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 β-amyloid (Aβ) 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-βAPP). Here we report that the majority of histopathologically-affected fibers in human IBM biopsies were type II fast fibers. Skeletal muscle from MCK-βAPP mice exhibited higher transgene expression and steady-state levels of human βAPP 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 βAPP- and Aβ-mediated damage in IBM. These findings also highlight parallels between the MCK-βAPP mice and the human IBM condition.