Munc18c regulates insulin-stimulated GLUT4 translocation to the transversetubules in skeletal muscle

To examine the intracellular trafficking and translocation of GLUT4 in skel etal muscle, we have generated transgenic mouse lines that specifically exp ress a GLUT4-EGFP (enhanced green fluorescent protein) fusion protein under the control of the human skeletal muscle actin promoter. These transgenic mice displayed EGFP fluorescence restricted to skeletal muscle and increase d glucose tolerance characteristic of enhanced insulin sensitivity. The GLU T4-EGFP protein localized to the same intracellular compartment as the endo genous GLUT4 protein and underwent insulin- and exercise-stimulated translo cation to both the sarcolemma and transverse-tubule membranes. Consistent w ith previous studies in adipocytes, overexpression of the syntaxin 4-bindin g Munc18c isoform, but not the related Munc18b isoform, in vivo specificall y inhibited insulin-stimulated GLUT4 EGFP translocation, Surprisingly, howe ver, Munc18c inhibited GLUT4 translocation to the transverse-tubule membran e without affecting translocation to the sarcolemma membrane. The ability o f Munc18c to block GLUT4-EGFP translocation to the transverse-tubule membra ne but not the sarcolemma membrane was consistent with substantially reduce d levels of syntaxin 4 in the transverse-tubule membrane. Together, these d ata demonstrate that Munc18c specifically functions in the compartmentalize d translocation of GLUT4 to the transverse-tubules in skeletal muscle, In a ddition, these results underscore the utility of this transgenic model to d irectly visualize GLUT4 translocation in skeletal muscle.