Doxorubicin Administration Increases Markers of Autophagy in Skeletal Muscle

Abstract

Doxorubicin is an effective antitumor agent used in cancer treatment. However, doxorubicin can also cause muscle toxicity and can result in significant reduction in skeletal muscle mass and function. The mechanism(s) by which doxorubicin induces toxicity in skeletal muscle is unclear. However, doxorubicin-induced toxicity is associated with increased generation of reactive oxygen species and oxidative damage within muscle fibers. In this regard, autophagy can be induced by oxidative stress and it is also a constitutively active catabolic process that degrades oxidized proteins. PURPOSE: We hypothesized that systemic doxorubicin administration in rats would promote increased autophagy in skeletal muscle as evidenced by increased components of the autophagy system. METHODS: To test this postulate, adult, male Sprague-Dawley rats were randomly assigned to placebo or doxorubicin groups. The doxorubicin animals received doxorubicin hydrochloride (20 mg/kg body weight IP) 24 hours prior to sacrifice, whereas the placebo groups received saline injections. The soleus muscles were excised and used for biochemical analyses. RESULTS: Doxorubicin administration resulted in increased levels of mRNA and protein abundance of proteins involved in autophagy. Specifically, the mRNA levels of cathepsin L (+3.6±0.2), LC3 (+1.7±0.3), beclin (+3.5±0.6), and ATG12 (+3.4±0.5) were significantly (p<0.05) elevated in soleus muscle following doxorubicin administration. Also, the protein levels of cathepsin L (+1.5±0.1) and beclin (+1.4±0.1) were significantly (p<0.05) elevated in soleus muscle isolated from animals treated with doxorubicin. CONCLUSION: These findings demonstrate that doxorubicin administration increases the expression of several key autophagy regulatory genes in skeletal muscle. These increases suggest that autophagy is upregulated in skeletal muscle following doxorubicin administration and may lead to a reduction in skeletal muscle mass and function.