Technical Abstract: Sustained high levels of muscle IGF-I result in only a transient stimulation of muscle protein accretion. The objective of this study was to determine if IGF-induced changes in the local abundance of IGFBPs occur that could potentially modulate the effects of IGF-I on muscle growth. We hypothesized that IGFBP-5 expression, but not IGFBP-3, would be increased in skeletal muscle of mice that overexpress IGF-I selectively in fast-twitch muscles (SIS2). Homozygous SIS2 and wildtype mice were studied in a 2 x 2 factorial design (n=8) with genotype and gender as factors. At 3, 5, 10, and 20 wk of age, hind limb muscles were collected and weighed. IGFBP-3 and -5 protein abundances were measured by Western blot analysis of pooled muscle extracts. Muscle mass was 20% greater in SIS2 compared to wildtype mice by 10 wk of age (P < 0.01), and the difference was maintained thereafter. IGFBP-3 abundance was unaffected by local IGF-I production; in males there was a 46% decrease with age (P < 0.001) whereas in females levels increased after 5 wk of age (P < 0.03). IGFBP-5 increased twofold between 3 and 20 wk of age (P < 0.001), regardless of genotype or gender. Thus, although muscle IGFBP-3 or -5 abundances were not regulated by local IGF-I, it is possible that the increase in IGFBP-5 with age was sufficient to suppress the IGF-I-induced growth response.