Compensatory responses of the insulin signaling pathway restore muscle glucose uptake following long-term denervation.

We investigated the role of muscle activity in maintaining normal glucose homeostasis via transection of the sciatic nerve, an extreme model of disuse atrophy. Mice were killed 3, 10, 28, or 56 days after transection or sham surgery. There was no difference in muscle weight between sham and transected limbs at 3 days post surgery, but it was significantly lower following transection at the other three time points. Transected muscle weight stabilized by 28 days post surgery with no further loss. Myocellular cross-sectional area was significantly smaller at 10, 28, and 56 days post transection surgery. Additionally, muscle fibrosis area was significantly greater at 56 days post transection. In transected muscle there was reduced expression of genes encoding transcriptional regulators of metabolism (PPARα, PGC-1α, PGC-1ß, PPARδ), a glycolytic enzyme (PFK), a fatty acid transporter (M-CPT 1), and an enzyme of mitochondrial oxidation (CS) with transection. In denervated muscle, glucose uptake was significantly lower at 3 days but was greater at 56 days under basal and insulin-stimulated conditions. Although GLUT 4 mRNA was significantly lower at all time points in transected muscle, Western blot analysis showed greater expression of GLUT4 at 28 and 56 days post surgery. GLUT1 mRNA was unchanged; however, GLUT1 protein expression was also greater in transected muscles. Surgery led to significantly higher protein expression for Akt2 as well as higher phosphorylation of Akt. While denervation may initially lead to reduced glucose sensitivity, compensatory responses of insulin signaling appeared to restore and improve glucose uptake in long-term-transected muscle.