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Hydock, David S.

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Doxorubicin (Dox) is a highly effective anticancer drug used to treat several cancer types; however, its use is limited due to its cytotoxicity (cardiotoxicity and myotoxicity). Doxorubicin-induced cardiotoxicity might occur within days and lead to congestive heart failure. Doxorubicin-induced myotoxicity involves fatigue, cachexia, and skeletal muscle dysfunction. Although the exact mechanisms causing Dox-induced cytotoxicity are not entirely understood, an alteration in the phosphocreatine system seems to be a central mechanism where studies showed Dox decreased phosphocreatine (PCr), creatine (Cr), impaired creatine kinase (CK) enzyme function, and decreased creatine transporter (CrT) expression in cultured cardiomyocytes. Ultimately, Dox-induced cytotoxicity might compromise quality of life and impair activities of daily living in cancer patients. Creatine supplementation is one promising non-pharmacological therapeutic intervention to alleviate Dox-induced cytotoxicity. One study showed that two weeks of Cr supplementation alleviated Dox-induced skeletal muscle fatigue; however, the effects of Cr supplementation on Dox-induced cytotoxicity specific to the phosphocreatine system have yet to be explored. The purpose of this study was to examine the effects of different doses of Cr supplementation before Dox treatment on mitochondrial CK (MtCK), cytosolic CK (CK-M), and creatine transporter (CrT) expression in cardiac and skeletal muscle. Sixty male rats were randomly assigned to one of two, four-week Cr feeding interventions (standard Cr diet or Cr loading diet) or a control diet group (Con, n = 20). Rats in the standard Cr diet (Cr1, n = 20) were fed 2% Cr for four weeks. Rats in the Cr loading diet (Cr2, n = 20) were fed 4% Cr for one week followed by 2% Cr for three weeks. After four weeks of feeding, rats received either a bolus 15 mg/kg Dox injection or a saline injection as a placebo (Sal). Five days following injections, left ventricle (LV), extensor digitorum longus (EDL), soleus (SOL), and diaphragm (DIA) were excised, weighed, and western blotting was performed to quantify MtCK, CK-M, and CrT expression. Enzyme-linked immunosorbent assays (ELISA) was done to verify western blot results. No significant main effects or interactions were observed for CK-M and CrT expression in LV but a significant drug effect was observed for MtCK with Con+Dox, Cr1+Dox, and Cr2+Dox expressing significantly lower MtCT than Con+Sal (p < 0.05). Enzyme-linked immunosorbent assays showed a main drug effect and a diet x drug interaction for MtCK in LV. In EDL, SOL, and DIA muscle, no main effects or interactions were observed for MtCK, CK-M, or CrT expression. Doxorubicin treatment decreased cardiac MtCK expression but Cr supplementation did not protect against these alterations. Impairments in MtCK might play a role in Dox-induced cardiotoxicity but nutritional Cr supplementation did not seem to provide protection. Further work should explore additional interventions to protect against Dox-induced MtCK changes.


176 pages

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