Pathogenic accumulation of APP in fast twitch muscle of IBM patients and a transgenic model.
Inclusion body myositis (IBM) is the most common age-related degenerative skeletal muscle disorder. The aberrant intracellular accumulation of the beta-amyloid (Abeta) peptide within skeletal muscle is a pathological hallmark of IBM. Skeletal muscle is comprised of both slow and fast twitch fibers, which are present in different proportions in various muscles. It remains unclear if fast and/or slow twitch fibers are differentially involved in IBM pathogenesis. To better understand the molecular pathogenesis of IBM, we analyzed human IBM muscle biopsies and muscle from a transgenic mouse model of IBM (MCK-betaAPP). Here we report that the majority of histopathologically-affected fibers in human IBM biopsies were type II fast fibers. Skeletal muscle from MCK-betaAPP mice exhibited higher transgene expression and steady-state levels of human betaAPP in fast type IIB fibers compared to slow type I fibers. These findings indicate that fast twitch fibers may selectively accumulate and be more vulnerable to betaAPP- and Abeta-mediated damage in IBM. These findings also highlight parallels between the MCK-betaAPP mice and the human IBM condition.
Sugarman
Michael C
MC
Department of Neurobiology and Behavior, University of California, 1109 Gillespie Neuroscience Facility, Irvine, CA 92697-4545, USA.
Kitazawa
Masashi
M
Baker
Michael
M
Caiozzo
Vincent J
VJ
Querfurth
Henry W
HW
LaFerla
Frank M
FM
D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism* / Q000473:pathology*; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
D016564:Amyloid beta-Protein Precursor