SGLT1, a novel cardiac glucose transporter, mediates increased glucose uptake in PRKAG2 cardiomyopathy

Banerjee, Sanjay K.; Wang, David W.; Alzamora, Rodrigo; Huang, Xueyin N.; Pastor-Soler, Nuria M.; Hallows, Kenneth R.; McGaffin, Kenneth R.; Ahmad, Ferhaan

Abstract

Human mutations in the gene PRKAG2 encoding the gamma 2 subunit of AMP-activated protein kinase (AMPK) cause a glycogen storage cardiomyopathy. Transgenic mice (TG(T400N)) with the human T400N mutation exhibit inappropriate activation of AMPK and consequent glycogen storage in the heart. Although increased glucose uptake and activation of glycogen synthesis have been documented in PRKAG2 cardiomyopathy, the mechanism of increased glucose uptake has been uncertain. Wildtype (WT), TG(T400N), and TG(alpha 2DN) (carrying a dominant negative, kinase dead alpha 2 catalytic subunit of AMPK) mice were studied at ages 2-8 weeks. Cardiac mRNA expression of sodium-dependent glucose transporter 1 (SGLT1), but not facilitated-diffusion glucose transporter 1 (GLUT1) or GLUT4, was increased similar to 5- to 7-fold in TCT400N mice relative to WT. SGLT1 protein was similarly increased at the cardiac myocyte sarcolemma in TG(T400N) mice. Phlorizin, a specific SGLT1 inhibitor, attenuated cardiac glucose uptake in TG(T400N) mice by similar to 40%, but not in WT mice. Chronic phlorizin treatment reduced cardiac glycogen content by similar to 25% in TG(T400N) mice. AICAR, an AMPK activator, increased cardiac SGLT1 mRNA expression similar to 3-fold in WT mice. Relative to TG(T400N) mice, double transgenic (IG(T400N)/TG(alpha 2DN)) mice had decreased (similar to 50%) cardiac glucose uptake and decreased (similar to 70%) cardiac SGLT1 expression. TG(T400N) hearts had increased binding activity of the transcription factors HNF-1 and Sp1 to the promoter of the gene encoding SGLT1. Our data suggest that upregulation of cardiac SGLT1 is responsible for increased cardiac glucose uptake in the TG(T400N) mouse. Increased AMPK activity leads to upregulation of SGLT1, which in turn mediates increased cardiac glucose uptake. (c) 2010 Elsevier Ltd. All rights reserved.

Más información

Título de la Revista: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volumen: 49
Número: 683-692
Editorial: ELSEVIER SCI LTD
Fecha de publicación: 2010
Página de inicio: 683
Página final: 692
Idioma: English
URL: http://linkinghub.elsevier.com/retrieve/pii/S0022282810002403
DOI:

10.1016/j.yjmcc.2010.06.003