Cephalotaxus harringtonia and Their Constituents Harringtonine Alkaloids Inhibit FoxO1 and 3a Activity and Atrophy-Related Gene Expression in C2C12 Myotubes.

Abstract

The expression of the forkhead box O (FoxO) transcription factor, FoxO, in the skeletal muscle is involved in muscle atrophy caused by disuse, fasting, diabetes, and cachexia. Since inhibition of FoxO activity has been shown to be effective in preventing muscle atrophy in genetically engineered animals, inhibition of FoxO activity by dietary components may contribute to the prevention of muscle atrophy. In this study, 4,006 plant extracts were evaluated for FoxO1 and FoxO3a inhibitory activity using a reporter gene assay system, and the extracts from Cephalotaxus harringtonia showed potent inhibitory activities. These extracts also suppressed dexamethasone-induced expression of FoxO target genes, such as atrogin-1 and cathepsin L in C2C12 myotubes. Furthermore, harringtonine alkaloids, harringtonine and homoharringtonine, contained in Cephalotaxus harringtonia inhibited FoxOs activities and suppressed dexamethasone-induced expression of FoxO target genes in C2C12 myotubes, suggesting that harringtonine alkaloids contributed to the effects observed in C2C12 myotubes treated with Cephalotaxus harringtonia extract. However, these extracts and harringtonine alkaloids did not improve weakness in dexamethasone-atrophic myotubes. In conclusion, harringtonine alkaloids from Cephalotaxus harringtonia suppressed FoxO1 and 3a activity and the expression of their target atrophy genes in C2C12 myotubes, but these alkaloids had no the effect on dexamethasone-induced reduction in muscle contractility.