Technical Abstract: Sustained high levels of muscle IGF-I result in only a transient stimulation of muscle growth. We hypothesized that the sustained IGF-I activation of the IGF-IR in muscle of mice that overexpress IGF-I selectively in fast-twitch muscles (SIS2) would result in down regulation of IGF-1R abundance. At 5 and 10 wk of age SIS2 (n=32) and wildtype (Wt; n=35) mice were administered either saline or 2.5 mg LR3-IGF-I (LR3) / kg BW. Mice were killed five minutes after injection and quadriceps were recovered. IGF-IR and ERK 1/2 abundances and their degree of tyrosine phosphorylation were measured by Western blot analysis. Total IGF-1R abundance (in 30 ug of membrane protein) did not differ between genotypes (P > 0.05), but baseline (saline injected) IGF-IR tyrosine phosphorylation (relative to total IGF-1R) was greater in SIS2 (0.51 +/- 0.01) than WT (0.42 +/- 0.01) muscles (P < 0.01), regardless of age (P > 0.05). LR3 increased the tyrosine phosphorylation of both the IGF-1R (0.88 +/- 0.05; P < 0.01) and ERK 1/2 (0.56 +/- 0.06; P < 0.01) in both WT and SIS2 mice (P > 0.05). Baseline ERK 1/2 phosphorylation did not differ (0.28 +/- 0.05; P > 0.05), but there was less total ERK 1/2 (in 50 ug of soluble protein) in muscle of SIS2 mice (WT =189 +/- 8 AU, SIS2=169 +/- 9 AU; P < 0.05). Thus, chronically high IGF-I expression in muscle increases the activation of the IGF-1R, but this is not realized in an increase in total ERK 1/2 activity.