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      Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting.

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          Abstract

          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.

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          Author and article information

          Journal
          FASEB J.
          FASEB journal : official publication of the Federation of American Societies for Experimental Biology
          FASEB
          1530-6860
          0892-6638
          Sep 2015
          : 29
          : 9
          Affiliations
          [1 ] *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.
          [2 ] *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 simon.wing@mcgill.ca.
          Article
          fj.15-270579
          10.1096/fj.15-270579
          26048142
          81617b95-de0c-40e5-a4e7-45e498929b5e

          cachexia, deubiquitylation, sarcopenia

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