RESUMO
Muscle histology of sporadic inclusion body myositis (sIBM) demonstrates inflammatory findings and degenerative features including accumulation of TAR DNA-binding protein of 43â¯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.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Miosite de Corpos de Inclusão/metabolismo , Animais , Linhagem Celular Transformada , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica/genética , Proteínas de Choque Térmico/metabolismo , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Doenças Musculares/genética , Miosite de Corpos de Inclusão/patologia , Proteômica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , TransfecçãoRESUMO
An 82-year-old man was suspected to have experienced a transient ischemic attack since he developed transient weakness in the right upper limb twice. On admission, neurologic examination yielded normal findings except for mild cognitive impairment. Brain CT and images showed an unexpected finding of acute focal subarachnoid hemorrhage in the left central sulcus, although MR angiography and venography did not show any abnormality. T(2)(*) weighted images showed superficial siderosis in the bilateral frontal lobes, which indicated the possibility of a recurrent subarachnoid hemorrhage. We propose that focal subarachnoid hemorrhage should be included in the differential diagnosis of transient ischemic attack.