title: Atrogin-1 Deficiency Leads to Myopathy and Heart Failure in Zebrafish.
abstract: Orchestrated protein synthesis and degradation is fundamental for proper cell function. In muscle, impairment of proteostasis often leads to severe cellular defects finally interfering with contractile function. Here, we analyze for the first time the role of Atrogin-1, a muscle-specific E3 ubiquitin ligase known to be involved in the regulation of protein degradation via the ubiquitin proteasome and the autophagy/lysosome systems, in the in vivo model system zebrafish (Danio rerio). We found that targeted inactivation of zebrafish Atrogin-1 leads to progressive impairment of heart and skeletal muscle function and disruption of muscle structure without affecting early cardiogenesis and skeletal muscle development. Autophagy is severely impaired in Atrogin-1-deficient zebrafish embryos resulting in the disturbance of the cytoarchitecture of cardiomyocytes and skeletal muscle cells. These observations are consistent with molecular and ultrastructural findings in an Atrogin-1 knockout mouse and demonstrate that the zebrafish is a suitable vertebrate model to study the molecular mechanisms of Atrogin-1-mediated autophagic muscle pathologies and to screen for novel therapeutically active substances in high-throughput in vivo small compound screens (SCS).
authors: Molecular Cardiology, University of Ulm, 89081 Ulm, Germany. anja.buehler@uniklinik-ulm.de.
authors: Anja
authors: A
authors: Bühler
authors: Molecular Cardiology, University of Ulm, 89081 Ulm, Germany. monika.forster@uni-ulm.de.
authors: Monika
authors: M
authors: Kustermann
authors: Molecular Cardiology, University of Ulm, 89081 Ulm, Germany. tiziana.bummer@uni-ulm.de.
authors: Tiziana
authors: T
authors: Bummer
authors: Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany. wolfgang.rottbauer@uniklinik-ulm.de.
authors: Wolfgang
authors: W
authors: Rottbauer
authors: Department of Biomedical Sciences, University of Padova, 35129 Padova, Italy. marco.sandri@unipd.it.
authors: Marco
authors: M
authors: Sandri
authors: Molecular Cardiology, University of Ulm, 89081 Ulm, Germany. steffen.just@uniklinik-ulm.de.
authors: Steffen
authors: S
authors: Just
mesh_terms: D000818:Animals; D001343:Autophagy; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D044783:F-Box Proteins; D029961:Zebrafish Proteins; C544337:fbxo32 protein, zebrafish
keywords: Atrogin-1; autophagy; heart failure; myopathy; zebrafish