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

Abstract

BackgroundThe 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 ResultsTransgenic mice with cardiomyocyte‐specific overexpression of human T400N mutant PRKAG2 cDNA (TGT400N) and transgenic mice with cardiomyocyte‐specific RNA interference knockdown of SGLT1 (TGSGLT1‐DOWN) were crossed to produce double‐transgenic mice (TGT400N/TGSGLT1‐DOWN). Tet‐off transgenic mice conditionally overexpressing cardiac SGLT1 in the absence of doxycycline were also constructed (TGSGLT‐ON). Relative to TGT400N mice, TGT400N/TGSGLT1‐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. TGT400N/TGSGLT1‐DOWN mice had less left ventricular dilation at age 12 weeks compared to TGT400N mice. Relative to wildtype (WT) mice, TGSGLT1‐ON mice exhibited increases in heart/body weight ratio, glycogen content, and markers of cardiac hypertrophy at ages 10 and 20 weeks. TGSGLT1‐ON mice had increased myocyte size and interstitial fibrosis, and progressive left ventricular dysfunction. When SGLT1 was suppressed after 10 weeks of overexpression (TGSGLT1‐ON/OFF), there was a reduction in cardiac hypertrophy and improvement in left ventricular failure.ConclusionsCardiac 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.

Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

“…SGLT1 expression levels were increased in diabetic or ischemic cardiomyopathy (Banerjee et al, 2009). Although the functional roles of SGLT1 have not been determined in such nonepithelial tissues, it has been reported that SGLT1 is involved in the pathophysiology of a murine model of PRKAG2 cardiomyopathy (Ramratnam et al, 2014). Because the maximal plasma level of unbound canagliflozin in clinical studies (20-60 nM, see above) is ∼1/30 to 1/10 of the K i value for SGLT1 (770.5 nM), the oral administration of clinical doses of canagliflozin would not inhibit SGLT1 in the heart or skeletal muscle.…”

Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization

“…RNA extraction, reverse transcription PCR extraction, cDNA sequencing, and real-time quantitative PCR (QPCR) were performed as we have previously described [18–20]. Briefly, total RNA was isolated from whole heart with TRIzol (Invitrogen).…”

Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

“…Furthermore, STZ-diabetic T1DM rats have increased cardiac expression of autophagy proteins that are specific for glycogen [139]. Interestingly in this regard, cardiac-specific knockdown of SGLT1 has been reported to prevent glycogen storage cardiomyopathy in a mouse model carrying a mutation in the gene for the gamma2 subunit of AMPK [141, 142]. The relevance of this finding for the diabetic heart has not been tested.…”