Electrical stimulation-induced muscle contraction does not reduce intramuscular accumulation of Doxorubicin 24 hours following administration

Background: Doxorubicin (Dox) is a commonly used chemotherapeutic drug. Although an effective anti-cancer agent, it can be profoundly toxic to skeletal muscle (SM). Dox has been demonstrated to accumulate rapidly in SM, leading to tissue damage and cellular dysfunction. Exercise prior to Dox treatment may reduce drug accumulation. However, little is known about the effects of exercise on intramuscular accumulation following Dox administration. Electrical stimulation (stim) could be a low-effort way to exercise SM following Dox administration; however, it has yet to be investigated in this context. Aim: This study aimed to determine if various stim protocols could reduce Dox accumulation in rodent hindlimb muscles 24 hours following drug administration. Hypothesis: Stim-induced muscle contraction will reduce intramuscular accumulation of Dox in a time- and intensity-dependent manner when compared to unstimulated muscles. Methods: Male Sprague-Dawley rats (n=42) were randomly assigned to one of six stim protocols (1 Hz or 3 Hz, for 5, 15, or 30 minutes) or a true control group. Stim groups received a single intraperitoneal dose of Dox (4.5 mg/kg). Twenty-four hours following Dox administration, the assigned stim protocol was carried out on the left sciatic nerve while the right leg served as an intra-individual control. Tissues and plasma were immediately harvested following the stim protocol to determine the acute effects of SM contraction. Drug and metabolite concentrations were assessed in both tissue and plasma using high-performance liquid chromatography. Results: None of the stim protocols investigated led to a reduction in intramuscular accumulation of Dox in the white gastrocnemius [summed data: 3.09±0.76 (stimulated leg) vs. 2.49±0.16 nmol/kg (unstimulated leg), p>0.05] or the soleus [summed data: 1.8±0.27 (stimulated leg) vs.1.5±0.23 nmol/kg (unstimulated leg), p>0.05]. These data are supported by plasma Dox concentrations which were similar in all groups (p>0.05), suggesting minimal uptake or release of Dox by SM. The concentration of Doxorubicinol, a highly toxic metabolite of Dox, also remained unchanged in both muscles and plasma (p>0.05). Conclusion: Electrical stimulation-induced muscle contraction did not reduce intramuscular accumulation of Dox 24 hours following drug administration. While unable to reduce accumulation, stim may still be a valuable tool for maintaining muscle mass and function during Dox treatment. Further investigation is required to characterize and optimize the role of stim during chemotherapy. Funding: This study was funded by a Rene Guilbeault Research Award. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.