@article{3153039,
    title = "Nitric oxide stress in sporadic inclusion body myositis muscle fibres:
inhibition of inducible nitric oxide synthase prevents interleukin-1
beta-induced accumulation of beta-amyloid and cell death",
    author = "Schmidt, Jens and Barthel, Konstanze and Zschuentzsch, Jana and Muth, and Ingrid E. and Swindle, Emily J. and Hombach, Anja and Sehmisch, Stephan and and Wrede, Arne and Luehder, Fred and Gold, Ralf and Dalakas, Marinos C.",
    journal = "Brain Sciences",
    year = "2012",
    volume = "135",
    number = "4",
    pages = "1102-1114",
    publisher = "Oxford University Press",
    issn = "-",
    doi = "10.1093/brain/aws046",
    keywords = "myositis; nitric oxide; beta-amyloid; neuroinflammation; IL-1 beta",
    abstract = "Sporadic inclusion body myositis is a severely disabling myopathy. The
design of effective treatment strategies is hampered by insufficient
understanding of the complex disease pathology. Particularly, the nature
of interrelationships between inflammatory and degenerative
pathomechanisms in sporadic inclusion body myositis has remained
elusive. In Alzheimer’s dementia, accumulation of beta-amyloid has been
shown to be associated with upregulation of nitric oxide. Using
quantitative polymerase chain reaction, an overexpression of inducible
nitric oxide synthase was observed in five out of ten patients with
sporadic inclusion body myositis, two of eleven with dermatomyositis,
three of eight with polymyositis, two of nine with muscular dystrophy
and two of ten non-myopathic controls. Immunohistochemistry confirmed
protein expression of inducible nitric oxide synthase and demonstrated
intracellular nitration of tyrosine, an indicator for intra-fibre
production of nitric oxide, in sporadic inclusion body myositis muscle
samples, but much less in dermatomyositis or polymyositis, hardly in
dystrophic muscle and not in non-myopathic controls. Using fluorescent
double-labelling immunohistochemistry, a significant co-localization was
observed in sporadic inclusion body myositis muscle between
beta-amyloid, thioflavine-S and nitrotyrosine. In primary cultures of
human myotubes and in myoblasts, exposure to interleukin-1 beta in
combination with interferon-gamma induced a robust upregulation of
inducible nitric oxide synthase messenger RNA. Using fluorescent
detectors of reactive oxygen species and nitric oxide,
dichlorofluorescein and diaminofluorescein, respectively, flow cytometry
revealed that interleukin-1 beta combined with interferon-gamma induced
intracellular production of nitric oxide, which was associated with
necrotic cell death in muscle cells. Intracellular nitration of tyrosine
was noted, which partly co-localized with amyloid precursor protein, but
not with desmin. Pharmacological inhibition of inducible nitric oxide
synthase by 1400W reduced intracellular production of nitric oxide and
prevented accumulation of beta-amyloid, nitration of tyrosine as well as
cell death inflicted by interleukin-1 beta combined with
interferon-gamma. Collectively, these data suggest that, in skeletal
muscle, inducible nitric oxide synthase is a central component of
interactions between interleukin-1 beta and beta-amyloid, two of the
most relevant molecules in sporadic inclusion body myositis. The data
further our understanding of the pathology of sporadic inclusion body
myositis and may point to novel treatment strategies."
}