# The SGLT2 inhibitor empagliflozin promotes increased fatty acid oxidation in skeletal muscle cells

## TL;DR

This study shows that empagliflozin, an SGLT2 inhibitor, changes energy metabolism in muscle cells by increasing fatty acid and leucine breakdown while reducing glucose and acetoacetate use.

## Contribution

The study reveals a novel metabolic effect of empagliflozin on skeletal muscle cells, specifically promoting fatty acid oxidation.

## Key findings

- Empagliflozin increased fatty acid and leucine catabolism in human myotubes.
- The drug reduced glucose and acetoacetate oxidation and glycolysis in muscle cells.
- AMPK and ACC phosphorylation was increased by empagliflozin in human myotubes.

## Abstract

In this study we investigated the potential for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) to modify energy metabolism in human primary skeletal muscle cells and mouse C2C12 skeletal muscle cells. The results showed that treatment of human myotubes with EMPA for 96 h decreased oxidation of exogenously added glucose and acetoacetate measured as CO2 production, whereas CO2 production from exogenously added fatty acids and leucine was increased compared to control cells. Uptake of acetoacetate by the cells was decreased by EMPA. Moreover, there were no EMPA-induced changes in glucose, fatty acid or leucine uptake by human myotubes, neither was lactate concentration in cell culture medium changed after exposure to EMPA. Treatment with EMPA increased phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in human myotubes, while there was no effect of EMPA in human myotubes on gene expression of selected metabolic genes. Real time cell metabolic analysis in C2C12 cells showed that EMPA reduced basal respiration and glycolysis, while under conditions promoting use of endogenous fatty acids, maximal respiration and ATP production was increased by EMPA. In summary, treatment of skeletal muscle cells in vitro with EMPA caused changes in energy metabolism promoting enhanced fatty acid and leucine catabolism, decreased metabolism of glucose and acetoacetate, and reduced glycolysis. The observed changes in energy metabolism may be related to AMPK activation.

The online version contains supplementary material available at 10.1007/s00210-025-04670-2.