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.