Asunto(s)
Pueblo Asiatico/genética , Miopatías Distales/genética , Enfermedades de la Laringe/genética , Mutación Missense , Proteínas Asociadas a Matriz Nuclear/genética , Enfermedades Faríngeas/genética , Proteínas de Unión al ARN/genética , Adulto , Anciano , Femenino , Humanos , Inmunohistoquímica , LinajeRESUMEN
Sporadic inclusion body myositis (sIBM) is the most commonly acquired myopathy in middle-aged and elderly people. The muscle histology is characterized by both inflammation and degeneration, including sarcoplasmic aggregation of TDP-43. Cylindromatosis (CYLD) is a deubiquitinating enzyme that targets Lys63-linked ubiquitin chains and negatively regulates signal transduction pathways, such as NF-κB signalling pathways. We examined localization of CYLD as well as phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in muscle tissues of sIBM patients and muscle-specific wild-type TDP-43 transgenic (TDP-43 TG) mice. We investigated whether overexpression of CYLD can affect muscle toxicity in the cell models treated by endoplasmic reticulum (ER) stress inducers tunicamycin and thapsigargin. CYLD expressed with phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in the nuclear and perinuclear regions of muscle fibres of wild-type TDP-43 TG mice and the degenerative myofibres of sIBM patients with rimmed vacuoles and endomysial cellular infiltration. Although expression levels of CYLD decreased and cell viability was reduced in cells treated with ER stress inducers, wild-type CYLD, but not the catalytic mutant, substantially improved cell viability based on the deubiquitinase activity. Dysregulation of CYLD may reinforce myodegeneration in the pathophysiology of sIBM by attenuating autophagic clearance of protein aggregates. Regulating CYLD in muscle fibres might serve as a novel therapeutic strategy for sIBM treatment.
Asunto(s)
Enzima Desubiquitinante CYLD/fisiología , Miositis por Cuerpos de Inclusión/fisiopatología , Anciano , Animales , Enzima Desubiquitinante CYLD/genética , Estrés del Retículo Endoplásmico , Humanos , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Miositis por Cuerpos de Inclusión/metabolismo , Fosforilación , Proteómica , Ubiquitina/metabolismo , Vacuolas/metabolismoRESUMEN
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
BACKGROUND: The incidence of sporadic inclusion body myositis (sIBM) has been much lower in Japanese than in Western populations. Because of a few reports on Asian populations, it is unclear whether the clinical characteristics of sIBM are identical in Caucasian and Japanese patients. METHODS: We compared 18 patients with sIBM, divided into 3 groups by age-of-onset, with previous cohort studies. We calculated the ΔIBM functional rating scale/time duration (ΔIBMFRS/Δtime) as an index of functional disability progression. Patients' electrophysiology was analyzed in relation to their clinical characteristics. RESULTS: The cohort was 83.3% male and showed uniform initial muscle weakness in the lower and/or upper limbs. An older age-at-onset was associated with a more rapid progression, and patients with a longer duration frequently showed F-wave abnormalities and findings of chronic denervation. CONCLUSIONS: The clinical characteristics of sIBM were relatively homogeneous beyond the ethnic differences. Aging might be a synergistic factor for the progression of sIBM pathology.