Insulin-like growth factor-I (IGF-I) and especially IGF-I variants are anabolic in dexamethasone-treated rats

Preclinical work by the CSIRO/Adelaide group (Australia), conducted by the team that originally designed and synthesized the IGF-1 analogs with N-terminal extension and arginine substitution at position 3 — including what is now commercialized as IGF-1 LR3 (Long R3 IGF-I). This article is a foundational reference for the biological rationale of the structural modification: greater potency despite lower receptor affinity.

The experimental model was adult rats subjected to dexamethasone-induced catabolism (20 µg/day subcutaneous), which produces significant loss of body mass and negative nitrogen balance — experimental analog of glucocorticoid-induced muscle wasting. Animals received continuous infusion via subcutaneous osmotic pump of native IGF-1 or variants (Long R3 IGF-I and des(1-3)IGF-I) at rising doses, with assessment of body weight, nitrogen retention and muscle protein synthesis/degradation.

Results were consistent and dose-dependent. The IGF-1 variants demonstrated approximately 2.5-fold higher potency than native IGF-1 — paradoxically, despite binding 3-fold worse to the IGF-1R receptor. The authors attributed the higher functional potency to low affinity of variants for IGFBPs (IGF binding proteins), which increases the free circulating fraction and tissue bioavailability. This mechanistic finding is central to understanding why LR3 produces superior anabolic effect compared to endogenous IGF-1 even at similar pharmacologic doses.

Only the highest dose of IGF-1 produced modest weight gain, while the variants promoted more robust gain and positive nitrogen balance. The study underpinned the subsequent development of LR3 IGF-I (LongR3) as a research tool and cell culture biomanufacturing reagent, while also providing scientific rationale for its off-label use in bodybuilding. It remains a primary reference for the comparative pharmacology of IGF-1 analogs.