G.O.5 Deciphering protein aggregates in myofibrillar myopathies – A proteomics approach

Abstract Myofibrillar myopathies (MFM) encompass a genetic heterogenous group of muscle disorders characterized by formation of intracellular protein aggregates in skeletal muscle fibers. We applied a proteomic approach to decipher the aggregate composition in MFM subtypes with the aim to identify novel disease-relevant proteins, disease-specific proteomic profiles and new candidates for MFM-causing proteins. Muscle biopsies of 21 genetically clarified MFM patients (filaminopathy, myotilinopathy, desminopathy, ZASPopathy) were analyzed. Aggregates and intraindividual controls (muscle fibers without aggregates) were collected by laser microdissection. A label-free mass spectrometric approach was used for identification and relative quantification of proteins. A total of 588 different proteins were identified. Up to 193 proteins showed an accumulation in protein aggregates in the different MFM subtypes (ratio >1.8 compared to intraindividual controls). Many of these proteins have never been described in the context of MFM so far. A subset of proteins including desmin, filamin C, Xin, Xirp2 and many other proteins was detected in aggregates in all patients. The comparison of MFM subtypes revealed disease-specific patterns of aggregate compositions with clear differences in ratios of most abundant proteins. Filamin C, desmin, myotilin and ZASP showed the highest accumulation in aggregates of related MFM subtypes. Our proteomic data provide essential new insights in the composition of pathological protein aggregates in MFM. Proteomic profiles of aggregates seem to be specific for the different MFM subtypes and expand our knowledge about proteins involved in pathogenesis of filaminopathy, desminopathy, myotilinopathy and ZASPopathy. The list of abundant proteins in aggregates also include potential new MFM proteins. These should to be considered in future genetic studies in MFM patients with so far unknown mutation.