Molecular pathology of myofibrillar myopathies.

Myofibrillar myopathies (MFMs) are clinically and genetically heterogeneous muscle disorders that are defined morphologically by the presence of foci of myofibril dissolution, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins. MFMs are the paradigm of conformational protein diseases of the skeletal (and cardiac) muscles characterised by intracellular protein accumulation in muscle cells. Understanding of this group of disorders has advanced in recent years through the identification of causative mutations in various genes, most of which encode proteins of the sarcomeric Z-disc, including desmin, alphaB-crystallin, myotilin, ZASP and filamin C. This review focuses on the MFMs arising from defects in these proteins, summarising genetic and clinical features of the disorders and then discussing emerging understanding of the molecular pathogenic mechanisms leading to muscle fibre degeneration. Defective extralysosomal degradation of proteins is now recognised as an important element in this process. Several factors--including mutant proteins, a defective ubiquitin-proteasome system, aggresome formation, mutant ubiquitin, p62, oxidative stress and abnormal regulation of some transcription factors--are thought to participate in the cascade of events occurring in muscle fibres in MFMs.