Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice

Masato Miyake; Masashi Kuroda; Hiroshi Kiyonari; Kenji Takehana; Satoshi Hisanaga; Masatoshi Morimoto; Jun Zhang; Miho Oyadomari; Hiroshi Sakaue; Seiichi Oyadomari

doi:10.1371/journal.pone.0179955

Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice

PLoS One. 2017 Jun 23;12(6):e0179955. doi: 10.1371/journal.pone.0179955. eCollection 2017.

Authors

Masato Miyake^{1

2

3}, Masashi Kuroda⁴, Hiroshi Kiyonari⁵, Kenji Takehana⁶, Satoshi Hisanaga¹, Masatoshi Morimoto¹, Jun Zhang^{1

2}, Miho Oyadomari^{1

2}, Hiroshi Sakaue^{2

4}, Seiichi Oyadomari^{1

2

3}

Affiliations

¹ Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
² Department of Molecular Research, Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan.
³ Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan.
⁴ Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
⁵ Animal Resource Development Unit and Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan.
⁶ Department of R&D planning, EA Pharma Co.,Ltd., Tokyo, Japan.

Abstract

Background: Formation 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.

Objective: The aim of the present study was to develop a convenient mouse model of skeletal muscle wasting with repressed 43S preinitiation complex assembly.

Material and methods: A 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.

Results: HSA-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.

Conclusions: As 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.

MeSH terms

Actins / genetics
Actins / metabolism
Amino Acids / metabolism
Animals
Disease Models, Animal*
Homeostasis / physiology
Humans
Intracellular Space / metabolism
Ligands
Mechanistic Target of Rapamycin Complex 1
Mice, Inbred C57BL
Mice, Transgenic*
Multiprotein Complexes / metabolism
Muscle, Skeletal* / metabolism
Muscular Atrophy* / metabolism
Muscular Atrophy* / pathology
Promoter Regions, Genetic
Protein Serine-Threonine Kinases / metabolism
TOR Serine-Threonine Kinases / metabolism
Tacrolimus / analogs & derivatives
eIF-2 Kinase / genetics
eIF-2 Kinase / metabolism

Substances

AP20187
Actins
Amino Acids
Ligands
Multiprotein Complexes
Mechanistic Target of Rapamycin Complex 1
PERK kinase
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
eIF-2 Kinase
eIF2alpha kinase, mouse
Tacrolimus

Grants and funding

This work was supported mainly by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Culture (MEXT) of Japan and Grants-in-Aid for Young Scientist from Japan Society for Promotion of Science (JSPS), and partly by the Inoue Foundation for Science, the Mitsubishi Foundation, the Uehara Memorial Foundation, the Naito Foundation, the Cell Science Research Foundation, Takeda Science Foundation, Sankyo Foundation, Ono Medical Research Foundation, Mochida Memorial Foundation, the Ube Foundation, Kowa Life Science Foundation, Suzuken Memorial Foundation, Kanae Foundation and Japan Diabetes Foundation. The funders provided support in the form of research grant for SO or MM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.