Corticosteroids and muscle wasting: role of transcription factors, nuclear cofactors, and hyperacetylation

Abstract

Purpose of review: The purpose of this review is to discuss novel insight into mechanisms of glucocorticoid-regulated muscle wasting, in particular the role of transcription factors and nuclear cofactors. In addition, novel strategies that may become useful in the treatment or prevention of glucocorticoid-induced muscle wasting are reviewed.

Recent findings: Studies suggest that glucocorticoid-induced upregulation of the transcription factors Forkhead box O 1 and CCAAT/enhancer-binding protein beta and downregulation of MyoD and myogenin are involved in glucocorticoid-induced muscle wasting. In addition, glucocorticoid-induced hyperacetylation caused by increased expression of the nuclear cofactor p300 and its histone acetyl transferase activity and decreased expression and activity of histone deacetylases plays an important role in glucocorticoid-induced muscle proteolysis and wasting. Other mechanisms may also be involved in glucocorticoid-induced muscle wasting, including insulin resistance and store-operated calcium entry. Novel potential strategies to prevent or treat glucocorticoid-induced muscle wasting include the use of small molecule histone deacetylase activators, dissociated glucocorticoid receptor agonists, and 11beta-hydroxysteroid dehydrogenase type 1 inhibitors.

Summary: An increased understanding of molecular mechanisms regulating glucocorticoid-induced muscle wasting will help develop new strategies to prevent and treat this debilitating condition.

Fig. 1

Potential mechanisms involved in glucocorticoid-induced muscle wasting. Although regulation of certain transcription factors and nuclear cofactors is emphasized in this review, other mechanisms are probably involved as well. Studies suggest that the expression and activity of FOXO transcription factors and C/EBPβ are upregulated by glucocorticoids and that hyperacetylation caused by increased p300/HAT and decreased HDAC expression and activity may contribute to transcription factor activation. Proteasome-dependent degradation may contribute to reduced expression and activity of the “anabolic transcription factors” MyoD and myogenin, further accentuating the loss of muscle mass. Although there is evidence that glucocorticoid-induced hyperacetylation stimulates muscle protein degradation, the role of hyperacetylation in the regulation of the ubiquitin-proteasome pathway and of autophagic/lysosomal protein degradation is not known at present (as indicated by the question mark).