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This study examined the effects of creatine supplementation (Cr) and resistance training (RT) on the myotoxicity that accompanies treatment with the chemotherapy drug doxorubicin (DOX). Male rats were randomly assigned to control (CON), DOX, RT+DOX, Cr+DOX, and Cr+RT+DOX groups. DOX groups received 1 mg/kg daily DOX injections for 12 days, Cr groups were fed a diet supplemented with 3% Cr, and RT groups were housed in resistance training model cages. Forelimb grip strength was assessed at baseline and at day 40 at which time the soleus and extensor digitorum longus were excised and analyzed for positive and negative myogenic regulator factor expression. Grip strength increased from baseline to day 40 only in CON and Cr+RT+DOX groups but not in DOX, Cr+DOX or RT+DOX suggesting that combined Cr and RT helps maintain grip strength with DOX treatment. Myostatin expression was lower in solei from RT+DOX, Cr+DOX, and Cr+RT+DOX when compared to CON but not in DOX, and a trend toward higher muscle ring finger (MuRF) expression in the DOX only group was observed. These data suggest that Cr supplementation with RT may be an effective non-pharmacological therapeutic strategy to battle DOX myotoxicity through modulation of negative myogenic regulatory factors.