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. KeywordsUbiquitin; Skeletal muscle; Myofibrillar proteins; Deubiquitination; Cachexia Increased ubiquitination of muscle proteins in atrophic conditionsThe first observations of activation of the ubiquitin-proteasome system (UPS) in conditions of muscle wasting were reported approximately twenty years ago (Haas and Riley, 1988;Medina et al., 1991). Amongst these findings were key observations that the increases in rates of proteolysis observed upon fasting or denervation -prototypic conditions of muscle wasting due to systemic regulatory factors or loss of neural activity respectively -were largely due to an ATP dependent mechanism (Furuno et al., 1990;Wing and Goldberg, 1993). Importantly, expression of ubiquitin and ubiquitinated proteins increased in skeletal muscle in parallel with these increases in rates of ATP dependent proteolysis (Medina et al.,

An ethanolic extract of Artemisia dracunculus L. regulates gene expression of ubiquitin–proteasome system enzymes in skeletal muscle: Potential role in the treatment of sarcopenic obesity

“…Repression of both deubiquitinases in the vastus lateralis is associated with PMI5011-mediated increases in each of the genes encoding ubiquitin. The role of the deubiquitinases in muscle atrophy is not well understood, but up-regulation of Usp14 and Usp19 may function to increase the pool of free ubiquitin available to meet the demands for ubiquitin modification during muscle loss [41]. Consistent with this idea, our results suggest genes encoding ubiquitin are up-regulated in vastus lateralis in response to PMI5011-mediated suppression of Usp14 and Usp19 .…”

Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training

“…Alternatively, a down‐regulation of deubiquitinases (e.g. USP19 and USP14) in order to promote ubiquitination could be another mechanism that activates UPS‐mediated protein degradation . A reduced mRNA expression of deubiquitinases has been documented in multiple conditions associated with muscle atrophy such as fasting, tumours, high‐dose glucocorticoid therapy, and denervation .…”

“…Deubiquintinases may potentially be upregulated in cachexia in order to regenerate free ubiquitin from the ubiquitin chains. This would therefore ensure enough free ubiquitin molecules are present for protein degradation via the UPS . However, as only a limited number of studies have investigated, this potential explanation suggests that further investigation is warranted.…”

“…USP19 and USP14) in order to promote ubiquitination could be another mechanism that activates UPS-mediated protein degradation. 79 A reduced mRNA expression of deubiquitinases has been documented in multiple conditions associated with muscle atrophy such as fasting, tumours, high-dose glucocorticoid therapy, and denervation. [80][81][82] Deubiquintinases may potentially be upregulated in cachexia in order to regenerate free ubiquitin from the ubiquitin chains.…”

Chronically endurance-trained individuals preserve skeletal muscle mitochondrial gene expression with age but differences within age groups remain

“…; Pickering and Davies ), was lower in YT compared to YS participants. While not all genes identified by the pathway analysis currently have a well‐defined role in skeletal muscle (i.e., BIRC4 or USP11) many including USP19, USP2, and UBR2 are associated with skeletal muscle dysfunction (Wing ; Hockerman et al. ).…”