Intracellular β-amyloid accumulation leads to age-dependent progression of Ca2+ dysregulation in skeletal muscle.
Intramyofiber accumulation of β-amyloid fragments (Aβ) 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 βAPP (MCK-βAPP). MCK-βAPP 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-βAPP 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-βAPP 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 β-amyloid-induced disuption of Ca(2+) handling may represent an early event in the pathogenesis of IBM.
Lopez
Josè R
JR
Department of Anesthesia, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Shtifman
Alexander
A
D000375:Aging / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D004558:Electric Stimulation; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D017895:Manganese Compounds / Q000494:pharmacology; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008839:Microelectrodes; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020746:Calcium Channels, L-Type; D017895:Manganese Compounds; D002118:Calcium