Abstract 14247: Transgenic Overexpression of Cardiac Sodium/Glucose Cotransporter 1 (SGLT1) in Mice Mimics PRKAG2 Cardiomyopathy, Whereas Transgenic Knockdown of Cardiac SGLT1 Attenuates PRKAG2 Cardiomyopathy
OBJECTIVES: We recently discovered that expression and activity of a novel cardiac glucose transporter, SGLT1, are increased in glycogen storage cardiomyopathy secondary to mutations in PRKAG2. We sought to determine the role of SGLT1 in the pathogenesis of PRKAG2 cardiomyopathy.
METHODS: Tet-off transgenic mice conditionally overexpressing cardiac SGLT1 in the absence of doxycycline were constructed (TGSGLT-UP). Doxycycline was withdrawn at ages 3-9 weeks to induce cardiac overexpression of SGLT1. Transgenic mice with cardiac-specific overexpression of human T400N mutant PRKAG2 cDNA (TGT400N) and cardiac-specific RNAi knockdown of SGLT1 (TGSGLT1-DOWN) were crossed to produce double transgenic mice (TGT400N/TGSGLT1-DOWN).
RESULTS: After withdrawal of doxyclycine for 6 weeks, relative to wild-type (WT) mice, TGSGLT1-UP mice showed a 31.5-fold increase in SGLT1 expression (P<0.001), a 12.3-fold increase in expression of the hypertrophic marker Nppa1 (P<0.01), a higher heart/body weight ratio (4.1 ± 0.2 vs 5.5 ± 0.1 mg/g, P<0.001) and higher cardiac glycogen content (0.16 ± 0.01 vs 3.09 ± 0.01 µg/mg, P<0.001). Histology showed glycogen-laden myocytes similar to PRKAG2 cardiomyopathy. TGSGLT1-UP mice had left ventricular dilation (end-diastolic diameter WT 3.0 ± 0.1 vs TGSGLT1-UP 3.8 ± 0.3, P<0.05) and decreased fractional shorting (WT 65 ± 2% vs TGSGLT1-UP 41 ± 5%, P<0.005). Relative to TGT400N mice, TGT400N/TGSGLT1-DOWN mice exhibited a 37% decrease in the expression of SGLT1 (P<0.05), a decreased heart/body weight ratio (14.2 ± 0.4 vs 16.5 ± 0.6 mg/g, P<0.005), lower cardiac glycogen content (83 ± 10 vs 104 ± 6 µg/mg, P=0.08), and decreased left ventricular dilation (end-diastolic diameter 2.5 ± 0.1 vs. 3.2 ± 0.2, P<0.01).
CONCLUSION: Cardiac overexpression of the novel glucose transporter SGLT1 mimics the phenotype of PRKAG2 cardiomyopathy in mice, whereas knockdown of SGLT1 in a murine model of PRKAG2 cardiomyopathy attenuates the disease phenotype. Therefore, SGLT1 is likely an important mediator in the development of the disease phenotype in response to the disease genotype. This is the first report of cardiac myocyte-specific transgenic knockdown of a target gene.
- © 2012 by American Heart Association, Inc.