Background: Cancer-associated cardiac cachexia (CACC) refers to cardiac injury in cancer patients in a malignant state, but preclinical animal models remain inadequately developed.
Methods: This study established CACC models in C57BL/6J and BALB/c mice using orthotopic, intra-abdominal, and hematogenous metastatic tumor induction. Multimodal cardiac assessments, including echocardiography, transmission electron microscopy for myocardial ultrastructural and mitochondrial analysis, and ex vivo cardiomyocyte contractility assays, were systematically applied.
Results: Metastatic burden triggered CACC characterized by cardiac mass reduction, epicardial fat depletion, interstitial fibrosis, and electrocardiographic abnormalities. Histopathological analysis revealed cardiomyocyte atrophy, myofibrillar disarray, mitochondrial dysfunction, and ubiquitin-mediated Myh6 degradation via MuRF-1, accompanied by compensatory Myh7 upregulation. These findings mechanistically link tumor-induced cachexia to cardiac dysfunction through contractile protein remodeling.
Conclusion: This work establishes a preclinical framework for targeting ubiquitin pathways to mitigate the morbidity of cancer-related cardiopathy. Our integrated approach delineates a hierarchical progression from subcellular dysfunction to macroscopic cardiac deterioration.
| [1] |
Zaorsky NG, Churilla TM, Egleston BL, et al. Causes of death among cancer patients. Ann Oncol. 2017;28:400-407.
|
| [2] |
Tomasin R, Martin A, Cominetti MR. Metastasis and cachexia: alongside in clinics, but not so in animal models. J Cachexia Sarcopenia Muscle. 2019;10:1183-1194.
|
| [3] |
Belloum Y, Rannou-Bekono F, Favier FB. Cancer-induced cardiac cachexia: pathogenesis and impact of physical activity (review). Oncol Rep. 2017;37:2543-2552.
|
| [4] |
Ausoni S, Calamelli S, Saccà S, Azzarello G. How progressive cancer endangers the heart: an intriguing and underestimated problem. Cancer Metastasis Rev. 2020;39:535-552.
|
| [5] |
Anker SD, Sharma R. The syndrome of cardiac cachexia. Int J Cardiol. 2002;85:51-66.
|
| [6] |
Murphy KT. The pathogenesis and treatment of cardiac atrophy in cancer cachexia. Am J Physiol Heart Circ Physiol. 2016;310:H466-H477.
|
| [7] |
Tichy L, Parry TL. The pathophysiology of cancer-mediated cardiac cachexia and novel treatment strategies: a narrative review. Cancer Med. 2023;12:17706-17717.
|
| [8] |
Anker MS, von Haehling S, Landmesser U, Coats AJS, Anker SD. Cancer and heart failure-more than meets the eye: common risk factors and co-morbidities. Eur J Heart Fail. 2018;20:1382-1384.
|
| [9] |
Brancaccio M, Pirozzi F, Hirsch E, Ghigo A. Mechanisms underlying the cross-talk between heart and cancer. J Physiol. 2020;598:3015-3027.
|
| [10] |
Kazemi-Bajestani SM, Becher H, Fassbender K, Chu Q, Baracos VE. Concurrent evolution of cancer cachexia and heart failure: bilateral effects exist. J Cachexia Sarcopenia Muscle. 2014;5:95-104.
|
| [11] |
Burch GE, Phillips JH, Ansari A. The cachetic heart. A clinico-pathologic, electrocardiographic and roentgenographic entity. Dis Chest. 1968;54:403-409.
|
| [12] |
Toepfer CN, Garfinkel AC, Venturini G, et al. Myosin sequestration regulates sarcomere function, Cardiomyocyte energetics, and metabolism, informing the pathogenesis of hypertrophic cardiomyopathy. Circulation. 2020;141:828-842.
|
| [13] |
Anker MS, von Haehling S, Coats AJS, et al. Ventricular tachycardia, premature ventricular contractions, and mortality in unselected patients with lung, colon, or pancreatic cancer: a prospective study. Eur J Heart Fail. 2021;23:145-153.
|
| [14] |
Lee DH, Park S, Lim SM, et al. Resting heart rate as a prognostic factor for mortality in patients with breast cancer. Breast Cancer Res Treat. 2016;159:375-384.
|
| [15] |
Fernandes LG, Tobias GC, Paixão AO, Dourado PM, Voltarelli VA, Brum PC. Exercise training delays cardiac remodeling in a mouse model of cancer cachexia. Life Sci. 2020;260:118392.
|
| [16] |
Mühlfeld C, Das SK, Heinzel FR, et al. Cancer induces cardiomyocyte remodeling and hypoinnervation in the left ventricle of the mouse heart. PLoS One. 2011;6:e20424.
|
| [17] |
Tian M, Nishijima Y, Asp ML, Stout MB, Reiser PJ, Belury MA. Cardiac alterations in cancer-induced cachexia in mice. Int J Oncol. 2010;37:347-353.
|
| [18] |
Xu H, Crawford D, Hutchinson KR, et al. Myocardial dysfunction in an animal model of cancer cachexia. Life Sci. 2011;88:406-410.
|
| [19] |
Braun TP, Zhu X, Szumowski M, et al. Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J Exp Med. 2011;208:2449-2463.
|
| [20] |
Burfeind KG, Michaelis KA, Marks DL. The central role of hypothalamic inflammation in the acute illness response and cachexia. Semin Cell Dev Biol. 2016;54:42-52.
|
| [21] |
Perera S, Holt MR, Mankoo BS, Gautel M. Developmental regulation of MURF ubiquitin ligases and autophagy proteins nbr1, p62/SQSTM1 and LC3 during cardiac myofibril assembly and turnover. Dev Biol. 2011;351:46-61.
|
| [22] |
Peris-Moreno D, Taillandier D, Polge C. MuRF1/TRIM63, master regulator of muscle mass. Int J Mol Sci. 2020;21:6663.
|
| [23] |
Ogilvie LM, Delfinis LJ, Coyle-Asbil B, et al. Cardiac atrophy, dysfunction, and metabolic impairments: a cancer-induced cardiomyopathy phenotype. Am J Pathol. 2024;194:1823-1843.
|
RIGHTS & PERMISSIONS
2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.
PDF
