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.
Shtifman
Alexander
A
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St., Boston, MA 02135, United States. alex.shtifman@caritaschristi.org
Ward
Christopher W
CW
Laver
Derek R
DR
Bannister
Mark L
ML
Lopez
Jose R
JR
Kitazawa
Masashi
M
LaFerla
Frank M
FM
Ikemoto
Noriaki
N
Querfurth
Henry W
HW
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002413:Cations, Divalent / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000187:drug effects* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000503:physiopathology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology / Q000633:toxicity*; D011817:Rabbits
D016229:Amyloid beta-Peptides; D002413:Cations, Divalent; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002118:Calcium