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Int J Mol Sci. 2016 Jan 30;17(2). pii: E187. doi: 10.3390/ijms17020187.

Atrogin-1 Deficiency Leads to Myopathy and Heart Failure in Zebrafish.

Author information

1
Molecular Cardiology, University of Ulm, 89081 Ulm, Germany. anja.buehler@uniklinik-ulm.de.
2
Molecular Cardiology, University of Ulm, 89081 Ulm, Germany. monika.forster@uni-ulm.de.
3
Molecular Cardiology, University of Ulm, 89081 Ulm, Germany. tiziana.bummer@uni-ulm.de.
4
Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany. wolfgang.rottbauer@uniklinik-ulm.de.
5
Department of Biomedical Sciences, University of Padova, 35129 Padova, Italy. marco.sandri@unipd.it.
6
Molecular Cardiology, University of Ulm, 89081 Ulm, Germany. steffen.just@uniklinik-ulm.de.

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).

KEYWORDS:

Atrogin-1; autophagy; heart failure; myopathy; zebrafish

PMID:
26840306
PMCID:
PMC4783921
DOI:
10.3390/ijms17020187
[Indexed for MEDLINE]
Free PMC Article

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