Abstract Body: Background:
Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by mutations in the DMD gene that eliminate functional dystrophin, leading to progressive motor decline and life-threatening cardiorespiratory complications. We investigated the therapeutic potential of empagliflozin (EMPA), a sodium/glucose cotransporter-2 inhibitor, on cardiac function and its impact on myocardial proteomic and metabolomic profiles in DMD.
Methods:
Adult male mdx mice (12-14 weeks) and DMD^mdx rats (14-16 weeks) received EMPA, 30 mg/kg/day for mice and 10 mg/kg/day for rats, via drinking water for 4 months. Age- and sex-matched C57BL/10J mice and Sprague Dawley rats served as controls. Echocardiography at baseline and 12 weeks measured left ventricular ejection fraction (LVEF), fractional shortening (FS), cardiac output, heart rate, and stroke volume. In DMD^mdx rats, high-throughput proteomic and metabolomic analyses of left ventricular tissue were performed, followed by in-silico pathway and transcription factor evaluations.
Results:
Cardiac function was markedly declined in both model of DMD (In C57BL/10J mice, the left ventricular ejection fraction (LVEF) was 68 ± 6.3%, while in Sprague Dawley rats, it was 71±4.3%). Chronically EMPA treatment increased LVEF (66 ± 5.8% versus 53.0 ± 5.7% in vehicle-treated mdx mice) and improved fractional shortening and cardiac output (p≤0.05, respectively). Similarly, DMD^mdx rats exhibited enhanced LVEF (72.8 ± 8.0% compared to 60.9 ± 5.8% in vehicle treated DMD^mdx rats). Proteomic analysis identified four differentially expressed proteins (Htra3, Dcaf1, Hmgcs2, Ark2n; FDR<0.05). Pathway analysis showed suppressed Jak-STAT and p53 signalling but activated of hypoxia and TGF-β pathways. Interestingly, the dysregulation of TBX3 and TBX5 which may contribute to the dystrophic heart's electrical disturbances and conduction system abnormalities are significantly regulated by EMPA. Metabolomics revealed decreased xanthine (p=0.022) and thiamine (p=0.049) but increased phosphoserine (p=0.016) in dystrophic rat hearts after EMPA treatment.
Conclusion:
EMPA treatment improved cardiac function in DMD models, enhancing LVEF and cardiac output. Proteomic and metabolomic analyses revealed significant changes in protein expression and metabolic pathways, suggesting that EMPA may modulate key pathways involved in DMD pathogenesis, offering potential as a therapeutic strategy for managing cardio metabolic complications.