G.P.61: Analyses of the pathogenesis in muscle-specific wild-type TDP-43 transgenic mice

Abstract

Recently, several studies have shown the abnormal accumulation of TAR DNA-binding protein of 43 kDa (TDP-43) in the affected muscles of patients with sporadic inclusion body myositis (sIBM). However, it remains to be elucidated whether the accumulation of TDP-43 in sIBM muscles serves as a primary trigger or a secondary event following muscle degeneration in sIBM pathology. The aim of this study is to answer whether overexpression of TDP-43 in the muscle tissues can actually cause myofiber degeneration. We initially investigated whether overexpression of wild-type TDP-43 or supplementation of aggregated recombinant TDP-43 protein into the culture media can affect on cell viability in C2C12 myoblast cells. We next generated muscle specific wild-type TDP-43 transgenic mice using creatine kinase promoter and examined biochemically and histopathologically these mice. Overexpression of wild-type TDP-43 and supplementation of aggregated recombinant TDP-43 protein under acidic condition reduced cell viability in C2C12 cells. Muscle specific wild-type TDP-43 transgenic mice showed an elevation of serum creatine kinase and lactate dehydrogenase levels and myopathic changes with necrotic and regenerative fibers, vacuolation, and aggregation of TDP-43 in myofibers at 18 months of age. In contrast, deposition of amyloid β was not observed in the affected fibers. Our observation revealed that overexpression of wild-type TDP-43 caused degenerative change with vacuolation and aggregated TDP-43 in the myofibers, regardess of sarcoplasmic deposition of amyloid β, and then served as a primary cause of muscle toxicity. Muscle specific wild-type TDP-43 transgenic mice mimicked a part of the pathogenesis in sIBM, and might be a useful tool for better understanding of TDP-43 proteinopathy including sIBM.