Transgenic Knockdown of Cardiac Sodium/Glucose Cotransporter 1 (SGLT1) Attenuates PRKAG2 Cardiomyopathy, Whereas Transgenic Overexpression of Cardiac SGLT1 Causes Pathologic Hypertrophy and Dysfunction in Mice

BACKGROUND: The expression of a novel cardiac glucose transporter, SGLT1, is increased in glycogen storage cardiomyopathy secondary to mutations in PRKAG2. We sought to determine the role of SGLT1 in the pathogenesis of PRKAG2 cardiomyopathy and its role in cardiac structure and function. METHODS AND RESULTS: Transgenic mice with cardiomyocyte‐specific overexpression of human T400N mutant PRKAG2 cDNA (TG(T400N)) and transgenic mice with cardiomyocyte‐specific RNA interference knockdown of SGLT1 (TG(SGLT1‐DOWN)) were crossed to produce double‐transgenic mice (TG(T400N)/TG(SGLT1‐DOWN)). Tet‐off transgenic mice conditionally overexpressing cardiac SGLT1 in the absence of doxycycline were also constructed (TG(SGLT‐ON)). Relative to TG(T400N) mice, TG(T400N)/TG(SGLT1‐DOWN) mice exhibited decreases in cardiac SGLT1 expression (63% decrease, P<0.05), heart/body weight ratio, markers of cardiac hypertrophy, and cardiac glycogen content. TG(T400N)/TG(SGLT1‐DOWN) mice had less left ventricular dilation at age 12 weeks compared to TG(T400N) mice. Relative to wildtype (WT) mice, TG(SGLT1‐ON) mice exhibited increases in heart/body weight ratio, glycogen content, and markers of cardiac hypertrophy at ages 10 and 20 weeks. TG(SGLT1‐ON) mice had increased myocyte size and interstitial fibrosis, and progressive left ventricular dysfunction. When SGLT1 was suppressed after 10 weeks of overexpression (TG(SGLT1‐ON/OFF)), there was a reduction in cardiac hypertrophy and improvement in left ventricular failure. CONCLUSIONS: Cardiac knockdown of SGLT1 in a murine model of PRKAG2 cardiomyopathy attenuates the disease phenotype, implicating SGLT1 in the pathogenesis. Overexpression of SGLT1 causes pathologic cardiac hypertrophy and left ventricular failure that is reversible. This is the first report of cardiomyocyte‐specific transgenic knockdown of a target gene.