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

Neurobiol Aging. 2010 Dec;31(12):2080-90. doi: 10.1016/j.neurobiolaging.2008.11.003. Epub 2008 Dec 23.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / physiology
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Calcium / antagonists & inhibitors*
  • Calcium / metabolism*
  • Calcium Signaling / drug effects
  • Calcium Signaling / genetics
  • Cations, Divalent / antagonists & inhibitors
  • Cations, Divalent / metabolism
  • Mice
  • Mice, Transgenic
  • Muscle Contraction / drug effects*
  • Muscle Contraction / genetics
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / physiopathology
  • Myositis, Inclusion Body / metabolism*
  • Myositis, Inclusion Body / physiopathology
  • Peptide Fragments / genetics
  • Peptide Fragments / physiology
  • Peptide Fragments / toxicity*
  • Rabbits

Substances

  • Amyloid beta-Peptides
  • Cations, Divalent
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Calcium