Cardiac alterations in cancer-induced cachexia in mice

Tian, Min; Nishijima, Yoshinori; Michelle, L.; Stout, Michael B.; Reiser, Peter J.; Belury, Martha A.

doi:10.3892/ijo_00000683

Cited by 48 publications

(31 citation statements)

References 38 publications

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“…Notably, cardiac contractile function was maintained in the SS-31-treated C26 mice independent of preservation of cardiac mass. While the mechanisms are unclear, this observation is consistent with findings by Tian et al which revealed a significant reduction in absolute cardiac mass in C26 tumor-bearing mice and pair-fed mice compared to non-tumor-bearing mice; however, fractional shortening was maintained in pair-fed mice compared to C26 tumor-bearing mice [30].…”

Section: Discussionsupporting

confidence: 91%

“…Muscle mass was also preserved in C26 mice treated with SS-31. While changes in food intake could contribute to our findings, pair-fed and cachectic C26 tumor-bearing mice showed significant differences in cardiorespiratory muscle function and muscle mass when compared [29,30]. These data suggest that the effects to diaphragm and cardiac muscle were the result of tumor growth and SS-31 treatment.…”

Section: Discussionmentioning

confidence: 64%

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Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

et al. 2020

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Cancer cachexia is a syndrome characterized by profound cardiac and diaphragm muscle wasting, which increase the risk of morbidity in cancer patients due to failure of the cardiorespiratory system. In this regard, muscle relies greatly on mitochondria to meet energy requirements for contraction and mitochondrial dysfunction can result in muscle weakness and fatigue. In addition, mitochondria are a major source of reactive oxygen species (ROS) production, which can stimulate increased rates of muscle protein degradation. Therefore, it has been suggested that mitochondrial dysfunction may be an underlying factor that contributes to the pathology of cancer cachexia. To determine if pharmacologically targeting mitochondrial dysfunction via treatment with the mitochondria-targeting peptide SS-31 would prevent cardiorespiratory muscle dysfunction, colon 26 (C26) adenocarcinoma tumor-bearing mice were administered either saline or SS-31 daily (3 mg/kg/day) following inoculation. C26 mice treated with saline demonstrated greater ROS production and mitochondrial uncoupling compared to C26 mice receiving SS-31 in both the heart and diaphragm muscle. In addition, saline-treated C26 mice exhibited a decline in left ventricular function which was significantly rescued in C26 mice treated with SS-31. In the diaphragm, muscle fiber cross-sectional area of C26 mice treated with saline was significantly reduced and force production was impaired compared to C26, SS-31-treated animals. Finally, ventilatory deficits were also attenuated in C26 mice treated with SS-31, compared to saline treatment. These data demonstrate that C26 tumors promote severe cardiac and respiratory myopathy, and that prevention of mitochondrial dysfunction is sufficient to preclude cancer cachexia-induced cardiorespiratory dysfunction. Author contributions AJS, HHS and ARJ designed the study. AJS, BMR, MPW, OK, JY, DDC and DDF performed the experiments and analyzed the data. HHS provided the SS-31. AJS and ARJ wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 64%

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

et al. 2020

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“…In the present study, mice did not show signs of systemic inflammation, as the circulating levels of CRP and TWEAK were not increased, and this was paralleled by the absence of muscle wasting. Thus, our data suggest that tumor burden per se induces cardiac remodeling that precedes muscle wasting, which might be exacerbated when cachexia is established, as previously reported [20,21]. This cardiac remodeling observed in tumor-bearing mice was characterized by alterations on mitochondrial proteome with emphasis on the up-regulation of the biological process “cardiac tissue morphogenesis” and the down-regulation of “cellular respiration”.…”

Section: Discussionsupporting

confidence: 82%

Exercise Training Impacts Cardiac Mitochondrial Proteome Remodeling in Murine Urothelial Carcinoma

Ferreira

Neuparth

Nogueira-Ferreira

et al. 2018

IJMS

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Cardiac dysfunction secondary to cancer may exert a negative impact in patients’ tolerance to therapeutics, quality of life, and survival. The aim of this study was to evaluate the potential therapeutic effect of exercise training on the heart in the setting of cancer, after diagnosis. Thus, the molecular pathways harbored in heart mitochondria from a murine model of chemically-induced urothelial carcinoma submitted to 8-weeks of high intensity treadmill exercise were characterized using mass spectrometry-based proteomics. Data highlight the protective effects of high intensity exercise training in preventing left ventricle diastolic dysfunction, fibrosis, and structural derangement observed in tumor-bearing mice. At the mitochondrial level, exercise training counteracted the lower ability to produce ATP observed in the heart of animals with urothelial carcinoma and induced the up-regulation of fatty acid oxidation and down-regulation of the biological process “cardiac morphogenesis”. Taken together, our data support the prescription of exercise training after cancer diagnosis for the management of disease-related cardiac dysfunction.

