Abstract Body: Objective:
Heart failure in cancer patients remains underrepresented and challenging due to non-specific treatments and an incomplete understanding of cancer or cancer cachexia–induced cardiomyopathy. This study explores the roles of sarcomere impairment, altered Ca²⁺ handling, and metabolic reprogramming in contributing to left ventricular (LV) dysfunction.
Methods:
Male BALB/c mice were subcutaneously inoculated with mouse colon-26 adenocarcinoma (C26) or IL-6–silenced C26 (C26 shIL-6) cells, while controls received PBS. Twenty days post-injection, cardiac function was evaluated via electrocardiography, transthoracic echocardiography, and ex vivo working heart assays. Isolated ventricular cardiomyocytes were analyzed for intracellular Ca²⁺ transients and force–calcium relationships. Cardiac inflammation, metabolism, and fibrosis were quantified alongside proteomic analysis.
Results:
Despite similar tumor sizes, C26 mice exhibited cachexia with loss of subcutaneous fat and skeletal muscle and elevated serum IL-6. Both tumor-bearing groups trended toward impaired LV systolic and diastolic function, with a significant reduction in maximum calcium-activated tension (T_max; p < 0.05) in skinned cardiomyocyte preparations. Cachectic mice showed increased intracellular Ca²⁺ transients, suggesting upregulated SERCA2 activity. While macrophage and T-cell infiltration and interstitial fibrosis were unchanged, neutrophil infiltration was enhanced in the cachectic group. Additionally, β-myosin heavy chain expression was upregulated, and metabolic profiling revealed a shift toward glucose utilization with reduced fatty acid oxidation, corroborated in h9c2 cells exposed to conditioned media from C26 and C26 shIL-6 cells. Unbiased proteomic analysis demonstrated significant downregulation of Bag3, Hspa4, Pln, Serca2, Pfkm, and Shdh exclusively in cachectic hearts.
Discussion
In conclusion, cancer-induced cachexia in C26 mice leads to LV dysfunction, characterized by altered calcium handling in cardiomyocytes, metabolic reprogramming, and sarcomere impairment. These findings highlight key mechanisms contributing to cardiomyopathy in cachexia and provide potential targets for therapeutic intervention in cancer-related cardio metabolic dysfunction.