Low‑dose spironolactone attenuates metabolic defects in the skeletal muscle of letrozole‑induced hyperandrogenic female rats

Abstract

Purpose Hyperandrogenism is characterized by high levels of testosterone, which has been reported to cause insulin resistance and other metabolic adversities. Spironolactone (SPL) is a mineralocorticoid receptor blocker with anti-inflammatory effects. However, it is unknown whether SPL would restore skeletal muscle defect against letrozole-induced hyperandrogenism. Therefore, the present study investigated the hypothesis that low-dose SPL would attenuate skeletal muscle defect in hyperandrogenic female rats. Methods Eight-week-old female Wistar rats were divided into three groups, namely, control, letrozole (LET)-treated, and LET + SPL-treated groups. The control received vehicle, LET-treated group received 1 mg/kg of LET, and LET + SPL-treated group received a combination of LET and SPL (0.25 mg/kg). The administrations were done by oral gavage for 21 days uninterruptedly. Biochemical analyses were determined with appropriate assay methods. Results The results of this experiment showed that letrozole increased plasma testosterone and leptin and caused insulin resistance and increased triglyceride, total cholesterol, free fatty acids, pro-inflammatory markers (TNF-α and NF-κB), lipid peroxidation markers (MDA), and apoptosis in the skeletal muscle. Nevertheless, administration of low-dose SPL attenuated these alterations in skeletal muscles. Conclusion The present study demonstrates that letrozole-induced hyperandrogenism causes metabolic-driven apoptosis in the skeletal muscles. Hence, low-dose SPL mitigates metabolic defect and apoptosis in the skeletal muscles of hyperandrogenic female rats.