title: Skeletal muscle atrophy is induced by Fbxw7β via atrogene upregulation.
abstract: Muscle atrophy decreases skeletal muscle mass and is induced by inherited cachectic symptoms, genetic disorders, and sarcopenia. However, the molecular pathways associated with the onset of muscle atrophy are still unclear. In this study, we evaluated Fbxw7β, a gene associated with the development of muscle atrophy in vitro and in vivo. Among the three Fbxw7 isoforms, ectopically overexpressed Fbxw7β induced the expression of myogenin and major atrogene markers (atrogin-1 and MuRF-1) and reduced myoblast differentiation. In addition, endogenous expression of Fbxw7β was also upregulated by dexamethasone, which mimics muscle atrophy in vitro, accompanied by induction of myogenin and atrogene expression in primary myoblasts. Functional analysis of Fbxw7β using short hairpin RNA (shRNA) and a dominant-negative mutant (ΔFbox) suggested that Fbxw7β regulated muscle atrophy in vitro and in vivo. In particular, ΔFbox did not reduce the sizes of muscle fibers and did not induce myogenin and atrogene expression in vivo. Therefore, our findings demonstrated, for the first time, that Fbxw7β induced muscle atrophic phenotypes via atrogenes in adult muscle precursor cells and myofibers; this mechanism could be a potential therapeutic target for skeletal muscle atrophy.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Science, Seoul, 01812, South Korea.|Department of Biotechnology, Korea University, Seoul, 02841, South Korea.
authors.forename: Kyungshin
authors.initials: K
authors.lastname: Shin
authors.affiliation: Division of Life Sciences, Korea University, Seoul, 02841, South Korea.
authors.forename: Young-Gyu
authors.initials: YG
authors.lastname: Ko
authors.affiliation: Department of Surgery, Hanyang University College of Medicine, Seoul, 04763, South Korea.
authors.forename: Jaemin
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Science, Seoul, 01812, South Korea.
authors.forename: Heechung
authors.initials: H
authors.lastname: Kwon
mesh_terms: D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000503:physiopathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D018008:Myogenin / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D000070584:Tripartite Motif Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D009124:Muscle Proteins; D018008:Myogenin; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D000070584:Tripartite Motif Proteins; D003907:Dexamethasone; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Fbxw7β; atrogenes; dexamethasone; myogenin; skeletal muscle atrophy