Factors involved in GLUT-1 glucose transporter gene transcription in cardiac muscle

Glucose constitutes a major fuel for the heart, and high glucose uptake dur ing fetal development is coincident with the highest level of expression of the glucose transporter GLUT-1 during life. We have previously reported th at GLUT-1 is repressed perinatally in rat heart, and GLUT-1, which shows a low level of expression in the fetal stage, becomes the main glucose transp orter in the adult. Here, we show that the perinatal expression of GLUT-1 a nd GLUT-1 glucose transporters in heart is controlled directly at the level of gene transcription. Transient transfection assays show that the -99/-33 fragment of the GLUT-1 gene is sufficient to drive transcriptional activit y in rat neonatal cardiomyocytes. Electrophoretic mobility shift assays dem onstrate that the transcription factor Sp1, a trans-activator of GLUT-1 pro moter, binds to the -102/-82 region of GLUT-2 promoter during the fetal sta te but not during adulthood. Mutation of the Sp1 site in this region demons trates that Sp1 is essential for maintaining a high transcriptional activit y in cardiac myocytes. Sp1 is markedly down-regulated both in heart and in skeletal muscle during neonatal life, suggesting an active role for Sp1 in the regulation of GLUT-1 transcription. In all, these results indicate that the expression of GLUT-1 and GLUT-I in heart during perinatal development is largely controlled at a transcriptional level by mechanisms that might b e related to hyperplasia and that are independent from the signals that tri gger cell hypertrophy in the developing heart. Furthermore, our results pro vide the first functional insight into the mechanisms regulating muscle GLU T-1 gene expression in a live animal.