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Overexpression of the Acid-Labile Subunit of the IGF Ternary Complex in Transgenic Mice

Departments of Internal Medicine (L.J.M.) and Physiology (J.V.S., Y.G., T.M., L.J.M.), University of Manitoba, Winnipeg, Manitoba, Canada R3E 0W3; and Department of Pediatrics, Baylor College of Medicine (A.S., S.K.D., D.R.P.), Houston, Texas 77030

Address all correspondence and requests for reprints to: L. J. Murphy, M.B., Ph.D., Departments of Internal Medicine and Physiology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0W3. E-mail: ljmurph{at}cc.umanitoba.ca

The ternary complex, composed of IGF-I or IGF-II, IGF-binding protein-3, and the acid-labile subunit, is responsible for transport of the majority of the IGF-I and IGF-II present in the circulation. Acid-labile subunit is developmentally and hormonally regulated, suggesting an important, although unclear, role in regulating the availability and action of the IGFs. To investigate the biological role of acid-labile subunit, we generated transgenic mice, which constitutively overexpress a human acid-labile subunit cDNA driven by the cytomegalovirus promoter. Two independent transgenic strains, CMVALS-1 and CMVALS-2, with mean serum levels of human acid-labile subunit of 19.3 ± 4.2 and 20.2 ± 3.2 µg/ml respectively, were characterized. Total acid-labile subunit, endogenous plus transgene derived, was measured by Western blotting and was found to be significantly increased in transgenic compared with wild-type mice (1.51 ± 0.02-fold; P < 0.001). There were no significant differences in serum IGF-binding protein-3 or IGF-I levels between transgenic and wild-type mice. Similar chromatographic elution patterns were observed when sera from transgenic and wild-type mice were preincubated with [¹²⁵I]IGF-I, indicating that acid-labile subunit overexpression had no measurable effect on compartmentalization of IGF-I in the circulation. Transgene-derived human acid-labile subunit mRNA was detected in 17-d-old embryos and all adult mouse tissues examined.

A significant reduction in litter size was also observed in each of the acid-labile subunit transgenic mouse strains. This reduction in litter size was due to a maternal effect, as it was apparent when transgenic female mice were crossed with wild-type male mice, but not when male transgenic mice were crossed with female wild-type mice.

The transgenic mice were phenotypically normal at birth, but demonstrated a significant reduction in postnatal body weight gain, particularly during the first 3 wk of life. Over the first 3 months of life, average body weights were significantly reduced by 5.3 ± 0.6%, 4.2 ± 0.6%, 8.1 ± 0.9%, and 5.6 ± 0.8%, compared with those in wild-type mice, for male and female CMVALS-1 mice and male and female CMVALS-2 mice, respectively. Double transgenic mice, generated by crossing acid-labile subunit transgenic mice with transgenic mice that overexpress IGF-binding protein-3, demonstrated a significantly more marked reduction in body weight gain than acid-labile subunit transgenic mice.

These data demonstrate that overexpression of acid-labile subunit has significant effects on postnatal growth and reproduction. As there is little measurable alteration in the circulating components of the IGF system, these effects are most likely to be mediated via disturbances in tissue IGF availability.

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