SGLT1, a novel cardiac glucose transporter, mediates increased glucose uptake in PRKAG2 cardiomyopathy.
Human mutations in the gene PRKAG2 encoding the gamma2 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(alpha2DN) (carrying a dominant negative, kinase dead alpha2 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 approximately 5- to 7-fold in TG(T400N) 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 approximately 40%, but not in WT mice. Chronic phlorizin treatment reduced cardiac glycogen content by approximately 25% in TG(T400N) mice. AICAR, an AMPK activator, increased cardiac SGLT1 mRNA expression approximately 3-fold in WT mice. Relative to TG(T400N) mice, double transgenic (TG(T400N)/TG(alpha2DN)) mice had decreased ( approximately 50%) cardiac glucose uptake and decreased (approximately 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.
Banerjee
Sanjay K
SK
Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213-2582, USA.
Wang
David W
DW
Alzamora
Rodrigo
R
Huang
Xueyin N
XN
Pastor-Soler
Núria M
NM
Hallows
Kenneth R
KR
McGaffin
Kenneth R
KR
Ahmad
Ferhaan
F
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism*
D051269:Sodium-Glucose Transporter 1; C526223:PRKAG2 protein, human; D055372:AMP-Activated Protein Kinases; D005947:Glucose