Chronic doxorubicin administration impacts satellite cell and capillary abundance in a muscle-specific manner

Anthracycline chemotherapies are effective at reducing disease recurrence and mortality in cancer patients. However, these drugs also contribute to skeletal muscle wasting and dysfunction. The purpose of this study was to assess the impact of chronic doxorubicin (DOX) administration on satellite cell and capillary densities in different skeletal muscles. We hypothesized that DOX would reduce satellite cell and capillary densities of the soleus (SOL) and extensor digitorum longus (EDL) muscles, along with muscle fiber size. Ovariectomized female Sprague-Dawley rats were randomized to receive three bi-weekly intraperitoneal injections of DOX (4 mg∙kg^-1; cumulative dose 12 mg∙kg^-1) or vehicle (VEH; saline). Animals were euthanized 5d following the last injection and the SOL and EDL were dissected and prepared for immunohistochemical and RT-qPCR analyses. Relative to VEH, CSA of the SOL and EDL fibers were 26% and 33% smaller, respectively, in DOX (P < 0.05). In the SOL, satellite cell and capillary densities were 39% and 35% lower, respectively, in DOX (P < 0.05), whereas in the EDL satellite cell and capillary densities were unaffected by DOX administration (P > 0.05). Proliferating satellite cells were unaffected by DOX in the SOL (P > 0.05). In the SOL, MYF5 mRNA expression was increased in DOX (P < 0.05), while in the EDL MGF mRNA expression was reduced in DOX (P < 0.05). Chronic DOX administration is associated with reduced fiber size in the SOL and EDL; however, DOX appeared to reduce satellite cell and capillary densities only in the SOL. These findings highlight that therapeutic targets to protect skeletal muscle from DOX may vary across muscles.