Transgenic mouse model of inclusion body myositis

Abstract

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscles fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease (AD). Accumulation of the amyloid-β peptide (Aβ), which is derived from proteolysis of the larger amyloid-β precursor protein (βAPP), appears to be an early pathological event in AD and also in IBM, where in the latter, it occurs predominantly intracellularly within affected myofibers. To elucidate the possible role of βAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which βAPP overexpression was selectively targeted to skeletal muscle using the muscle creatine kinase promoter. Skeletal muscle from transgenic mice older than 10 months was shown to contain intracellular immunoreactivity to βAPP and its proteolytic derivatives, which was quantifiable by ELISA. In this transgenic model, selective overexpression of βAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance.

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