Proteomic Analysis In 72 Myofibrillar Myopathy (Mfm) Patients Identifies New Disease-Relevant Proteins Accumulating In Aggregates And Reveals Subtype-Specific Proteomic Profiles

Myofibrillar myopathies (MFM) are a group of usually autosomal dominant inherited muscle disorders characterized by focal disintegration of myofibrils and by the formation of intramyoplasmic protein aggregates. Known diseases genes encode proteins that are located at or associated with the Z-disc. We extended our previous proteomic analysis in MFM to identify novel disease-relevant proteins that accumulate in aggregate areas and to search for subtype-specific proteomic profiles. We analyzed skeletal muscle samples from 72 MFM patients. Aggregate samples and intraindividual control samples (from normally looking muscle fibers) were collected from 10 μ m muscle sections by laser microdissection and analyzed by a label-free mass spectrometric approach for identification and relative quantification of proteins. We detected 4716 different proteins in the samples and 291 of these showed a statistically significant accumulation in aggregate samples with a ratio >1.5 compared to controls (mean ratio 4.5). Z-disc and Z-disc-associated proteins, especially desmin, filamin C and their binding partners, constituted the most abundant group of over-represented aggregate proteins followed by proteins involved in protein quality control and protein degradation, extracellular and sarcolemmal proteins, components of signaling pathways and proteins involved in actin dynamics and myofibrillar organization. Subgroup analysis revealed a characteristic basic pattern of aggregate composition but also significant differences regarding the accumulation ratio, order and proportion of individual proteins that enabled the definition of subtype-specific proteomic profiles. Our proteomic findings expand the knowledge about proteins and pathways that seem to be involved in the pathogenesis of MFM. The identification of specific proteomic profiles in different MFM subtypes can be useful in differential diagnosis of protein aggregation myopathies.