Binding of a Novel 11β-Hydroxysteroid to the Apelin Receptor (APLNR) and Its Possible Role in Regulating Skeletal Muscle Health in Mice

Several molecules have been investigated for their potential to improve muscle health in models of muscle damage simulating sarcopenia, injury, or aging. Some small molecules induced beneficial effects on skeletal muscle by stimulating the apelin receptor (APLNR). This receptor has emerged as a promising pharmacological target for modulating muscle homeostasis. Using an in silico approach, we recently identified 11β-hydroxypregnenolone (11β-OHP5) as a potential skeletal muscle (SKM) modulator. We hypothesized that 11β-OHP5 interacts with and activates APLNR. This study employed several research approaches: (1) in silico molecular docking and molecular dynamics to explore the feasibility of 11β-OHP5 interacting with APLNR; (2) in vitro activation analysis to APLNR; (3) in vitro analysis C2C12 myoblast differentiation; (4) analysis of the molecule’s presence in mouse skeletal muscle and its differential presence between young and older mice. The results show that 11β-OHP5, acting through APLNR, positively affects myoblast differentiation and may participate in the exercise-induced benefits in aging mice. We show that 11β-OHP5 interacts with APLNR, induces myogenic responses, is found in SKM; its concentration decreases with age, and exercise restores it. More work is necessary to understand the physiology of this possible endogenous molecule.