Rebastinib inhibits FoxO1 activity and reduces dexamethasone-induced atrophy and its-related gene expression in cultured myotubes.

Abstract

FoxO1, a transcription factor, is upregulated in skeletal muscle during atrophy and inactivation of FoxO1 is a potential strategy to prevent muscle loss. This study identified Rebastinib as a potent suppressor of FoxO1 activity among protein kinase inhibitors. To determine whether Rebastinib inhibits atrophy-related ubiquitin ligases gene expression and mitigates atrophy in mouse skeletal muscle-derived cells, we investigated its protective effects of the compound against dexamethasone (DEX)-induced muscle atrophy using C2C12 myotubes. Rebastinib inhibited the DEX-induced upregulation of atrogin-1 and MuRF-1 mRNA, and atrogin-1 protein. Rebastinib also suppressed protein degradation and increased myotube diameter in DEX-treated C2C12 myotubes. Additionally, Rebastinib ameliorated the DEX- and cachexia-induced reduction in contractile force generation. Although the precise mechanisms underlying the action of Rebastinib against muscle atrophy and its efficacy in vivo remains to be elucidated, this compound shows great potential as a therapeutic agent for muscle atrophy.