Amyloid-β protein impairs Ca2+ release and contractility in skeletal muscle.

Inclusion body myositis (IBM), the most common muscle disorder in the elderly, is partly characterized by dysregulation of β-amyloid precursor protein (βAPP) expression and abnormal, intracellular accumulation of full-length βAPP and β-amyloid epitopes. The present study examined the effects of β-amyloid accumulation on force generation and Ca(2+) release in skeletal muscle from transgenic mice harboring human βAPP and assessed the consequence of Aβ(1-42) modulation of the ryanodine receptor Ca(2+) release channels (RyRs). β-Amyloid laden muscle produced less peak force and exhibited Ca(2+) transients with smaller amplitude. To determine whether modification of RyRs by β-amyloid underlie the effects observed in muscle, in vitro Ca(2+) release assays and RyR reconstituted in planar lipid bilayer experiments were conducted in the presence of Aβ(1-42). Application of Aβ(1-42) to RyRs in bilayers resulted in an increased channel open probability and changes in gating kinetics, while addition of Aβ(1-42) to the rabbit SR vesicles resulted in RyR-mediated Ca(2+) release. These data may relate altered βAPP metabolism in IBM to reductions in RyR-mediated Ca(2+) release and muscle contractility.