20-Hydroxyecdysone activates the protective arm of the RAAS via the MAS receptor

• Published in: Journal of molecular endocrinology Vol. 68; no. 2; pp. 77 - 87
• Main Authors: Lafont, René, Serova, Maria, Didry-Barca, Blaise, Raynal, Sophie, Guibout, Louis, Dinan, Laurence, Veillet, Stanislas, Latil, Mathilde, Dioh, Waly, Dilda, Pierre J
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 23.12.2021; Society for Endocrinology & BioScientifica Ltd
• Subjects: 17β-Estradiol; Aldosterone; Angiotensin; Animals; Antagonists; Cell Line; Cell Membrane - drug effects; Cell Membrane - metabolism; Cooperativity; Ecdysteroid receptors; Ecdysteroids; Ecdysterone - chemistry; Ecdysterone - metabolism; Ecdysterone - pharmacology; Energy Metabolism - drug effects; Estrogen receptors; Estrogens; G protein-coupled receptors; Gene expression; Gene Expression Regulation; Mice; Muscles - drug effects; Muscles - metabolism; Myoblasts; Myostatin; Protein Binding; Proto-Oncogene Mas - agonists; Proto-Oncogene Mas - genetics; Proto-Oncogene Mas - metabolism; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Steroid - metabolism; Renin; Renin-Angiotensin System - drug effects; Retinoid X receptors; siRNA; Steroids; MAS receptor; estrogen; myoblast; renin–angiotensin–aldosterone system (RAAS); ecdysteroid; muscle; G protein-coupled receptor (GPCR); 20-hydroxyecdysone (20E)
• ISSN: 0952-5041; 1479-6813
• DOI: 10.1530/JME-21-0033

20-Hydroxyecdysone (20E) is a steroid hormone that plays a key role in insect development through nuclear ecdysteroid receptors (EcR/RXR complex) and at least one membrane GPCR receptor (DopEcR). It also displays numerous pharmacological effects in mammals, where its mechanism of action is still debated, involving either an unidentified GPCR or the estrogen ERβ receptor. The goal of this study was to better understand 20E mechanism of action in mammals. A mouse myoblast cell line (C2C12) and the gene expression of myostatin (a negative regulator of muscle growth) were used as a reporter system of anabolic activity. Experiments using protein-bound 20E established the involvement of a membrane receptor. 20E-like effects were also observed with angiotensin(1–7), the endogenous ligand of MAS. Additionally, the effect on myostatin gene expression was abolished by Mas receptor knock-down using siRNA or pharmacological inhibitors. 17β-Estradiol (E2) also inhibited myostatin gene expression, but protein-bound E2 was inactive, and E2 activity was not abolished by angiotensin(1–7) antagonists. A mechanism involving cooperation between the MAS receptor and a membrane-bound palmitoylated estrogen receptor is proposed. The possibility to activate the MAS receptor with a safe steroid molecule is consistent with the pleiotropic pharmacological effects of ecdysteroids in mammals and, indeed, the proposed mechanism may explain the close similarity between the effects of angiotensin(1–7) and 20E. Our findings open up many possible therapeutic developments involving stimulation of the protective arm of the renin–angiotensin–aldosterone system (RAAS) with 20E.