Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2005
Publication Date: 12/1/2005
Citation: Oliver, W.T., Rosenberger, J., Lopez, R., Gomez, A., Cummings, K.K. Fiorotto, M.L. 2005. The local expression and abundance of insulin-like growth factor (IGF) binding proteins in skeletal muscle are regulated by age and gender but not local IGF-I "in vivo". Endocrinology. 146(12):5455-5462. Interpretive Summary: Insulin-like growth factor I (IGF-I) is a hormone that promotes the growth of skeletal muscle. The magnitude of its effects are regulated by a variety of factors, including a family of inhibitory proteins called the IGF binding proteins. We wished to determine what factors alter the amount of these proteins in muscle, and in particular whether IGF-I itself can do so. We determined that in mouse muscle, four IGF binding proteins are expressed (IGFBP-3, -4, -5, and -6), and their production is not altered if the amount of IGF-I in the muscle is high. IGFBP-4 and –5 increased with age in both males and females. With puberty, IGFBP-3 increased in females and decreased in males, whereas IGFBP-6 decreased in females, and was unchanged in males. These changes were not sufficient to alter the actions of IGF-I on the muscle. However, the IGFBPs have effects that are independent of IGF and may contribute to gender and age effects on muscle growth. These findings are important for our understanding of how long-term exposure to growth promoting agents alters skeletal muscle.
Technical Abstract: We wished to determine whether sustained IGF-I production in skeletal muscle increases local IGF binding protein (IGFBP) abundance, thereby mitigating the long-term stimulation of muscle growth by IGF-I. Muscle growth of transgenic mice that overexpress IGF-I in muscle (SIS2) and of wild-type (Wt) mice was compared. At 3, 5, 10, and 20 wk of age, hind-limb muscle weights and IGFBP-3, -4, -5, and -6 mRNA and protein abundances were quantified. Additional mice were injected with IGF-I or LR3-IGF-I, and phosphorylation of the type 1 IGF receptor (IGF-1R) was compared. Muscle mass was 20% greater in SIS2 compared with Wt mice by 10 wk of age (P < 0.01), and this difference was maintained to 20 wk. IGFBP mRNA and protein abundances were unaffected by genotype. IGFBP-4 and -5 protein abundances increased with age, whereas for IGFBP-3 and -6, there was a sexual dimorphic response (P < 0.01); after 5 wk of age, IGFBP-3 decreased in males but increased in females, whereas IGFBP-6 decreased in females and remained unchanged in males. These protein expression patterns resulted from differences at both the transcriptional and posttranscriptional levels. LR3-IGF-I stimulated IGF-1R phosphorylation to a greater extent than IGF-I at both 5 and 10 wk of age (P < 0.01), regardless of gender or genotype (P > 0.21). Thus, variations in local IGF-I levels do not appear to regulate muscle IGFBP expression. The age- and gender-specific differences in muscle IGFBP expression are not sufficient to alter the response of the muscle to the IGFs but may impact the IGF-independent effects of these IGFBPs.