|Oliver, William - BAYLOR COLL OF MEDICINE|
|Cummings, Kathleen - BAYLOR COLL OF MEDICINE|
|Rosenberger, Judy - BAYLOR COLL OF MEDICINE|
|Lopez, Rusmely - BAYLOR COLL OF MEDICINE|
|Gomez, Adam - BAYLOR COLL OF MEDICINE|
Submitted to: Endocrinology
Publication Type: Abstract Only
Publication Acceptance Date: March 4, 2005
Publication Date: June 4, 2005
Citation: Oliver, W.T., Cummings, K.K., Rosenberger, J., Lopez, R., Gomez, A., Fiorotto, M.L. 2005. In vivo, skeletal muscle IGF-I activates Akt directly via the IGF-1R and indirectly by enhancing insulin receptor phosphorylation [abstract]. The Endocrine Society's 87th Annual Meeting "Shaping the Future of Endocrinology: Today's Research...Tomorrow's Care". Abstract P3-715, p. 721. Interpretive Summary: Not Required for an Abstract.
Technical Abstract: In the immature muscle, local IGFs and an enhanced sensitivity to insulin are largely responsible for driving the high postnatal rate of skeletal muscle growth. We hypothesized that high tissue levels of IGF-I increase basal activation of the IGF-IR, and enhance the anabolic effects of insulin by promoting insulin receptor phosphorylation. To test this hypothesis, we studied SIS2 transgenic mice with muscle-specific overexpression of IGF-I. At 5 wk of age SIS2 and wildtype (WT) mice were injected iv with LR3-IGF-I (LR3) or insulin at one of six doses (0.025 to 2.5 mg/kg BW), or saline. Mice were killed five minutes later and quadriceps muscles were recovered. IGF-1R, insulin receptor, ERK 1/2, and Akt abundances and their degree of tyrosine phosphorylation were measured by Western blot analysis. Total IGF-1R abundances did not differ between genotypes (P > 0.05), but basal (saline injected) IGF-1R phosphorylation was greater in SIS2 than WT muscles (P < 0.01). LR3 increased the phosphorylation of the IGF-1R (P < 0.01), regardless of genotype (P > 0.05). Total insulin receptor abundance did not differ between genotypes (P > 0.05), and basal insulin receptor phosphorylation was undetectable. LR3, at the higher doses, induced insulin receptor activation (P < 0.05). Exogenous insulin increased insulin receptor phosphorylation to a greater extent in SIS2 compared to WT mice (P < 0.05). Basal ERK 1/2 phosphorylation did not differ between genotypes (P > 0.05), but there was less total ERK 1/2 in muscle of SIS2 mice (P < 0.05). LR3 and insulin increased ERK 1/2 phosphorylation (P < 0.01), regardless of genotype (P > 0.05). Total Akt abundance was similar in SIS2 and WT mice (P > 0.05), but basal Akt phosphorylation was higher in SIS2 mice (P < 0.10). LR3 and insulin increased Akt phosphorylation (P < 0.05) to a greater extent in SIS2 compared to WT mice (P < 0.05). Thus, sustained high IGF-I expression in muscle increased the basal activation of the IGF-1R, but not the response to exogenous LR3. This was realized as an increase in total basal activation of Akt, but not of ERK 1/2. Additionally, high local IGF-I expression increased the phosphorylation of the insulin receptor and Akt in response to exogenous insulin These data suggest that in skeletal muscle local IGFs can promote muscle growth both directly through activation of the IGF-1R, and indirectly by enhancing the activation of the insulin-signaling pathway.