Androgens are hormones that control the development of male sexual characteristics. The strongest hormone among the androgens is called 5?-dihydrotestosterone (5?-DHT). Among other things, it is essential for bone and muscle function and for the development of secondary male sexual characteristics during puberty. As a driver of bone and muscle formation, 5?-DHT increases bone mineral density and promotes the growth of skeletal muscles to increase muscle strength.
In this international study, the scientists were able to show that one of the adhesion G protein-coupled receptors - GPR133 - is activated by the androgenic steroid hormone 5?-DHT. This activation can, among other things, increase the contractile force of skeletal muscles, whereby our study also uses a newly developed, potent activator of this receptor to specifically trigger this effect," says Ines Liebscher, Professor of Signal Transduction at the University of Leipzig and co-leader of the study.
Boosting muscle strength with a chance of significantly fewer negative effects of androgens
The activation of GPR133 by the new agonist AP503 increases muscle strength without triggering a specific negative effect that is otherwise observed when androgens are administered. Among other things, an increased and prolonged supply of testosterone can promote the development of prostate cancer, which can be seen in mice after only two weeks of androgen administration through corresponding tissue changes in the prostate. This side effect has not yet been observed during treatment with AP503.Furthermore, the current study uses structural biology methods to clarify the molecular basis of the interaction between the steroid hormone, the substance AP503 and GPR133. This now enables targeted optimization of the activator and thus further development towards a new therapeutic agent. On this basis, new drugs with a lower side-effect profile could be developed that are used to strengthen the muscles.
The current publication is the result of a long-standing and successful collaboration between the Rudolf Schönheimer Institute of Biochemistry and the working group of Jin-Peng Sun from Shandong University in China. The researchers are currently working on several follow-up studies to investigate the use of the substance AP503 in disease processes and the role of GPR133 in the organism in more detail. The data has currently been verified in animal models. The transferability of the findings to humans must be investigated in follow-up studies.
Original publication in Cell: Identification, structure, and agonist design of an androgen membrane receptor. https://doi.org/10.1016/j.cell.2025.01.006
