Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep. — VialBase Research
This is the clearest published statement of the LR3 trade-off: the analogue's low IGF binding protein affinity is exactly why it is more potent and exactly why it escapes normal physiologic regulation of IGF-1 bioavailability. It is also animal-only evidence, and the growth it produced was organ-specific rather than muscle mass.
- LR3 IGF-1 has a low affinity for IGF binding proteins (IGFBP), which reduces physiologic regulation of IGF-1 bioavailability — the authors treat this as a limitation of the analogue, not an advantage
- Prior experimental infusion of the human recombinant LR3 IGF-1 analogue into late gestation fetal sheep increased fetal organ growth and skeletal muscle myoblast proliferation
- The peptide sequence of LR3 IGF-1 also differs from native sheep IGF-1, so the authors developed an ovine-specific recombinant IGF-1 (oIGF-1) to overcome both limitations
- One week of oIGF-1 infusion increased organ growth of the heart, kidneys, spleen and adrenal glands and stimulated in vivo myoblast proliferation versus saline
- oIGF-1 did not increase skeletal muscle fractional protein synthetic rate or hindlimb muscle mass, and hepatic and muscular IGFBP-1 to -3 gene expression was similar to saline
Summary
This is animal research in fetal sheep with supporting in vitro work — there is no human data in it. IGF-1 is a critical fetal growth-promoting hormone, and the authors note that experimental infusion of the IGF-1 analogue human recombinant LR3 IGF-1 into late gestation fetal sheep increased fetal organ growth and skeletal muscle myoblast proliferation. They then state the analogue’s two limitations explicitly: LR3 IGF-1 has a low affinity for IGF binding proteins (IGFBP), thus reducing physiologic regulation of IGF-1 bioavailability, and the peptide sequences for LR3 IGF-1 and sheep IGF-1 differ. To overcome those limitations they developed an ovine-specific recombinant IGF-1 (oIGF-1) and tested it in three stages: in vitro myoblast proliferation in response to oIGF-1; anabolic signalling from serial skeletal muscle biopsies in fetal sheep given oIGF-1 or saline for 2 hours; and a 1-week infusion measuring fetal body and organ growth, in vivo myoblast proliferation, skeletal muscle fractional protein synthetic rate, IGFBP expression in muscle and liver, and IGF-1 signalling pathways. oIGF-1 stimulated myoblast proliferation in vitro. Infused for 1 week it increased growth of the heart, kidneys, spleen and adrenal glands and stimulated skeletal myoblast proliferation compared with saline — but without increasing muscle fractional synthetic rate or hindlimb muscle mass. Hepatic and muscular gene expression of IGFBPs one to three was similar between oIGF-1 and saline. The authors conclude that oIGF-1 promotes tissue and organ-specific growth in the normal sheep fetus.
Key Findings
- The paper states directly that LR3 IGF-1 has a low affinity for IGF binding proteins, thus reducing physiologic regulation of IGF-1 bioavailability — the mechanism marketed as LR3’s advantage is described here as a reason to move away from it
- LR3 IGF-1’s peptide sequence differs from native sheep IGF-1, a second reason the investigators built a species-matched analogue (oIGF-1) instead of continuing with LR3
- Prior LR3 IGF-1 infusion into late gestation fetal sheep had increased fetal organ growth and skeletal muscle myoblast proliferation — the animal precedent this study builds on
- oIGF-1 stimulated myoblast proliferation in vitro, and 1 week of in vivo infusion increased growth of the heart, kidneys, spleen and adrenal glands plus in vivo myoblast proliferation versus saline
- oIGF-1 did not increase skeletal muscle fractional protein synthetic rate or hindlimb muscle mass — proliferation of muscle precursor cells did not translate into measurable muscle mass over the study window
- Hepatic and muscular gene expression of IGFBPs one to three was similar between oIGF-1 and saline infusion
Relevance to IGF-1-LR3
This study is the cleanest published articulation of the central trade-off with IGF-1-LR3, and it is worth stating without softening: LR3’s low affinity for IGF binding proteins is simultaneously the reason it is more potent than native IGF-1 and the reason it is less regulated. Binding proteins are the body’s mechanism for controlling how much IGF-1 is bioavailable at any moment; an analogue engineered to evade them delivers more unbuffered signal and forfeits that control. These authors treated that property as a limitation serious enough to justify building a different molecule. The second point worth carrying forward is what the growth actually looked like: even with a species-matched analogue, the effect was organ-specific — heart, kidneys, spleen, adrenals — with myoblast proliferation but no increase in muscle protein synthetic rate or hindlimb muscle mass. That is a poor match for how LR3 is sold. And all of it is fetal sheep. There are no human trials of LR3 IGF-1 in this evidence set.
Citation
Stremming J, White A, Donthi A, et al. Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep. Frontiers in physiology. 2022;13:954948. doi:10.3389/fphys.2022.954948.
See Also
- Parent compound: IGF-1-LR3
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