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“…Tumor-bearing mice also exhibited increased cardiac fibrosis, decreased cardiac myofibrillar proteins, increased protein ubiquitination, and altered composition of MHC. Increased expression of brain natriuretic peptide, c-Fos and decreased peroxisome proliferator-activated receptor α and its responsive gene carnitine palmitoyltransferase 1 are noted in tumor-bearing mice[17, 18]. The expression of biomarkers of protein degradation is increased in the hearts of female CD2F1 mice with systolic and diastolic dysfunction induced by colon-26 tumor cells[19].…”

Section: Introductionmentioning

confidence: 99%

“…The expression of biomarkers of protein degradation is increased in the hearts of female CD2F1 mice with systolic and diastolic dysfunction induced by colon-26 tumor cells[19]. Others have found heart failure, decreased cardiac cell size, increased autophagy and normal caspase 3 activity and protein ubiquitination in male (but not female) CD2F1 (Balb/c X DBA2) mice injected with colon-26 adenocarcinoma cells[18, 20, 21]. In sum, animal models demonstrate reduced cardiac function, increased cardiac fibrosis with variable evidence for altered protein ubiquitination.…”

Section: Introductionmentioning

confidence: 99%

Impaired cardiac performance, protein synthesis, and mitochondrial function in tumor-bearing mice

et al. 2019

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BackgroundTo understand the underlying mechanisms of cardiac dysfunction in cancer, we examined cardiac function, protein synthesis, mitochondrial function and gene expression in a model of heart failure in mice injected with Lewis lung carcinoma (LLC1) cells.Experimental designSeven week-old C57BL/J6 male and female mice were injected with LLC1 cells or vehicle. Cardiac ejection fraction, ventricular wall and septal thickness were reduced in male, but not female, tumor-bearing mice compared to vehicle-injected control mice. Cardiac protein synthesis was reduced in tumor-bearing male mice compared to control mice (p = 0.025). Aspect ratio and form factor of cardiac mitochondria from the tumor-bearing mice were increased compared control mice (p = 0.042 and p = 0.0032, respectively) indicating a more fused mitochondrial network in the hearts of tumor-bearing mice. In cultured cardiomyocytes maximal oxygen consumption and mitochondrial reserve capacity were reduced in cells exposed to tumor cell-conditioned medium compared to non-conditioned medium (p = 0.0059, p = 0.0010). Whole transcriptome sequencing of cardiac ventricular muscle from tumor-bearing vs. control mice showed altered expression of 1648 RNA transcripts with a false discovery rate of less than 0.05. Of these, 54 RNA transcripts were reduced ≤ 0.5 fold, and 3 RNA transcripts were increased by ≥1.5-fold in tumor-bearing mouse heart compared to control. Notably, the expression of mRNAs for apelin (Apln), the apelin receptor (Aplnr), the N-myc proto-oncogene, early growth protein (Egr1), and the transcription factor Sox9 were reduced by >50%, whereas the mRNA for growth arrest and DNA-damage-inducible, beta (Gadd45b) is increased >2-fold, in ventricular tissue from tumor-bearing mice compared to control mice.ConclusionsLung tumor cells induce heart failure in male mice in association with reduced protein synthesis, mitochondrial function, and the expression of the mRNAs for inotropic and growth factors. These data provide new mechanistic insights into cancer-associated heart failure that may help unlock treatment options for this condition.

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Cardiac alterations in cancer-induced cachexia in mice

Cited by 48 publications

References 38 publications

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

Exercise Training Impacts Cardiac Mitochondrial Proteome Remodeling in Murine Urothelial Carcinoma

Impaired cardiac performance, protein synthesis, and mitochondrial function in tumor-bearing mice

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