenuates cardiac failure in tumour‐bearing cachectic animals

Toneto

Ramos

Salomão

et al. 2016

J cachexia sarcopenia muscle

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BackgroundThe condition known as cachexia presents in most patients with malignant tumours, leading to a poor quality of life and premature death. Although the cancer‐cachexia state primarily affects skeletal muscle, possible damage in the cardiac muscle remains to be better characterized and elucidated. Leucine, which is a branched chain amino acid, is very useful for preserving lean body mass. Thus, this amino acid has been studied as a coadjuvant therapy in cachectic cancer patients, but whether this treatment attenuates the effects of cachexia and improves cardiac function remains poorly understood. Therefore, using an experimental cancer‐cachexia model, we evaluated whether leucine supplementation ameliorates cachexia in the heart.MethodsMale Wistar rats were fed either a leucine‐rich or a normoprotein diet and implanted or not with subcutaneous Walker‐256 carcinoma. During the cachectic stage (approximately 21 days after tumour implantation), when the tumour mass was greater than 10% of body weight, the rats were subjected to an electrocardiogram analysis to evaluate the heart rate, QT‐c, and T wave amplitude. The myocardial tissues were assayed for proteolytic enzymes (chymotrypsin, alkaline phosphatase, cathepsin, and calpain), cardiomyopathy biomarkers (myeloperoxidase, tissue inhibitor of metalloproteinases, and total plasminogen activator inhibitor 1), and caspase‐8, ‐9, ‐3, and ‐7 activity.ResultsBoth groups of tumour‐bearing rats, especially the untreated group, had electrocardiography alterations that were suggestive of ischemia, dilated cardiomyopathy, and sudden death risk. Additionally, the rats in the untreated tumour‐bearing group but not their leucine‐supplemented littermates exhibited remarkable increases in chymotrypsin activity and all three heart failure biomarkers analysed, including an increase in caspase‐3 and ‐7 activity.ConclusionsOur data suggest that a leucine‐rich diet could modulate heart damage, cardiomyocyte proteolysis, and apoptosis driven by cancer‐cachexia. Further studies must be conducted to elucidate leucine's mechanisms of action, which potentially includes the modulation of the heart's inflammatory process.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 38%

Nutritional leucine supplementation attenuates cardiac failure in tumour‐bearing cachectic animals

Toneto

Ramos

Salomão

et al. 2016

J cachexia sarcopenia muscle

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“…As for cancer cachexia, increased calpain mRNA levels were reported in the skeletal muscle of animals bearing the AH-130 hepatoma (Busquets et al, 2000). The contribution of calpain activity to muscle wasting induced by tumor growth in rats bearing the Yoshida AH-130 hepatoma was suggested by the progressive reduction of both calpastatin and the 130 kDa Ca 2+ -ATPase levels (Costelli et al, 2001), as well as by the increased cleavage in vitro of specific fluorogenic substrates (Costelli et al, 2002; Borges et al, 2014). More recently increased calpain expression was reported in the muscle of tumor-bearing rats treated with sorafenib (Toledo et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Interference with Ca2+-Dependent Proteolysis Does Not Alter the Course of Muscle Wasting in Experimental Cancer Cachexia

Minero

Penna

et al. 2017

Front. Physiol.

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Protein hypercatabolism significantly contributes to the onset and progression of muscle wasting in cancer cachexia. In this regard, a major role is played by the ATP-ubiquitin-proteasome-dependent pathway and by autophagy. However, little is known about the relevance of the Ca2+-dependent proteolytic system. Since previous results suggested that this pathway is activated in the skeletal muscle of tumor hosts, the present study was aimed to investigate whether inhibition of Ca2+-dependent proteases (calpains) may improve cancer-induced muscle wasting. Two experimental models of cancer cachexia were used, namely the AH-130 Yoshida hepatoma and the C26 colon carcinoma. The Ca2+-dependent proteolytic system was inhibited by treating the animals with dantrolene or by overexpressing in the muscle calpastatin, the physiologic inhibitor of Ca2+-dependent proteases. The results confirm that calpain-1 is overexpressed and calpastatin is reduced in the muscle of rats implanted with the AH-130 hepatoma, and show for the first time that the Ca2+-dependent proteolytic system is overactivated also in the C26-bearing mice. Yet, administration of dantrolene, an inhibitor of the Ca2+-dependent proteases, did not modify tumor-induced body weight loss and muscle wasting in the AH-130 hosts. Dantrolene was also unable to reduce the enhancement of protein degradation rates occurring in rats bearing the AH-130 hepatoma. Similarly, overexpression of calpastatin in the tibialis muscle of the C26 hosts did not improve muscle wasting at all. These observations suggest that inhibiting a single proteolytic system is not a good strategy to contrast cancer-induced muscle wasting. In this regard, a more general and integrated approach aimed at targeting the catabolic stimuli rather than the proteolytic activity of a single pathway would likely be the most appropriate therapeutic intervention.

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“…The absence of muscular oxidative damage in our model could be attributed to the upregulation of catalase expression, exclusively, in atrophied muscles [17]. Other experimental studies have also shown that mice bearing Walker 256 and MAC13/16 tumors developed cardiac cachexia in response to DNA and/or protein oxidative damage in heart tissues [20, 36]. Additionally, mice bearing C26 tumor exhibited an upregulation in gene-specific inflammation within heart and manifested a reduction in cardiomyocytes diameter, loss of ventricular mass, and systolic dysfunction [37–39].…”

Section: Multiorgan Presence Of Oxidative Stress Markers During Camentioning

confidence: 89%

The Janus-Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts

Assi

Rebillard

2016

Oxidative Medicine and Cellular Longevity

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Chronic inflammation and excessive loss of skeletal muscle usually occur during cancer cachexia, leading to functional impairment and delaying the cure of cancer. The release of cytokines by tumor promotes the formation of reactive oxygen species (ROS), which in turn regulate catabolic pathways involved in muscle atrophy. ROS also exert a dual role within tumor itself, as they can either promote proliferation and vascularization or induce senescence and apoptosis. Accordingly, previous studies that used antioxidants to modulate these ROS-dependent mechanisms, in cancer and cancer cachexia, have obtained contradictory results, hence the need to gather the main findings of these studies and draw global conclusions in order to stimulate more oriented research in this field. Based on the literature reviewed in this paper, it appears that antioxidant supplementation is (1) beneficial in cancer cachectic patients with antioxidant deficiencies, (2) most likely harmful in cancer patients with adequate antioxidant status (i.e., lung, gastrointestinal, head and neck, and esophageal), and (3) not recommended when undergoing radiotherapy. At the moment, measuring the blood levels of antioxidants may help to identify patients with systemic deficiencies. This approach is simple to realize but could not be a gold standard method for cachexia, as it does not necessarily reflect the redox state in other organs, like muscle.

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Oxidative and proteolytic profiles of the right and left heart in a model of cancer-induced cardiac cachexia

Cited by 20 publications

References 50 publications

Nutritional leucine supplementation attenuates cardiac failure in tumour‐bearing cachectic animals

Nutritional leucine supplementation attenuates cardiac failure in tumour‐bearing cachectic animals

Interference with Ca2+-Dependent Proteolysis Does Not Alter the Course of Muscle Wasting in Experimental Cancer Cachexia

The Janus-Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts

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