Deubiquitinases in skeletal muscle atrophy

Abstract

The ubiquitin proteasome system plays a critical role in skeletal muscle atrophy. A large body of research has revealed that many ubiquitin ligases are induced and play an important role in mediating the wasting. However, relatively little is known about the roles of deubiquitinases in this process. Although it might be expected that deubiquitinases would be downregulated in atrophying muscles to promote ubiquitination and degradation of muscle proteins, this has not to date been demonstrated. Instead several deubiquitinases are induced in atrophying muscle, in particular USP19 and USP14. USP19, USP2 and A20 are also implicated in myogenesis. USP19 has been most studied to date. Its expression is increased in both systemic and disuse forms of atrophy and can be regulated through a p38 MAP kinase signaling pathway. In cultured muscle cells, it decreases the expression of myofibrillar proteins by apparently suppressing their transcription indicating that the ubiquitin proteasome system may be activated in skeletal muscle to not only increase protein degradation, but also to suppress protein synthesis. Deubiquitinases may be upregulated in atrophy in order to maintain the pool of free ubiquitin required for the increased overall conjugation and degradation of muscle proteins as well as to regulate the stability and function of proteins that are essential in mediating the wasting. Although deubiquitinases are not well studied, these early insights indicate that some of these enzymes play important roles and may be therapeutic targets for the prevention and treatment of muscle atrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Keywords: Cachexia; Deubiquitination; Myofibrillar proteins; Skeletal muscle; Ubiquitin.

Fig. 1

Potential roles for deubiquitinases in skeletal muscle atrophy. Deubiquitinases may be activated to support or promote proteolysis by maintaining the pool of free ubiquitin that is required for the increased overall conjugation to substrates targeted for degradation. Deubiquitinases generate free ubiquitin by processing the products of the polyubiquitin genes Ubb and Ubc and the ubiquitin fusion genes Uba52 and Rps27a (A) as well as by removing ubiquitin from proteins committed to degradation by the proteasome or by the lysosome (B). Deubiquitinases may also act on specific protein substrates to reverse the functions of ubiquitination (C). In this way, they not only contribute to the pool of free ubiquitin, but importantly may promote muscle atrophy by stabilizing proteins that promote wasting (see text for more detailed discussion). If ubiquitination of these specific proteins does not target for degradation but confers other functions, deubiquitinases may promote atrophy by enhancing the functions of activators or by inhibiting the functions of repressors of pathways that promote wasting. Muscle atrophy could also be promoted by downregulation of deubiquitinases that normally stabilize substrates targeted for degradation or stabilize repressors of pathways that promote wasting. At this time, all of these possibilities remain speculative.