Bédard Nathalie, Jammoul Samer, Moore Tamara, Wykes Linda, Hallauer Patricia L, Hastings Kenneth E M, Stretch Cynthia, Baracos Vickie, Chevalier Stéphanie, Plourde Marie, Coyne Erin, Wing Simon S
*Polypeptide Laboratory and Crabtree Nutrition Laboratories, Department of Medicine, McGill University Health Centre, and Molecular Genetics Laboratory, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada; and Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
*Polypeptide Laboratory and Crabtree Nutrition Laboratories, Department of Medicine, McGill University Health Centre, and Molecular Genetics Laboratory, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada; and Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
FASEB J. 2015 Sep;29(9):3889-98. doi: 10.1096/fj.15-270579. Epub 2015 Jun 5.
The ubiquitin system plays a critical role in muscle wasting. Previous work has focused on the roles of ubiquitination. However, a role for deubiquitination in this process has not been established. Because ubiquitin-specific protease (USP)19 deubiquitinating enzyme is induced in skeletal muscle in many catabolic conditions, we generated USP19 knockout (KO) mice. These mice lost less muscle mass than wild-type (WT) animals in response to glucocorticoids, a common systemic cause of muscle atrophy as well as in response to denervation, a model of disuse atrophy. KO mice retained more strength and had less myofiber atrophy with both type I and type IIb fibers being protected. Rates of muscle protein synthesis were similar in WT and KO mice, suggesting that the sparing of atrophy was attributed to suppressed protein degradation. Consistent with this, expression of the ubiquitin ligases MuRF1 and MAFbx/atrogin-1 as well as several autophagy genes was decreased in the muscles of catabolic KO mice. Expression of USP19 correlates with that of MuRF1 and MAFbx/atrogin-1 in skeletal muscles from patients with lung cancer or gastrointestinal cancer, suggesting that USP19 is involved in human muscle wasting. Inhibition of USP19 may be a useful approach to the treatment of many muscle-wasting conditions.
泛素系统在肌肉萎缩中起关键作用。以往的研究主要集中在泛素化的作用上。然而，去泛素化在此过程中的作用尚未明确。由于泛素特异性蛋白酶（USP）19去泛素化酶在许多分解代谢条件下在骨骼肌中被诱导，我们构建了USP19基因敲除（KO）小鼠。在对糖皮质激素（一种常见的全身性肌肉萎缩原因）以及对失神经支配（一种废用性萎缩模型）的反应中，这些小鼠比野生型（WT）动物损失的肌肉量更少。KO小鼠保留了更多的力量，肌纤维萎缩更少，I型和IIb型纤维均受到保护。WT小鼠和KO小鼠的肌肉蛋白合成速率相似，这表明萎缩的减轻归因于蛋白质降解的抑制。与此一致的是，在分解代谢的KO小鼠肌肉中，泛素连接酶MuRF1和MAFbx/atrogin-1以及几个自噬基因的表达均降低。在肺癌或胃肠道癌患者的骨骼肌中，USP19的表达与MuRF1和MAFbx/atrogin-1的表达相关，这表明USP19参与了人类肌肉萎缩。抑制USP19可能是治疗多种肌肉萎缩病症的有效方法。
