RRC ID 54065
Author Tawara N, Yamashita S, Kawakami K, Kurashige T, Zhang Z, Tasaki M, Yamamoto Y, Nishikami T, Doki T, Zhang X, Matsuo Y, Kimura E, Tawara A, Maeda Y, Hauschka SD, Maruyama H, Ando Y.
Title Muscle-dominant wild-type TDP-43 expression induces myopathological changes featuring tubular aggregates and TDP-43-positive inclusions.
Journal Exp Neurol
Abstract 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.
Volume 309
Pages 169-180
Published 2018-11-1
DOI 10.1016/j.expneurol.2018.08.006
PII S0014-4886(18)30352-2
PMID 30130494
MeSH Animals Cell Line, Transformed DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Disease Models, Animal Endoplasmic Reticulum / metabolism 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 Transfection
IF 4.691
Times Cited 1
Human and Animal Cells C2C12(RCB0987)