Calcium handling proteins in the heart of tumor bearing mice

Abstract

Cachexia is a metabolic syndrome characterized by marked and unintentional weight loss and muscle atrophy. Other complications of this syndrome include fatigability, weakness, and loss of appetite. Cachexia can result from numerous sources such as: burns, AIDS, COPD, and cancer among others. The occurrence of cachexia reduces quality of life and indicates a poor prognosis with increased mortality. Currently, the means by which cachexia develops are poorly understood and additionally, there are no standard clinical methods approved to treat this syndrome. We hope the findings of our research can be applied clinically to patients afflicted with cachexia. Preliminary research in animal models of cachexia show depressed cardiac function, however, the molecular mechanism of dysfunction remains unknown. Using the heart tissue of mice injected with the Colon 26 adenocarcinoma, we looked at how the pathology affected the calcium channel handling proteins in the heart. To do this, we initially performed qPCR to identify gene expression changes that were significantly elevated or depressed in the tumor mice. After identifying possible gene expression targets we looked at protein levels using immunoblotting. Our results from the qPCR showed that Ryanodine Receptor 2 (RyR2) was elevated in the tumor mice when compared to control mice. Phospholamban (PLN) was also significantly depressed in the tumor mice when compared to control mice. At the protein level, we found significantly increased phosphorylated RyR2 (p-RyR2) with no change in total RyR2 levels. We also found no significant changes in PLN in terms of phosphorylation or total protein. Our findings may indicate that increased p-RyR2 is causing "leaky" Ca2+ channels, which may play a part in cardiac dysfunction. This indicates calcium handling is altered in the tumor-bearing mice, which is possibly contributing to cardiac dysfunction. This information furthers our understanding of the dysfunction in the heart with possible translational benefits. Patients affected with cachexia that have increased levels of p-RyR2 may be at risk for tachycardia or arrhythmia if calcium levels are unable to normalize.