Examination Of The Time Course Effect Of Creatine Supplementation On Acute Doxorubicin-induced Skeletal Muscle Dysfunction

Abstract

Chemotherapy drugs such as doxorubicin (Dox) may cause skeletal muscle dysfunction, and supplementing the diet with creatine (Cr) could counteract skeletal muscle dysfunction. Very little has been done, however, exploring the time course effects of Cr on Dox-induced skeletal muscle dysfunction. PURPOSE: To examine the effects of Cr on skeletal muscle function 1, 3, and 5 days following Dox treatment. METHODS: Male rats were randomly assigned to the control group (Con), the doxorubicin group (Dox), the standard Cr diet (2% Cr for 4 weeks) and doxorubicin group (Cr1+Dox), or the Cr loading diet (4% Cr for 1 week followed by 2% Cr 3 weeks) and doxorubicin group (Cr2+Dox). After 4 weeks of feeding, Dox groups received 15 mg/kg Dox and Con received saline. At 1, 3, and 5 days post-injection, grip force and extensor digitorum longus (EDL) forces during a 100 s ex vivo fatigue protocol were measured. RESULTS: No between group differences in grip force were observed 1 day post injection, but at 3 days, a between group difference in grip force was observed (p=0.03) with Dox and Cr1+Dox having lower grip forces than Con (-9.8% and -10.5%, respectively, p<0.05), but this difference was not observed in Cr2+Dox. A between group difference in grip force was also observed at the 5 day time point (p<0.0001) with Dox, Cr1+Dox, and Cr2+Dox having lower grip force than Con (-19.9%, -37.2%, and -19.5%, respectively, p<0.05). With ex vivo EDL function, no between group differences were observed 1 day post injection, but at day 3, EDLs from Dox generated less force than Con at the 10 s through 40 s and the 70 s through 100 s time points (p<0.05), but these differences were not observed in Cr1+Dox and Cr2+Dox. At day 5, Cr1+Dox EDLs generated significantly less force than Con at every time point during the 100 s fatigue protocol (p<0.05), and Cr2+Dox EDLs generated significantly less force than Con at the 10 s through 40 s time points (p<0.05). CONCLUSIONS: Cr supplementation provided protection against Dox-induced muscle dysfunction 3 days post injection, and this protection was more evident with the Cr loading diet (Cr2). This myoprotection, however, was not observed 5 days post Dox injection suggesting that Cr’s benefit may be limited to protecting against the early phases of acute Dox myotoxicity.