Transcriptional regulation of the gene for glucose transporter GLUT4 in skeletal muscle. Effects of diabetes and fasting

P.D Neufer,J.O Carey,G.L Dohm

doi:10.1016/s0021-9258(19)85177-3

Abstract

GLUT4 glucose transporter protein and mRNA levels in rat skeletal muscle are decreased with streptozotocin (STZ)-induced diabetes and increased by fasting, indicating that GLUT4 expression may be regulated at the pretranslational level. The purpose of the present study was to determine whether GLUT4 is subject to transcriptional regulation in skeletal muscle under the altered metabolic conditions of diabetes and fasting. Nuclei were isolated from red and white portions of the quadriceps and gastrocnemius/plantaris muscles of control, 7-day STZ-diabetic, and 3-day fasted rats. STZ-induced diabetes resulted in a 35% reduction in GLUT4 transcription in red skeletal muscle and thus accounted for a major portion of the corresponding 50% reduction in GLUT4 mRNA observed in red skeletal muscle. STZ-induced diabetes had no significant effect on GLUT4 transcription or mRNA in white skeletal muscle. Fasting, however, significantly increased both GLUT4 transcription (2.2-fold) and mRNA (2.9-fold) in white skeletal muscle with no change detected for either parameter in red skeletal muscle. The nearly 2-fold higher steady-state GLUT4 mRNA in red versus white skeletal muscle of control rats was not associated with any difference in basal transcription. These findings demonstrate that expression of the GLUT4 glucose transporter protein in skeletal muscle is subject to regulation in vivo at the level of transcription of the GLUT4 gene. In addition, GLUT4 transcription is regulated in a fiber type-specific manner in response to the metabolic challenges elicited by STZ-induced diabetes and fasting.

Highlights

GLUT4 glucose transporter protein and mRNA lev- addition to a severe reduction in glucose transport capacity els in rat skeletal muscle are decreased with strepto- [10,11,12], exhibit a reduction in skeletal muscle GLUT4 zotocin (STZ)-induceddiabetes and increasedby fasting, indicating that GLUT4 expression may be regulated at the pretranslational level
It is well established that GLUT4 mRNA in skeletal muscle is reduced with STZ-induced diabetes and increased with fasting [13,14,15,16,17,18], suggesting that GLUT4 may be regulated at the pretranslational level
STZ-induced diabetes markedly decreases both maximal insulin and contraction stimulated glucose transport in skeletal muscle [10]. This STZ-induced impairmentin glucose transport coincides with a decrease in skeletal muscle GLUT4 protein and mRNA content [13,14,15,16], both of which are reversible with insulin treatment [13, 15]

Summary

Introduction

GLUT4 glucose transporter protein and mRNA lev- addition to a severe reduction in glucose transport capacity els in rat skeletal muscle are decreased with strepto- [10,11,12], exhibit a reduction in skeletal muscle GLUT4 zotocin (STZ)-induceddiabetes and increasedby fasting, indicating that GLUT4 expression may be regulated at the pretranslational level. STZ-induced diabetes resulted in a 35% possibility that muscle GLUT4protein maybe subject to reduction in GLUT4 transcription in red skeletalmus- regulation at thepretranslational level was first suggested by cle and accounted for a major portion of the cor- Garvey et al [13] who reported a significant decrease in responding 50% reduction inGLUT4 mRNA observed GLUT4 mRNA in the quadriceps muscles of rats with STZ-. The nearly2-fold higher steady-stateGLUT4 fibers (types I and IIA) which are high in GLUT4 protein mRNA in red versus white skeletal muscle of control rats was not associated with any difference in basal transcription. These findings demonstratethat expression of the GLUT4 glucosetransporter protein in skeletal muscle is subject to regulation in vivo at the level of transcription of the GLUT4 gene. The intent of the present study was to determine whether these metabolically induced alterations in GLUT4 mRNA in skeletal muscle may be regulated at least in part at the level

Objectives

Results

Conclusion