Ligand-Induced Rapid Skeletal Muscle Atrophy In Hsa-Fv2e-Perk Transgenic Mice

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 2 alpha (eIF2 alpha), 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 alpha-actin (HSA) promoter-driven Fv2EPERK transgenic (Tg) mice.ResultsHSA-Fv2E-PERK Tg mice treated with the artificial dimerizer AP20187 phosphorylates eIF2a 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.