Dapagliflozin combined with 12 weeks of exercise in male rats enhanced systolic and mechanoenergetic response without affecting exercise-induced physiological myocardial hypertrophy.
Does dapagliflozin combined with exercise improve cardiac morphology and sarcomeric function in a rat model of exercise-induced cardiovascular remodeling?
Dapagliflozin and exercise induce distinct but complementary molecular adaptations that synergistically enhance systolic function and sarcomeric performance in a rat model.
Abstract Introduction Regular exercise training acts as a cardiovascular polypill, inducing physiological myocardial hypertrophy and improved performance. Sodium-glucose transport 2 inhibitor (SGLT2i) dapagliflozin (Dapa) is a key therapy for both systolic and diastolic heart failure, but its interaction with exercise-induced remodeling remains unclear. We aimed to investigate the combined effects of Dapa and exercise on cardiac morphology, sarcomeric function, and proteomic alterations in a previously well- established rat model of exercise induced cardiovascular remodeling. Methods Male Wistar rats were assigned to four groups: controls (CoCo), exercised (ExCo), Dapa-treated (CoDa), and exercised+Dapa (ExDa). Animals underwent 12 weeks of swim training; Dapa was given daily (1 mg/kg). Echocardiography and pressure–volume analysis evaluated left ventricular morphology and function, respectively. Permeabilized cardiomyocytes were investigated for sarcomeric force generation and troponin I (TnI) phosphorylation. Left ventricular proteomics characterized molecular alterations. Results Exercise induced relevant physiological hypertrophy, while dapagliflozin did not influence myocardial mass (post-mortem heart weight CoCo 1.19±0.04g, ExCo: 1.43±0.05g, CoDa: 1.22±0.04g, CoEx: 1.45±0.05g). Both improved systolic performance, load-independent contractility, and maximal cardiomyocyte force, with the combined group (ExDa) showing the most enhanced function. Total and Ser22/23 TnI phosphorylation decreased with both interventions. Thr144 hypophosphorylation was exercise-specific and accordingly, Ca-sensitivity increased only with exercise. Proteomics revealed 260 proteins altered by exercise and 180 by Dapa, with 56 overlapping. Shared adaptations involved mitochondrial metabolism (Gys1, Fdx1, Map1), redox regulation (Catalase), angiogenesis (Fgf1), and fibrosis-related signaling (Lgals3, Prmt1). Conclusions Dapagliflozin has not been associated with the hypertrophic response of the heart, which was improved mostly through exercise. The combined treatment has resulted in enchanced systolic and mechanoenergetic response. On a molecular level dapagliflozion and exercise induce mostly distinct but several complementary adaptations converging on contractile, metabolic, and mitochondrial pathways. The improved systolic function and sarcomeric performance suggests synergistic mechanisms of these two treatments in the athlete’s heart.
Kolodziejska et al. (Mon,) conducted a other in exercise induced cardiovascular remodeling. Dapagliflozin and exercise vs. controls was evaluated on cardiac morphology, sarcomeric function, and proteomic alterations. Dapagliflozin combined with 12 weeks of exercise in male rats enhanced systolic and mechanoenergetic response without affecting exercise-induced physiological myocardial hypertrophy.