title: Regulation of nicotinic acetylcholine receptor turnover by MuRF1 connects muscle activity to endo/lysosomal and atrophy pathways.
abstract: Muscle atrophy is a process of muscle wasting induced under a series of catabolic stress conditions, such as denervation, disuse, cancer cachexia, heart and renal failure, AIDS, and aging. Neuromuscular junctions (NMJs), the synapses between motor neurons and muscle fibers undergo major changes in atrophying muscles, ranging from mild morphological alterations to complete disintegration. In this study, we hypothesized that remodeling of NMJs and muscle atrophy could be linked together. To test this, we examined if a major atrophy-promoting E3 ubiquitin ligase, MuRF1, is involved in the maintenance of NMJs. Immunofluorescence revealed that MuRF1 is highly enriched close to the NMJ. Affinity precipitation and in vivo imaging showed that MuRF1 interacts in endocytic structures with both, acetylcholine receptor, the primary postsynaptic protein of the NMJ, as well as with Bif-1, an autophagy- and endocytosis-regulating factor. In vivo imaging, radio labeling, and weighing approaches demonstrated that metabolic destabilization of acetylcholine receptors and muscle atrophy induced by denervation were significantly rescued in MuRF1-KO animals. Notably, interaction with Bif-1, and the rescue of AChR lifetime and muscle atrophy were specific to MuRF1 but not MuRF2. Our data demonstrate an involvement of MuRF1 in membrane protein-turnover, including the degradation of AChRs at the NMJ under atrophying conditions where MuRF1 also interacts and associates with Bif-1.
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany, ruediger.rudolf@kit.edu.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Rudolf
authors.forename: Julius
authors.initials: J
authors.lastname: Bogomolovas
authors.forename: Siegfried
authors.initials: S
authors.lastname: Strack
authors.forename: Kyeong-Rok
authors.initials: KR
authors.lastname: Choi
authors.forename: Muzamil Majid
authors.initials: MM
authors.lastname: Khan
authors.forename: Anika
authors.initials: A
authors.lastname: Wagner
authors.forename: Kathrin
authors.initials: K
authors.lastname: Brohm
authors.forename: Akira
authors.initials: A
authors.lastname: Hanashima
authors.forename: Alexander
authors.initials: A
authors.lastname: Gasch
authors.forename: Dittmar
authors.initials: D
authors.lastname: Labeit
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004705:Endocytosis / Q000502:physiology; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D011978:Receptors, Nicotinic; D000070584:Tripartite Motif Proteins; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases