Empagliflozin does not rescue nor exacerbate doxorubicin-induced skeletal muscle wasting and metabolic dysfunction in male mice

This is the authors' abstract. We don't add key points for this paper.

Doxorubicin (DOX) can induce skeletal muscle and white adipose tissue (WAT) wasting, contributing to treatment-related body mass loss, functional decline and compromised treatment efficacy. Impaired protein turnover and energy metabolism have been proposed as contributing mechanisms. Sodium–glucose cotransporter-2 inhibitors (SGLT2is) induce glucosuria and systemic metabolic adaptations that may improve skeletal muscle protein homeostasis and metabolic regulation. Concurrently, the glucosuria-induced caloric loss associated with SGLT2is may interfere with tissue wasting. This study investigated whether empagliflozin (EMPA) modifies DOX-induced tissue wasting in male mice. C57BL/6J mice ( n = 36) were randomized to control, EMPA, DOX, or DOX-EMPA groups. DOX (4 mg/kg/week, intraperitoneally) and EMPA (10 mg/kg/day, oral gavage) were administered for 6-weeks. Whole-body energy metabolism was assessed by indirect calorimetry, followed by tissue weight and molecular analyses in skeletal muscle and WAT. EMPA neither attenuated nor exacerbated DOX-induced body weight, skeletal muscle, or WAT loss. Despite effective glucosuria, EMPA did not increase non-fasted circulating β-hydroxybutyrate levels or meaningfully modify DOX-associated alterations in whole-body energy metabolism, tissue wasting, molecular markers of skeletal muscle protein turnover and metabolic regulation, or metabolic and stress-related gene expression in WAT. In conclusion, EMPA did not protect against DOX-induced tissue wasting and associated metabolic dysfunction, nor did it aggravate these effects.