Beyond Performance: Creatine Delays the Onset of Fatigue and Augments Muscle Regeneration in Doxorubicin-Induced Myotoxicity

Doxorubicin (Dox) impairs myogenic regulatory factor (MRF) expression and induces myotoxicity, and previous studies showed that creatine (Cr) supplementation before Dox treatment prevents forelimb grip (FG) force reduction and alleviates fatigue. However, Cr supplementation’s effects on MRFs with Dox treatment are not well known. The effects of Cr on skeletal muscle function and MRFs 1, 3, and 5 days following Dox treatment are investigated. Male rats were randomly assigned to the control saline group (Con+Sal), control doxorubicin group (Con+Dox), standard Cr diet (2% Cr for 4 weeks) doxorubicin group (Cr1+Dox), or Cr loading diet (4% Cr for 1 week followed by 2% Cr 3 weeks) doxorubicin group (Cr2+Dox). After 4 weeks of feeding, Dox groups received 15 mg/kg Dox and Sal received saline as a placebo. At 1, 3, and 5 days postinjection, FG force and ex vivo muscle function of the extensor digitorum longus (EDL) were measured. Myf-6, Myf-5, MyoD, and myogenin expression was analyzed using Western blotting. At 5 days postinjection, Con+Dox, Cr1+Dox, and Cr2+Dox groups had significantly lower FG force than Con+Sal (P < .05). EDL maximal twitch force of Con+Dox, Cr1+Dox, and Cr2+Dox groups was significantly lower than Con+Sal (P < .05) at 3 and 5 days postinjection. At 1 and 5 days postinjection, Cr alleviated Dox-induced fatigue in EDL muscle. At 1-day postinjection, Cr1+Dox, and Cr2+Dox had significantly higher Myf-6 and myogenin expression than the Con+Sal group, and Cr2+Dox group had significantly higher Myf-5 and MyoD compared with the Con+Sal group (P < .05). Cr supplementation attenuated fatigue and enhanced early muscle repair and regeneration in Dox-induced myotoxicity.