title: The ubiquitin ligase Nedd4-1 participates in denervation-induced skeletal muscle atrophy in mice.
abstract: Skeletal muscle atrophy is a consequence of muscle inactivity resulting from denervation, unloading and immobility. It accompanies many chronic disease states and also occurs as a pathophysiologic consequence of normal aging. In all these conditions, ubiquitin-dependent proteolysis is a key regulator of the loss of muscle mass, and ubiquitin ligases confer specificity to this process by interacting with, and linking ubiquitin moieties to target substrates through protein:protein interaction domains. Our previous work suggested that the ubiquitin-protein ligase Nedd4-1 is a potential mediator of skeletal muscle atrophy associated with inactivity (denervation, unloading and immobility). Here we generated a novel tool, the Nedd4-1 skeletal muscle-specific knockout mouse (myo(Cre);Nedd4-1(flox/flox)) and subjected it to a well validated model of denervation induced skeletal muscle atrophy. The absence of Nedd4-1 resulted in increased weights and cross-sectional area of type II fast twitch fibres of denervated gastrocnemius muscle compared with wild type littermates controls, at seven and fourteen days following tibial nerve transection. These effects are not mediated by the Nedd4-1 substrates MTMR4, FGFR1 and Notch-1. These results demonstrate that Nedd4-1 plays an important role in mediating denervation-induced skeletal muscle atrophy in vivo.
authors.affiliation: Keenan Research Centre of the LiKaShing Knowledge Institute, St Michaels Hospital, Toronto, Ontario, Canada.
authors.forename: Preena
authors.initials: P
authors.lastname: Nagpal
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Plant
authors.forename: Judy
authors.initials: J
authors.lastname: Correa
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bain
authors.forename: Michiko
authors.initials: M
authors.lastname: Takeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawabe
authors.forename: Daniela
authors.initials: D
authors.lastname: Rotin
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.forename: Jane A E
authors.initials: JA
authors.lastname: Batt
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009121:Muscle Denervation; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D051881:Receptor, Notch1; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D054558:Protein Tyrosine Phosphatases, Non-Receptor