The effect of doxorubicin administration on skeletal muscle

Skeletal muscle (SM) is the largest organ in the human body and represents approximately 40% of the total body weight. Maintenance of SM mass and integrity is dependent on the delivery and removal of essential metabolic products as well as the dynamic balance between protein synthesis and degradation. The health and maintenance of skeletal muscle in cancer patients is of particular importance, as the significant loss of muscular mass is an indication of cachexia, a serious life-threatening condition. Doxorubicin (DOX) is a broad-spectrum anti-cancer chemotherapeutic and remains one of the most widely used chemotherapeutic agents for the treatment of solid tumors and hematological malignancies. The clinical use of DOX is limited by a well described dosedependent and cumulative cardiotoxic side effect. The majority of DOX-related research remains focused on reducing cardiotoxicity while little is known of the effect of the drug on SM. Therefore, the purpose of the thesis was to study the effects of DOX chemotherapy on SM. Study 1. The purpose of Study 1 was to examine the accumulation of doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) in skeletal muscle of the rat up to 8 days after the administration of a 1.5 or 4.5 mg/kg i.p. dose. Subsequent to either dose, DOX and DOXol were observed in skeletal muscle throughout the length of the experiment. Interestingly an efflux of DOX was observed after 96 hrs, followed by an apparent reuptake of the drug which coincided with a spike and rapid decrease of plasma DOX concentrations. The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation. Furthermore, there was no evidence that DOX preferentially accumulated in a specific muscle group with either dose. Study 2. Study 2 examined intracellular and interstitial nitric oxide (NO) concentrations in the SM following the administration of DOX. A single dose of 1.5 or 4.5 mg/kg was administered intraperitoneally to male Sprague-Dawley rats and interstitial (IS) and intracellular (IC) NO was quantified every 24 up to 192 hrs. post injection. There was no significant difference in IC NO following the injection of 1.5 mg/kg DOX when compared to control, however the administration of 4.5 mg/kg DOX resulted in lower (P<0.05) concentrations of NO in the IC. Interestingly, a consistently higher (P<0.05) concentration of NO in the IS was established following the administration of 1.5 mg/kg compared to control while no significant changes in IS NO resulted from the administration of the 4.5 mg/kg dose. The fluctuation of IS and IC NO were not a result of substrate availability as arginine concentrations remained stable throughout the experiment. Study 3. The purpose of Study 3 was to examine the effect of DOX administration on IC, IS and vascular concentrations of amino acids (AA) in SM of the rat up to 8 days after the administration of a 1.5 or 4.5 mg/kg i.p. dose. Intracellular total amino acids (TAA), essential amino acids (EAA) and branched-chain amino acids (BCAA) were significantly increased in each muscle group analyzed, following the 1.5 and 4.5 mg/kg doses compared to control. In the plasma, TAA were significantly increased compared to control where greater (P>0.05) concentrations were observed following the 1.5 mg/kg dose compared to the 4.5 mg/kg dose. Compared to control, the 1.5 mg/kg dose resulted in an increase (P<0.05) in interstitial TAA whereas the 4.5 mg/kg resulted in a sustained decrease (P