Effects of In Vivo Doxorubicin Treatment on Skeletal Muscle Function

Abstract

It is well known that the chemotherapy drug doxorubicin (DOX) is associated with a dose dependent cardiotoxicity, and thus the primary focus of DOX-induced side effects has been the heart. However, there is evidence that DOX also imparts a negative effect on skeletal muscle, but at this point, the nature of this DOX-induced myotoxicity is currently unknown. PURPOSE: To investigate the effects of varying in vivo DOX doses on skeletal muscle function. METHODS: Male rats were randomly assigned to receive 10 mg/kg DOX (DOX1), 12.5 mg/kg DOX (DOX2), 15 mg/kg DOX (DOX3), or control vehicle (CON). Five days following injections, animals were anesthetized and the soleus and extensor digitorum longus (EDL) muscles were excised for ex vivo muscle function analysis. Muscles were maintained in 37°C oxygenated Krebs buffer, and the proximal end of the muscle was mounted to a stationary glass hook while the distal end was affixed to an isometric force transducer. Maximal twitch contraction properties and fatigue rates were determined for all muscles using field stimulating platinum electrodes. RESULTS: Maximal twitch force was significantly reduced in solei from DOX2 and DOX3 when compared to controls (-60% and -72%, respectively, p<0.05). Likewise, DOX2 and DOX3 solei possessed a significantly lower maximal rate of force production (-64% and -72%, respectively, p<0.05) and maximal rate of force decline (-52% and -59%, respectively, p<0.05) when compared to CON. Only EDL muscles from DOX3 possessed significantly different maximal twitch force, maximal rate of force production, and maximal rate of force decline when compared to CON (-67%, -72%, and -60%, respectively, p<0.05). Using a 100 s fatigue protocol, fatigue rate pattern differences were observed in the solei only. Whereas CON solei produced less force than baseline at 70 seconds, DOX1, DOX2, and DOX3 all produced less force than baseline at 30 seconds. CONCLUSIONS: DOX treatment altered muscle function in a dose-dependent manner, and the effects were more profound in the soleus than the EDL. Skeletal muscle dysfunction may, therefore, be contributing to the fatigue experienced by cancer patients receiving DOX which suggests that approaches aimed at minimizing DOX-induced side effects should also target skeletal muscle.