Therapeutic effects of voluntary wheel running on cardiac dysfunction induced by cancer cachexia

[Speaker] Susumu Ueno:1
[Co-author] Miki Nonaka:2, Ryo Kakigi:3, Nagomi Kurebayashi:4, Takashi Murayama:4, Kiyoshi Terawaki:5, Takashi Sakurai:4, Yasuhito Uezono:2,6
1:Department of Occupational Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan, 2:Division of Cancer Pathophysiology, National Cancer Center Research Institute, Japan, 3:Department of Physiology, Juntendo University Graduate School of Medicine, Japan, 4:Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Japan, 5:Tsumura Kampo Research Laboratories, Kampo Research & Development Division, Tsumura & Co., Japan, 6:Division of Supportive Care Research, National Cancer Center, Exploratory Oncology Research & Clinical Trial Center, Japan

 Cardiovascular diseases in cancer patients with cachexia recently have become a great concern. However, the relationship between cancer cachexia and cardiac function remains unclear, because of few suitable models developing cancer cachexia similar to that of humans. We have established a novel cancer cachexia mouse model by implantation of the human stomach cancer cell line, showing anorexia, weight loss and low fat-free mass similar to those observed in human patients. Moreover, cardiac dysfunction is expected in this model, which has not been yet examined. In the present study, we firstly evaluated cardiac functions with the model. Secondly, we investigated effects of voluntary wheel running on cachexia-induced cardiac dysfunction using this model, as the exercise is considered to be one of therapy for chronic heart failure.
[Methods and Results]
 Cachexia-inducible 85As2 cell, derived from human stomach cancer cell, were inoculated once subcutaneously in both flanks (1 × 106 cells/site) to 8 weeks old male BALB/c nu/nu mice, which showed a symptomatic cachexia at 2 weeks after cancer implantation; decrease in body, skeletal muscle, and heart weight as well as food intake. With the model, we assigned into two groups as pre-cachexia (2 weeks after implantation) and cachexia (8 weeks after implantation) groups, respectively. The cachexia group developed severe cardiac atrophy with 69% decrease in heart weight compared to controls. In addition, left ventricular ejection fraction (LVEF) was markedly reduced in pre-cachexia (54.0 ± 2.2%) and cachexia (48.4 ± 0.2%) groups, respectively, compared with age-matched controls (64.9 ± 1.4% and 63.7 ± 1.0%, respectively). Moreover, voluntary wheel running improved LVEF with suppression of heart weight loss.
 These results imply that our 85As2 cachexia mice model is suitable for studying cancer cachexia with heat failure. Additionally, voluntary exercise could improve cachexia-induced cardiac dysfunction, suggesting a possible therapeutic effect of exercise on chronic heart failure induced by cancer cachexia.

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