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).
Highlights
Protein homeostasis describes the sum of processes involved in protein biogenesis, folding, modification, trafficking, assembly, and degradation within and outside of the cell [1]
By targeted gene inactivation, we demonstrate an important role of Atrogin-1 in regulating protein degradation in the embryonic zebrafish heart and skeletal muscle and thereby present a straight-forward in vivo model to further dissect the molecular pathogenetic mechanisms associated with autophagy
We found Atrogin-1 to be ubiquitously expressed at low levels, but with pronounced expression in muscle tissue at 72 h post fertilization (Figure S1J, J’)
Summary
Protein homeostasis (proteostasis) describes the sum of processes involved in protein biogenesis, folding, modification, trafficking, assembly, and degradation within and outside of the cell [1] In this context, protein degradation as a mechanism to control protein quality and quantity in the cell, is predominately accomplished by two highly effective proteolytic machineries, the autophagy/lysosome system and the Ubiquitin proteasome degradation system (UPS) [2]. By targeted gene inactivation, we demonstrate an important role of Atrogin-1 in regulating protein degradation in the embryonic zebrafish heart and skeletal muscle and thereby present a straight-forward in vivo model to further dissect the molecular pathogenetic mechanisms associated with autophagy
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