Background: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Methods: Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. Results: The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.

Cise might also be effective in addressing DOX’s skeletal muscle adverse effects, especially because posttreatment skeletal muscle dysfunction may cause patient difficulties with completing activities of daily living. The main aim of this study was to examine how resistance training (RT) and treadmill (TM) training play a role in preventing DOX-induced skeletal muscle dysfunction. Methods Male Sprague–Dawley rats were randomly placed into an RT, TM, or sedentary (SED) group for 10 wk and then received either a bolus injection of DOX (15 mg·kg−1) or saline as a control. Skeletal muscle function was then assessed ex vivo 5 d after injection. Results SED animals treated with DOX showed significantly lower maximal twitch force, maximal rate of force production, and maximal rate of force decline versus SED + saline in the soleus (SOL) (Type I muscle). In the extensor digitorum longus (Type II muscle), treatment with DOX resulted in a significantly lower maximal rate of force production and maximal rate of force decline. RT preserved maximal twitch force and maximal rate of force decline in the SOL. TM attenuated DOX-induced fatigue in the SOL but not in the extensor digitorum longus. Conclusion These findings suggest that RT and TM before DOX could be useful in preserving skeletal muscle function and minimizing fatigue after chemotherapy, but this protection may be dependent on the skeletal muscle type....

Supplementing the diet with creatine (Cr) to manage chemotherapy-induced skeletal muscle weakness and fatigue has potential, but little has been done exploring it as an intervention. This study examined the effects of Cr on skeletal muscle dysfunction induced by the chemotherapy drug doxorubicin (Dox). Soleus and extensor digitorum longus (EDL) from male Sprague-Dawley rats maintained in an organ bath were incubated in Krebs-Henseleit (KH) buffer with or without creatine monohydrate (25 mM) for 30 min. Skeletal muscle was then incubated in KH buffer with or without Dox (24 μM) for an additional 30 min. Baths were then refreshed with KH buffer, and a 100-s fatigue protocol was administered. At baseline (0 s time point), no significant differences in force production were observed in the slow, type I soleus, but the Dox-treated soleus fatigued quicker than the non-Dox-treated soleus; however, pretreatment with Cr extended the time to fatigue in the Dox-treated soleus. In the fast, type II EDL, Dox treatment decreased force production at baseline and increased fatigue, and Cr treatment prior to Dox attenuated this dysfunction. Creatine pretreatment mitigated Dox-induced skeletal muscle dysfunction ex vivo suggesting that Cr may play a role in managing Dox-induced skeletal muscle side effects.