Muscle-dominant wild-type TDP-43 expression induces myopathological changes featuring tubular aggregates and TDP-43-positive inclusions

Muscle histology of sporadic inclusion body myositis (sIBM) demonstrates inflammatory findings and degenerative features including accumulation of TAR DNA-binding protein of 43 kDa (TDP-43). However, whether sarcoplasmic accumulation of TDP-43 is a primary trigger of muscle degeneration or a seconda...

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Bibliographic Details
Published in:Experimental neurology 2018-11, Vol.309, p.169-180
Main Authors: Tawara, Nozomu, Yamashita, Satoshi, Kawakami, Kensuke, Kurashige, Takashi, Zhang, Ziwei, Tasaki, Masayoshi, Yamamoto, Yasuhiro, Nishikami, Tomo, Doki, Tsukasa, Zhang, Xiao, Matsuo, Yoshimasa, Kimura, En, Tawara, Akie, Maeda, Yasushi, Hauschka, Stephen D., Maruyama, Hirofumi, Ando, Yukio
Format: Article
Language:English
Subjects:
Animals
Calcium homeostasis
Cell Line, Transformed
Creatine kinase 8 promoter
Disease Models, Animal
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Endoplasmic Reticulum - metabolism
Endoplasmic reticulum stress
Endoplasmic Reticulum Stress - genetics
Endoplasmic Reticulum Stress - physiology
Gene Expression Regulation - genetics
Heat-Shock Proteins - metabolism
Immunoprecipitation
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Electron
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Muscle, Skeletal - ultrastructure
Muscular Diseases - genetics
Muscular Diseases - metabolism
Muscular Diseases - pathology
Myositis, Inclusion Body - metabolism
Myositis, Inclusion Body - pathology
Proteomics
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Sporadic inclusion body myositis
TAR DNA-binding protein of 43 kDa
Transfection
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Summary:Muscle histology of sporadic inclusion body myositis (sIBM) demonstrates inflammatory findings and degenerative features including accumulation of TAR DNA-binding protein of 43 kDa (TDP-43). However, whether sarcoplasmic accumulation of TDP-43 is a primary trigger of muscle degeneration or a secondary event resulting from muscle degeneration in the pathophysiology of sIBM remained unclear. Our study aimed to discover whether muscle-dominant expression of TDP-43 is a primary cause of muscle degeneration. We generated several lines of wild-type TDP-43 transgenic mice driven by a creatine kinase 8 promoter, and analyzed the phenotypes via biochemical, histological, and proteomic techniques. The mice showed increased serum levels of myogenic enzymes. Muscle histology demonstrated myopathic changes including fiber size variation, abundant tubular aggregates, and TDP-43 aggregation with upregulation of endoplasmic reticulum (ER) stress. Proteomic analysis with aggregated materials in degenerative myofibers identified increased sarcoplasmic reticulum (SR)/ER-resident proteins that regulated calcium homeostasis, as well as cytosolic 5′-nucleotidase 1A. Muscle-dominant wild-type TDP-43 expression indeed caused myotoxicity featuring tubular aggregates and TDP-43-positive inclusions. Our observation suggested that TDP-43 aggregates might not be sufficient to trigger the pathogenesis of sIBM although myofiber sarcoplasmic aggregation of TDP-43 led to myofiber degeneration via ER stress and possibly calcium dysregulation, independently of inflammatory process. •We first generated muscle-dominant wild-type TDP-43 transgenic mice.•The mice showed myopathic changes: tubular aggregate and TDP-43 inclusion.•Proteomics identified SR/ER-resident proteins and cytosolic 5′-nucleotidase 1A.•TDP-43 inclusion led to muscle degeneration via ER stress and calcium dysregulation.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2018.08.006