Acetylation and deacetylation--novel factors in muscle wasting

Abstract

We review recent evidence that acetylation and deacetylation of cellular proteins, including transcription factors and nuclear cofactors, may be involved in the regulation of muscle mass. The level of protein acetylation is balanced by histone acetyltransferases (HATs) and histone deacetylases (HDACs) and studies suggest that this balance is perturbed in muscle wasting. Hyperacetylation of transcription factors and nuclear cofactors regulating gene transcription in muscle wasting may influence muscle mass. In addition, hyperacetylation may render proteins susceptible to degradation by different mechanisms, including intrinsic ubiquitin ligase activity exerted by HATs and by dissociation of proteins from cellular chaperones. In recent studies, inhibition of p300/HAT expression and activity and stimulation of SIRT1-dependent HDAC activity reduced glucocorticoid-induced catabolic response in skeletal muscle, providing further evidence that hyperacetylation plays a role in muscle wasting. It should be noted, however, that although several studies advocate a role of hyperacetylation in muscle wasting, apparently contradictory results have also been reported. For example, muscle atrophy caused by denervation or immobilization may be associated with reduced, rather than increased, protein acetylation. In addition, whereas hyperacetylation results in increased degradation of certain proteins, other proteins may be stabilized by increased acetylation. Thus, the role of acetylation and deacetylation in the regulation of muscle mass may be both condition- and protein-specific. The influence of HATs and HDACs on the regulation of muscle mass, as well as methods to modulate protein acetylation, is an important area for continued research aimed at preventing and treating muscle wasting.

Fig 1

Protein acetylation is an important posttranslational modification regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities.

Fig 2

Acetylation may influence protein degradation by multiple mechanisms. (A) HATs may acetylate lysine residues (exemplified by lysine residue K1 in the figure) and may increase the ubiquitination of other lysine residues (exemplified by K2) through intrinsic ubiquitin ligase (E3) activity. (B) Acetylation of cellular chaperones, for example Hsp90, may result in dissociation of the chaperone from proteins, resulting in destabilization and degradation of the proteins. The figure is based on reports by Khochbin and co-workers [35,36].

Fig 3

Muscle wasting, mainly reflecting stimulated ubiquitin-proteasome-dependent and autophagy-lysosomal myofibrillar protein breakdown, may at least in part reflect hyperacetylation of cellular proteins regulated by increased p300/HAT expression and activity and decreased expression and activity of HDAC3 and 6 and SIRT1. Of note, whereas this model may reflect mechanisms involved in muscle wasting during various catabolic conditions, such as sepsis and high levels of glucocorticoids, the role of hyperacetylation may be different or even opposite in other conditions characterized by loss of muscle mass, for example denervation and immobilization.