Creatine Supplementation Mitigates Doxorubicin-Induced Skeletal Muscle Dysfunction but Not Cardiotoxicity

Creatine has demosntrated protective effects against muscle dysfunction, but its potential protection against doxorubicin-induced cardio and skeletal muscle toxicity remains poorly understood. We aimed to investigate the protective effects of creatine supplementation against doxorubicin-induced cardio and skeletal muscle myotoxicity. This study analyzed twenty male C57BL/6J mice, divided into three groups: Control (C; n = 6), Dox (n = 7) which received weekly doxorubicin injections (16 mg/kg i.p. in 20 days) and DoxCr (n = 7) with both doxorubicin and creatine supplementation (4%). Doxorubicin administration induced skeletal muscle atrophy in extensor digitorum longus (EDL) (-28%) and soleus muscles (-17%), accompanied by a decline in muscle strength. This atrophic response was concomitant with increased oxidative stress and elevated levels of IL-6. Cardiotoxic effects of doxorubicin were marked by a 15% reduction in cardiac mass and a significant 21% decrease in cardiomyocyte diameter, alongside a substantial 58% rise in IL-6 levels. On the opposite creatine supplementation mitigated doxorubicin-induced oxidative stress (elevated MDA and IL-6, and reduced GSH/GSSG ratio) and prevented skeletal muscle atrophy in both the EDL and soleus muscles, while also enhancing muscle strength. However, protective effects were not observed in cardiac muscle. Creatine protects skeletal, but not cardiac muscle against doxorubicin-induced toxicity, atrophy and strength loss.