Mouse model of the inclusion body myositis: pathophysiology of the muscle after knock-down of the inducible nitric oxide synthase (iNOS)

The inclusion body myositis is the most frequent acquired myopathy of the patient collective beyond the age of 55, and is largely unknown in its multifactorial pathogenesis. Conditions which accelerate or diminish the progression of the disease are also little known so far. Previous studies have shown that inhibition of iNOS could have a protective effect on the progression of inclusion body myositis. For the first time, the influence of the iNOS deficiency on the histopathologically detectable changes was investigated by a mouse model. Using double-transgenic mice for human presenilin and APP genes, an established model was used to compare both groups directly and under identical experimental conditions. The results of this work support the hypothesis that an iNOS deficiency actually has a protective effect on the myopathology of inclusion body myositis. This effect was clearly shown by the parameter CNI as well as by thioflavin staining. In both cases, the groups of IBM/iNOS -/- animals presented significantly less myopathic changes or significantly less amyloid than the IBM animals. Similar trends were also found in mRNA expression for inflammatory markers as well as in immunohistochemistry for MHC I. The iNOS deficiency of this group can be assumed as a decisive factor which could explain the differences between IBM and IBM/iNOS -/- animals, since both genotypes are otherwise identical. Increased signs of inflammation could only be demonstrated very little. The data thus support the hypothesis that a pure accumulation of β-amyloid is insufficient to trigger a vehement inflammation. While the IBM mouse model can be used to identify disease-specific patterns in the areas of protein aggregation and myopathic alterations, it shows significant deficits in the detection of inflammatory and NO-stress-induced changes. Because of these characteristics, it is important to examine in the future the extent to which the double-transgenic IBM model might possibly be used to investigate related myositides.2017-05-0