Dysregulation of lipid metabolism in cardiac muscle of mice with cachexia

Abstract

Approximately 30% of all cancer deaths are caused by cachexia, a condition of severe muscle loss and abnormal lipid metabolism. The objective of this study was to elucidate events that lead to impaired lipid metabolism and muscle wasting in cardiac muscle of mice exhibiting cancer‐induced muscle atrophy. In male CD2F1 mice injected with C26 tumor cells, body weight and mass of quadriceps, gastrocnemius and heart were significantly reduced after 18 days compared to mice injected with vehicle. In the highly oxidative cardiac muscle of mice bearing tumors, phosphorylated‐AMP dependent kinase (AMPK) was elevated. However, a rate limiting enzyme in β‐oxidation, carnitine palmitoyl transferase‐1β (CPT‐1β) mRNA expression was reduced by 40% while peroxisome proliferator‐activated receptor α (PPARα) mRNA was reduced by 35%. In contrast, mRNA levels of lipoprotein lipase (LPL) and adipose triglyceride lipase (ATGL) were induced, suggesting increased fatty acid uptake and lipolysis. Unexpectedly, uncoupling protein 2 (UCP2) mRNA was induced 5.3 fold. Activated AMPK with increased fatty acid uptake without induction of markers of β‐oxidation suggest that downstream events of AMPK are dysregulated in cachexia‐induced atrophy of cardiac muscle. Further work will determine whether induction of UCP2 alleviates reactive oxygen species (ROS) and results in thermogenesis. Supported by Cognis Corporation and OARDC.