Recently, the interdisciplinary field of cardio-oncology has emerged to study the mechanisms of cardiac dysfunction associated with cancer treatment and how to prevent it. In this study, we investigated possible therapeutic effects of voluntary wheel running (VWR) on cardiac dysfunction observed in a cancer-cachexia model mice established by our laboratory. VWR starting from 2 to 6 wks after implantation of tumor cells significantly suppressed the loss of heart and skeletal muscle weight as well as general symptoms of cachexia. Moreover, left ventricular ejection fraction significantly increased in cachexia group with VWR, compared to those without VWR. Microarray analysis revealed that the expression of gene “X”, which is an enzyme belonging to E3 ubiquitin ligase family and has not been reported to be related to skeletal muscular atrophy, increased in the myocardium of cachexia mice, and that this increase was suppressed by VWR. These results suggest that the mechanism of myocardial impairment may be different from that of skeletal muscle atrophy, and that VWR may improve not only cachexia symptoms but also cachexia-induced cardiac dysfunction. In addition, the gene “X” may be one of key factors which are associated with myocardial atrophy and cardiac dysfunction on cancer cachexia. The pathway mediated by the gene “X” is currently being further analyzed.