RESUMEN
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.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Músculo Esquelético/metabolismo , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Miositis por Cuerpos de Inclusión/metabolismo , Animales , Línea Celular Transformada , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/genética , Regulación de la Expresión Génica/genética , Proteínas de Choque Térmico/metabolismo , Inmunoprecipitación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Enfermedades Musculares/genética , Miositis por Cuerpos de Inclusión/patología , Proteómica , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , TransfecciónRESUMEN
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.