Intracellular beta-amyloid accumulation leads to age-dependent progression of Ca2+ dysregulation in skeletal muscle.

摘要

Intramyofiber accumulation of beta-amyloid fragments (Abeta) is a pathologic hallmark of inclusion-body myositis (IBM), a progressive skeletal muscle disorder. We investigated the temporal pattern of alterations in the resting cytoplasmic [Ca(2+)] ([Ca(2+)](i)) as well as the depolarization-evoked Ca(2+) release from the sarcoplasmic reticulum in skeletal muscle from transgenic mice expressing human betaAPP (MCK-betaAPP). MCK-betaAPP mice show an age-dependent increase in [Ca(2+)](i) along with a reduction in depolarization-evoked Ca(2+) release, which appear well before the other reported aspects of IBM, such as inclusion formation, inflammation, centralized nuclei, atrophy, and skeletal muscle weakness. In the young MCK-betaAPP animals the increase in resting [Ca(2+)](i) can be attributed largely to Ca(2+) influx through nifedipine-sensitive Ca(2+) channels. In the adult MCK-betaAPP mice, in addition to the nifedipine-sensitive pathway, there is also a substantial contribution by the intracellular compartments to the increase in [Ca(2+)](i). These results suggest that beta-amyloid-induced disuption of Ca(2+) handling may represent an early event in the pathogenesis of IBM.