Effects of SGLT2 inhibition with ertugliflozin on myocardial remodeling, energetics and gene expression in the presence and absence of diabetes in mice

Background: Inhibitors of sodium glucose linked transporter 2 (SGLT2i) improve heart failure (HF) outcomes in patients independent of diabetes. While animal studies suggest SGLT2i improve cardiac metabolism, the effect of SGLT2i on mitochondrial function in the heart is not known. Our goal was to assess the effects of SGLT2i on mitochondrial function, high energy phosphates and genes encoding mitochondrial proteins in hearts of mice with and without diet-induced diabetes. Methods & Results: Ertugliflozin (Ertu; formulated to 0.5 mg/g of diet) was given for 4 months to mice fed a high fat, high sucrose (HFHS) diet that causes diabetic cardiomyopathy or control diet (CD). Mitochondrial function was measured in isolated cardiac mitochondria. Myocardial energetics were assessed by NMR spectroscopy simultaneously with systolic function in isolated beating hearts. Myocardial gene expression was assessed by RNA seq using gene set enrichment analysis. HFHS diet caused myocardial hypertrophy and diastolic dysfunction, mitochondrial dysfunction (decreased ATP production, increased reactive oxygen species release) and an impaired energetic response to increased work demand - all of which were prevented by Ertu. Conctractile function, as reflected by the rate x pressure product (RPP), was super-normalized to a value 124% of CD hearts at high work demand. In control mice, Ertu had no effect on isolated mitochondria function or high energy phosphates, but similar to HFHS hearts, caused super-normalization of RPP to 125% of CD hearts. By GSEA the highest scoring gene set for Ertu treatment was oxidative phosphorylation (OXPHOS), which was up-regulated across all groups while controlling for diet with a Normalized Enrichment Score (NES) of +3.71, and was similarly up-regulated in HFHS-fed mice (NES, +3.32) and in CD-fed mice (NES, +3.34). Fatty acid metabolism (FAM) was the second-highest scoring gene set for Ertu, and, like OXPHOS, was up-regulated independent of diet (NES, +2.82). Conclusion: The super-normalization of contractile function and induction of the OXPHOS and FAM gene sets by Ertu are independent of diabetic status. Pro-metabolic remodeling of the myocardium by Ertu may support increased contractile function and contribute to the beneficial actions of Ertu in states such as heart failure that are associated with impaired cardiac mitochondrial function. Overall design: 4 representative left ventriclar cardiac tissue samples per group (out of 12 total available samples per group in the study) were assessed, for a total of 16 samples in the RNAseq. The reference group is the control diet (CD) group without Ertugliflozin treatment.