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 beta-amyloid precursor protein (beta APP) expression and abnormal, intracellular accumulation of full-length beta APP and beta-amyloid epitopes. The present study examined the effects of beta-amyloid accumulation on force generation and Ca2+ release in skeletal muscle from transgenic mice harboring human beta APP and assessed the consequence of A beta(1-42) modulation of the ryanodine receptor Ca2+ release channels (RyRs). beta-Amyloid laden muscle produced less peak force and exhibited Ca2+ transients with smaller amplitude. To determine whether modification of RyRs by beta-amyloid underlie the effects observed in muscle, in vitro Ca2+ release assays and RyR reconstituted in planar lipid bilayer experiments were conducted in the presence of A beta(1-42). Application of A beta(1-42) to RyRs in bilayers resulted in an increased channel open probability and changes in gating kinetics, while addition of A beta(1-42) to the rabbit SR vesicles resulted in RyR-mediated Ca2+ release. These data may relate altered BAPP metabolism in IBM to reductions in RyR-mediated Ca2+ release and muscle contractility. (C) 2008 Elsevier Inc. All rights reserved.