Upregulation of FOXO1 and FOXO3a Following Denervation and Dexamethasone Treatment

Abstract

Skeletal muscle atrophy occurs under a variety of conditions including disuse, denervation, and glucocorticoid treatment. Although an increase in the expression of MuRF1 and MAFbx is observed in almost all types of muscle atrophy, the regulation of these two atrophy associated genes is poorly understood. Promoter analysis of MuRF1 and MAFbx has revealed that each gene contains several FOXO binding elements, suggesting that this family of transcription factors may induce the activation of these genes. To determine if FOXO expression correlates with MuRF1 and MAFbx expression, the gastrocnemius and tibialis anterior muscles of adult mice were removed at multiple time points (1–14 days) following sciatic nerve transection or treatment with dexamethasone (1mg/kg). Northern blot analysis demonstrated that the pattern of FOXO1 and FOXO3a expression closely matched the expression of MuRF1 and MAFbx, even though the time course of expression of these genes differed between the two conditions. Following denervation, MuRF1, MAFbx, FOXO1, and FOXO3a were all upregulated at day 1, whereas upregulation was delayed with dexamethasone treatment. These findings demonstrate that the FOXO transcription factors are upregulated under atrophy conditions. Further, these data, together with our promoter analyses, strongly suggest that the FOXOs play an important role in the transcriptional activation of MuRF1 and MAFbx.