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Insulin-like peptide-3, an unknown testicular anabolic hormone

Insulin-like peptide-3, een onbekend testiculair anabool hormoon
The cells of Leydig - present in the body of both men and women - manufacture more anabolic hormones than good old testosterone. They also produce insulin-like peptide-3. Italian endocrinologist describe its anabolic properties in Frontiers in Endocrinology.

Insulin-like peptide-3
Insulin-like peptide-3 [often abbreviated as INSL3] is a rather obscure hormone, which is produced by Leydig's cells. In healthy men, concentrations of 600 picograms per millilitre of insulin-like peptide-3 are normal, in women concentrations of 100 picograms per millilitre. Insulin-like peptide-3 interacts with the receptor RXFP2.

Click on the figure below for a larger version.

Insulin-like peptide-3, an unknown testicular anabolic hormone

Anabolic effect
Through RXFP2, insulin-like peptide-3 plays an important role in the development of the testes, know endocrinologists since the last century. More recent is the discovery that via the same receptor insulin-like peptide-3 can make bones stronger. At the moment pharmacologists are looking for substances that have an anabolic effect on bone tissue via RXFP2. []

Is it possible that this type of medication - including insulin-like peptide-3 itself - also has an anabolic effect on muscle mass? The Italians wanted to answer that question with their test tube and animal studies.

In a concentration of 10 nanomoles, insulin-like peptide-3 activated the most important anabolic signal molecules in muscle cells, the Italians discovered [INSL3]. They did not observe these effects if they also administered a molecule that blocks the RXFP2 receptor [INSL3-beta-chain].

Insulin-like peptide-3, an unknown testicular anabolic hormone

Insulin-like peptide-3, an unknown testicular anabolic hormone

The figure above compares the effect of insulin-like peptide-3 on the production of muscle protein in muscle cells with that of the androgenic testosterone metabolite DHT. The anabolic effect of both substances is similar.

The Italians then looked at the effect of switching off [KO] of insulin-like peptide-3 on functioning muscles [control limbs] and non-functional muscles [denervated limbs] [denervation = switching off a muscle by cutting through neural pathways]. As you can see below, disabling insulin-like peptide-3 in the non-functional muscles caused the anabolic processes to fall back faster.

Insulin-like peptide-3, an unknown testicular anabolic hormone

""Here we provide evidence for the first time that the ablation of INSL3/RXFP2-signaling has detrimental effect on skeletal muscle, showing that Rxfp2−/− mice display worsened muscle loss and contractile force reduction after denervation compared to wild type controls, particularly in muscles with a highly beta-oxidative metabolism", write the researchers.

"Mechanistically, a major involvement of the alteration of the ubiquitin-proteasome system is suggested. This pattern is expected to be strengthened in humans, according to both the peculiar metabolic characteristics of muscle fibers and the endocrine dynamic of INSL3. Further investigations are warranted to address these insights."

Front Endocrinol (Lausanne). 2018 Sep 28;9:562.

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