CONTRACTION-INDUCED GLUCOSE TRANSPORT AND GLYCOGEN DEPLETION IN MUSCLES FROM MICE HETEROZYGOUS FOR IRS-1 PROTEIN

Abstract

1398 Insulin receptor substrate-1 (IRS1) plays a pivotal role in insulin-stimulated glucose transport (GT). A role for IRS1 in contraction-induced GT has not been identified, but few studies have addressed this topic. Mice heterozygous for a null allele in the IRS1 gene (IRS1-HZ) have an ≈50% reduction in IRS-1 protein in skeletal muscle compared to wild-type (WT) mice (Brüning et al. Cell 88:561). Our initial goal was to characterize contraction-induced GT in the extensor digitorum longus (EDL) muscles of WT mice. We then compared WT to IRS1-HZ mice. After WT mice were anesthetized, the sciatic nerve was isolated and electrically stimulated (0.1 msec pulses at 100 Hz in 250 msec trains at a rate of 1/sec for 5 min) for 2 bouts (2X) with 1 min recovery between bouts. We also studied muscles stimulated identically for 4 bouts (4X) to determine if additional contractile activity would further increase GT. Muscles were rapidly dissected out and GT was determined in vitro using 2-deoxyglucose. Contractile activity led to an ≈3-fold higher GT in the 2X group compared to unstimulated, contralateral EDL muscles (p<0.01). The 2X and 4X protocols elicited similar values for GT. We also evaluated the influence of the 2X protocol in IRS1-HZ mice and found an increase above basal that was similar to that in WT mice (p<0.01). Glycogen in unstimulated muscles was not different for IRS1-HZ vs. WT mice, and contractile activity elicited a comparable decline in muscle glycogen, regardless of genotype. In conclusion, our results indicate that a substantial reduction in IRS-1 expression does not alter contraction-induced glycogen depletion or GT stimulation in skeletal muscle.