Knockout of USP19 Deubiquitinating Enzyme Prevents Muscle Wasting by Modulating Insulin and Glucocorticoid Signaling
Knockout of USP19 Deubiquitinating Enzyme Prevents Muscle Wasting by Modulating Insulin and Glucocorticoid Signaling
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DOI：
10.1210/en.2018-00290
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发表时间：
2018-08-01
期刊：
影响因子：
4.8
通讯作者：
Wing, Simon S.
中科院分区：
文献类型：
--
作者：
Coyne, Erin S.;Bedard, Nathalie;Wing, Simon S.
肌肉萎缩是由于许多慢性疾病，以及长期糖皮质激素治疗和营养缺乏引起的。我们以前证明了USP19去泛素化酶在慢性糖皮质激素和去神经诱导的肌肉萎缩中起着重要作用。然而，USP19发挥其作用的机制仍然未知。为了进一步探索这一点，我们将小鼠禁食48小时，试图确定野生型和USP19敲除（KO）小鼠反应的早期差异，这些差异可以深入了解USP19的作用机制。由于蛋白质合成速率增加，USP 19 KO小鼠对禁食的反应表现出较少的肌纤维萎缩。在KO小鼠中胰岛素信号传导增强，如通过较低的循环胰岛素水平、增加的胰岛素刺激的葡萄糖处置和肌肉中Akt和S6K的磷酸化以及改善的总体葡萄糖耐量所揭示的。禁食和糖皮质激素治疗后糖皮质激素受体（GR）靶基因的表达减少，表明KO肌肉中糖皮质激素信号传导（在许多萎缩情况下至关重要）减少。这种GR信号传导的降低与USP19 KO肌肉中较低的GR蛋白水平相关。恢复USP19缺陷肌肉中的GR水平足以消除对肌纤维萎缩的保护。GR靶基因的表达也与人肌肉样品中USP19的表达相关。因此，USP19调节GR水平，并且这样做可以调节胰岛素和糖皮质激素信号传导，这是控制肌肉中的蛋白质周转和总体葡萄糖稳态的两个关键途径。
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.