Knockout of USP19 Deubiquitinating Enzyme Prevents Muscle Wasting by Modulating Insulin and Glucocorticoid Signaling

Abstract

Muscle atrophy arises because of many chronic illnesses, as well as from prolonged glucocorticoid treatment and nutrient deprivation. We previously demonstrated that the USP19 deubiquitinating enzyme plays an important role in chronic glucocorticoid- and denervation-induced muscle wasting. However, the mechanisms by which USP19 exerts its effects remain unknown. To explore this further, we fasted mice for 48 hours to try to identify early differences in the response of wild-type and USP19 knockout (KO) mice that could yield insights into the mechanisms of USP19 action. USP19 KO mice manifested less myofiber atrophy in response to fasting due to increased rates of protein synthesis. Insulin signaling was enhanced in the KO mice, as revealed by lower circulating insulin levels, increased insulin-stimulated glucose disposal and phosphorylation of Akt and S6K in muscle, and improved overall glucose tolerance. Glucocorticoid signaling, which is essential in many conditions of atrophy, was decreased in KO muscle, as revealed by decreased expression of glucocorticoid receptor (GR) target genes upon both fasting and glucocorticoid treatment. This decreased GR signaling was associated with lower GR protein levels in the USP19 KO muscle. Restoring the GR levels in USP19-deficient muscle was sufficient to abolish the protection from myofiber atrophy. Expression of GR target genes also correlated with that of USP19 in human muscle samples. Thus, USP19 modulates GR levels and in so doing may modulate both insulin and glucocorticoid signaling, two critical pathways that control protein turnover in muscle and overall glucose homeostasis.

The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high-fat-diet-induced obesity and glucose intolerance in mice

“…We have previously shown that silencing Usp19 in skeletal muscle of WT mice leads to protection from muscle wasting due to alterations in protein turnover [14]. In addition, silencing or gene inactivation of Usp19 in muscle cells has been shown to promote their differentiation in vitro [11] or enhance insulin signalling [15], respectively. Moreover, in the present work, when SVF cells were isolated from fat from WT and Usp19 −/− mice and cultured, we observed a significant decrease in adipogenesis and fat accumulation (Fig.…”

“…The mice were generally housed in groups (maximum n = 5 per cage), but males were frequently isolated due to aggressive behaviour. Usp19 −/− mice were generated in our laboratory, as previously described [15]. Heterozygous mice (C57BL/6 background) were mated to generate WT and Usp19 −/− mice.…”

“…Most notably, USP19 plays an important role in muscle; USP19 regulates myogenic differentiation [11], and female muscle mass through oestrogen receptor-dependent mechanisms [12]. Importantly, Usp19 expression is induced in muscle under catabolic stimuli [13] and the inactivation of the gene in mice is protective against muscle wasting [14,15].…”

<p>USP19 Enhances MMP2/MMP9-Mediated Tumorigenesis in Gastric Cancer</p>

“… 13 , 14 It has been shown that USPs play important roles in the regulation of unfolded protein response and misfolding-associated protein secretion. 15 , 16 USP6 was shown to induce transcription of MMP9 through the activation of nuclear factor-κB (NF-κB) in a USP-dependent manner. 17 USP6 also induced the formation of tumors, which suggested that targeting USP6 with specific inhibitors might be an effective anticancer approach.…”

Ubiquitin‐specific protease 19 blunts pathological cardiac hypertrophy via inhibition of the TAK1‐dependent pathway

“…USP19 is involved in various cellular processes, which include endoplasmic reticulum‐associated degradation, 4 misfolding‐associated protein secretion, 5 immune response, 6 cell growth 7 and adipogenesis 8 . Importantly, USP19 has been extensively documented as an atrophy‐promoting gene in skeletal muscles 9,10 through the function of down‐regulating muscle myoblast differentiation, 11 increasing protein degradation 12 and decreasing protein synthesis 13 . In particular, depletion of USP19 in muscle myoblast increases the expression level of myogenin, which is a myogenic transcriptional factor, and this inhibits the oestradiol‐induced repression of myogenesis and promotes the synthesis of myofibrillar proteins 14 .…”