Tissue retention of doxorubicin and its effects on cardiac, smooth, and skeletal muscle function

Cancer-related fatigue is a pervasive syndrome experienced by a majority of cancer patients undergoing treatment, and muscular dysfunction may be a key component in the development and progression of this syndrome. Doxorubicin (DOX) is a commonly used antineoplastic agent used in the treatment of many cancers. The purpose of this study was to determine the effect of DOX exposure on the function of cardiac, skeletal, and smooth muscle tissues and examine the role accumulation of DOX may play in this process. In these studies, rats were treated with DOX and measurements of cardiac, skeletal, and smooth muscle function were assessed 1, 3, and 5 days after exposure. All muscular tissues showed significant and severe dysfunction, yet there was heterogeneity both in the time course of dysfunction and in the accumulation of DOX. Cardiac and skeletal muscle exhibited a time-dependent progressive decline in function during the 5 days following DOX treatment. In contrast, vascular function showed a decline in function that could be characterized as rapid onset and was sustained for the duration of the 5-day observation period. DOX accumulation was greatest in cardiac tissue, yet all muscular tissues showed a similar degree of dysfunction. Our data suggest that in muscular tissues both DOX-dependent and DOX-independent mechanisms may be involved with the muscular dysfunction observed following DOX treatment. Furthermore, this study highlights the fact that dysfunction of skeletal and smooth muscle may be an underappreciated aspect of DOX toxicity and may be a key component of cancer-related fatigue in these patients.