Insulin-mediated translocation of GLUT-4-containing vesicles is preserved in denervated muscles

Skeletal muscle denervation decreases insulin-sensitive glucose uptake into this tissue as a result of marked GLUT-4 protein downregulation (similar t o 20% of controls). The process of insulin-stimulated glucose transport in muscle requires the movement or translocation of intracellular GLUT-4-rich vesicles to the cell surface, and it is accompanied by the translocation of several additional vesicular cargo proteins. Thus examining GLUT-4 translo cation in muscles from denervated animals allows us to determine whether th e loss of a major cargo protein, GLUT-4, affects the insulin-dependent beha vior of the remaining cargo proteins. We find no difference, control vs. de nervated, in the insulin-dependent translocation of the insulin-responsive aminopeptidase (IRAP) and the receptors for transferrin and insulin-like gr owth factor II/mannose 6-phosphate, proteins that completely (IRAP) or part ially co-localize with GLUT-4. We conclude that 1) denervation of skeletal muscle does not block the specific branch of insulin signaling pathway that connects receptor proximal events to intracellular GLUT-4-vesicles, and 2) normal levels of GLUT-4 protein are not necessary for the structural organ ization and insulin-sensitive translocation of its cognate intracellular co mpartment. Muscle denervation also causes a twofold increase in GLUT-1. In normal muscle, all GLUT-1 is present at the cell surface, but in denervated muscle a significant fraction (25.1 +/- 6.1%) of this transporter is found in intracellular vesicles that have the same sedimentation coefficient as GLUT-4-containing vesicles but can be separated from the latter by immunoad sorption. These GLUT1-containing vesicles respond to insulin and translocat e to the cell surface. Thus the formation of insulin-sensitive GLUT-1-conta ining vesicles in denervated muscle may be a compensatory mechanism for the decreased level of GLUT-4.