Exercise, but Not Metformin Prevents Muscle Function Loss due to Doxorubicin in Mice Using an In‐Situ Model

Abstract

Doxorubicin (DOX) is a clinically relevant chemotherapeutic known to cause severe side effects in heart and skeletal muscle. The deleterious effects DOX elicits on skeletal muscle are concerning due to the high rates of severe fatigue experienced by chemotherapy patients. Identifying treatments that prevent this skeletal muscle dysfunction is critically important. Exercise (EX) and metformin (MET) have both been suggested as treatments to reduce the toxic effects of DOX. However, their effects on muscle function in the gastrocnemius‐plantaris‐soleus (GPS) complex are unknown. Additionally, the mechanism by which DOX decreases muscle function are still under investigation. DOX can cause mitochondrial disruption, but the direct effects of mitochondrial function on muscle function have not been studied in this model. The purpose of this study is three fold: (1) to determine if DOX decreased muscle function of the GPS complex using an in‐situ muscle fatigue protocol, (2) determine if EX or MET treatment can prevent muscle function loss due to DOX, and (3) determine if muscle function loss is due to a decrease in mitochondrial respiratory function. C57BL/6 mice were randomly assigned to 4 groups: CON, DOX, DOX+EX, or DOX+MET. DOX was administered as a single intraperitoneal injection at 15 mg/kg body weight 3 days before sacrifice. Moderate EX treatment was done by treadmill running for 60 minutes for 5 days at 70% max prior to DOX injection. MET treatment was administered via oral gavage at 500 mg/kg body weight for 5 days beginning 2 days before DOX injection. GPS complex muscle function was measured in‐situ using tetanic contractions elicited by direct stimulation in a 6 minute fatigue protocol. Real time mitochondrial respiratory function was measured in gastrocnemius muscle. We report that DOX treatment caused ~20% body weight loss at 3 days, an effect that was partially prevented in DOX+EX (p<0.05) or DOX+MET (p=0.06). A small decrease in total force production was observed with DOX, which trended towards significance (0.08≥p≤0.04). DOX+EX treatment restored force production back to CON levels, but DOX+MET did not. The half relaxation rate was impaired by an average of 18% with DOX treatment (p<0.05). DOX+EX prevented this impairment of the half relaxation rate (p<0.05). DOX+MET did not restore impaired half relaxation rate caused by DOX. Mitochondrial respiration was not different between the groups, suggesting that the changes in muscle function occur independent of mitochondrial function. In conclusion, DOX treatment decreased muscle function in the GPS complex by impairing half relaxation rates. EX but not MET treatment prevented impaired half relaxation rate. These changes occurred independent of mitochondrial respiration.Support or Funding InformationMentoring Environment Grant, Brigham Young UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.