title: Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting.
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.
authors.affiliation: *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.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bédard
authors.affiliation: *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.
authors.forename: Samer
authors.initials: S
authors.lastname: Jammoul
authors.affiliation: *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.
authors.forename: Tamara
authors.initials: T
authors.lastname: Moore
authors.affiliation: *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.
authors.forename: Linda
authors.initials: L
authors.lastname: Wykes
authors.affiliation: *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.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Hallauer
authors.affiliation: *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.
authors.forename: Kenneth E M
authors.initials: KE
authors.lastname: Hastings
authors.affiliation: *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.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Stretch
authors.affiliation: *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.
authors.forename: Vickie
authors.initials: V
authors.lastname: Baracos
authors.affiliation: *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.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Chevalier
authors.affiliation: *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.
authors.forename: Marie
authors.initials: M
authors.lastname: Plourde
authors.affiliation: *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.
authors.forename: Erin
authors.initials: E
authors.lastname: Coyne
authors.affiliation: *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.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Wing
mesh_terms: D000368:Aged; D000818:Animals; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis* / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C440907:FBXO32 protein, human; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C559917:USP19 protein, human; C000600175:USP19 protein, mouse
keywords: cachexia; deubiquitylation; sarcopenia