Abstract
BackgroundFormation of 43S and 48S preinitiation complexes plays an important role in muscle protein synthesis. There is no muscle-wasting mouse model caused by a repressed 43S preinitiation complex assembly.ObjectiveThe aim of the present study was to develop a convenient mouse model of skeletal muscle wasting with repressed 43S preinitiation complex assembly.Material and methodsA ligand-activatable PERK derivative Fv2E-PERK causes the phosphorylation of eukaryotic initiation factor 2α (eIF2α), which inhibits 43S preinitiation complex assembly. Thus, muscle atrophic phenotypes, intracellular signaling pathways, and intracellular free amino acid profiles were investigated in human skeletal muscle α-actin (HSA) promoter-driven Fv2E-PERK transgenic (Tg) mice.ResultsHSA-Fv2E-PERK Tg mice treated with the artificial dimerizer AP20187 phosphorylates eIF2α in skeletal muscles and leads to severe muscle atrophy within a few days of ligand injection. Muscle atrophy was accompanied by a counter regulatory activation of mTORC1 signaling. Moreover, intracellular free amino acid levels were distinctively altered in the skeletal muscles of HSA-Fv2E-PERK Tg mice.ConclusionsAs a novel model of muscle wasting, HSA-Fv2E-PERK Tg mice provide a convenient tool for studying the pathogenesis of muscle loss and for assessing putative therapeutics.
Highlights
Skeletal muscles are involved in fundamental functions, such as enabling locomotion, maintaining body temperature, and storing nutrients
As a novel model of muscle wasting, human skeletal muscle α-actin (HSA)-Fv2E-PERK Tg mice provide a convenient tool for studying the pathogenesis of muscle loss and for assessing putative therapeutics
To determine whether protein synthesis suppression inhibits the maintenance of skeletal muscle and causes muscle atrophy, we characterized the previously established Tg mouse model under the control of a human skeletal muscle actin (HSA) promoter that induces muscle-specific gene expression
Summary
Skeletal muscles are involved in fundamental functions, such as enabling locomotion, maintaining body temperature, and storing nutrients. Calpain is suggested to be the early rate-limiting factor in myofibrillar proteolysis during muscle wasting [1]. They can degrade proteins required for the assembly and scaffolding of myofibrillar proteins, such as desmin, filamen, C-protein, tropomyosin, troponin T, troponin I, titin, nebulin, vimentin, gelsolin, and vinculin [4]. Ubiquitin–proteasome systems degrade the bulk of myofibrillar proteins during muscle wasting [5, 6]. Excessive autophagy causes an acute muscle loss owing to the imprudent clearance of necessary cellular components. Insufficient autophagy causes a chronic muscle loss due to the accumulation of damaged or aged cellular components. Editor: Ashok Kumar, University of Louisville School of Medicine, UNITED STATES Received: May 7, 2016 Accepted: June 7, 2017 Published: June 23, 2017
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