Whole-body exercise following doxorubicin administration alters skeletal muscle drug accumulation and amino acid pools.

Abstract

Doxorubicin is a commonly used chemotherapy that rapidly accumulates within muscle and disrupts nitric oxide formation and amino acid homeostasis. Exercise has been lauded as a potential countermeasure to protect skeletal muscle from the harmful effects of the drug; however, little is known about how exercise impacts these factors following doxorubicin administration. Young, healthy male Sprague-Dawley rats (n = 36) were randomly assigned to experimental groups. All groups except true control received a 4.5 mg/kg intraperitoneal injection of doxorubicin. Dox24 and Dox48 rats were drug-only controls, harvested at 24 and 48  h post-injection, respectively. The remaining groups performed exercise at 24 h and were sacrificed immediately following (1EXE), exercised at 24 h followed by 24 h of recovery (1EXE + REC), and exercised at both 24 and 48 h (2EXE). Recovery following exercise elevated intramuscular doxorubicin, which was reduced by a secondary bout (p < 0.05). Intramuscular nitric oxide formation was significantly reduced by doxorubicin, and exercise did not restore levels to that of true control. Essential amino acids were reduced by exercise (p < 0.05). Glutamate was reduced (p < 0.05) in all groups except Dox24. Methionine was elevated (p < 0.05) in all groups compared to true control. The data suggest that multiple bouts of exercise are likely required to continuously remove doxorubicin from muscle. Exercise could not restore impaired nitric oxide production. Depleted glutamate and increased methionine suggest increased metabolism and production to combat oxidative stress and energetic constraints. Depleted essential amino acid pools highlight the importance of dietary intervention in exercise oncology settings.