4-Hydroxyderricin and xanthoangelol, isolated from Angelica keiskei, prevent dexamethasone-induced muscle loss
Since decreasing of muscle mass leads to increase a risk of mortality, prevention of muscle wasting contributes to maintaining the quality of life. Recently, we have reported that glabridin, a prenylated flavonoid in licorice, prevents dexamethasone-induced muscle loss. In this study, we focused on other prenylated chalcones, 4-hydroxyderricin and xanthoangelol in Ashitaba (Angelica keiskei) and investigated their prevention effect on dexamethasone-induced muscle loss. It was found that 4-hydroxyderricin and xanthoangelol significantly prevented dexamethasone-induced protein degradation in C2C12 myotubes through suppressing the expression of ubiquitin ligases, Cbl-b and MuRF-1. These prenylated chalcones acted as the antagonists of glucocorticoid receptor and inhibited the binding of dexamethasone to this receptor and following its nuclear translocation. In addition, the chalcones suppressed phosphorylation of p38 and FoxO3a, as the upstream factors for ubiquitin ligases. Dexamethasone-caused protein degradation and upregulation of Cbl-b were attenuated by knockdown of glucocorticoid receptor, but not by knockdown of p38. In male C57BL/6J mice, Ashitaba extract, containing 4-hydroxyderricin and xanthoangelol, suppressed dexamethasone-induced muscle mass wasting accompanied by decreasing of the expression of ubiquitin ligases through inhibiting nuclear translocation of the glucocorticoid receptor and phosphorylation of FoxO3a. In conclusion, 4-hydroxyderricin and xanthoangelol are effective compounds to inhibit steroid-induced muscle loss.