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- W2079846667 abstract "Inclusion body myopathy type 3 (IBM-3) is a progressive dominant disease affecting fast skeletal muscle. It results from a point mutation in the SH1 helix of the myosin motor. Previously, we showed that homozygous expression of the analogous mutation in Drosophila indirect flight muscle (IFM) results in a flightless phenotype, severe abnormalities in myofibril structure, dramatically reduced ATPase and in vitro motility, increased myosin aggregation and production of autophagic and membranous inclusions (Wang et al., 2012, Mol Biol Cell 23:2057-65). We have now examined the dominant effects of the IBM-3 mutation in our model. Mutant and wild-type proteins accumulate in equimolar amounts in heterozygotes, since ATPase and in vitro motility levels display intermediate values. Heterozygotes show progressive defects in IFM function that are less severe than in homozygotes, correlating with deficits in fiber mechanics (Corcione et al., 2010, Biophys. J. 98: 544a). Surprisingly, we detect no defects in muscle morphology in heterozygotes. While increasing the mutant:wild-type gene dosage to 2:1 further compromises muscle function and produces minor myofibrillar defects in aged flies, no inclusion bodies are observed. We examined the accumulation of Ref(2)P, a polyubiquitin-binding protein that is commonly associated with protein aggregates, and found a dramatic upregulation only in the IBM-3 homozygotes. We defined the makeup of these aggregates by proteomic analysis and found alterations in proteins associated with mitochondrial function and the unfolded protein response. We plan to manipulate expression levels of such proteins in an attempt to improve mutant phenotypes.Supported by MDA grant 217900. We appreciate the assistance of Robert N. Cole and Robert O’Meally, JHU Mass Spectrometry and Proteomics Facility." @default.
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- W2079846667 date "2015-01-01" @default.
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- W2079846667 title "A Drosophila Model of Myosin-Based Inclusion Body Myopathy Type 3: Effects on Muscle Structure, Muscle Function and Aggregated Protein Profiles" @default.
- W2079846667 doi "https://doi.org/10.1016/j.bpj.2014.11.1651" @default.
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