Myofibrillar Myopathies: A Clinical and Myopathological Guide

Abstract

Myofibrillar myopathies (MFMs) are histopathologically characterized by desmin-positive protein aggregates and myofibrillar degeneration. Because of the marked phenotypic and pathomorphological variability, establishing the diagnosis of MFM can be a challenging task. While MFMs are partly caused by mutations in genes encoding for extramyofibrillar proteins (desmin, aB-crystallin, plectin) or myofibrillar proteins (myotilin, Z-band alternatively spliced PDZ-containing protein, filamin C, Bcl-2-associated athanogene-3, four-anda-half LIM domain 1), a large number of these diseases are caused by still unresolved gene defects. Although recent years have brought new insight into the pathogenesis of MFMs, the precise molecular pathways and sequential steps that lead from an individual gene defect to progressive muscle damage are still unclear. This review focuses on the clinical and myopathological aspects of genetically defined MFMs, and shall provide a diagnostic guide for this numerically significant group of protein aggregate myopathies.

Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

“…MFMs are sporadic or hereditary diseases of the striated muscle, which lead to severe physical disability and premature death [22]. Point mutations in the VCP gene cause, beside neurodegenerative diseases, MFM [22], but the molecular pathomechanisms that provoke muscle degeneration in these patients are still poorly understood.…”

“…Point mutations in the VCP gene cause, beside neurodegenerative diseases, MFM [22], but the molecular pathomechanisms that provoke muscle degeneration in these patients are still poorly understood. Here, to investigate the in vivo role of Vcp in the vertebrate heart and skeletal muscle, we inactivated zebrafish vcp using morpholino-modified antisense oligonucleotide (MO)- and Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9)-mediated reverse genetics as well as pharmacological approaches.…”

Cardiomyopathies Associated with Myofibrillar Myopathies

“…EMG reveals abnormal electrical irritability often with myotonic discharges. The motor unit potentials are mostly myopathic, sometimes in combination with neurogenic features (Schroder & Schoser, 2009). …”

“…Cardiomyopathy is a "classical" feature in MFM and may precede, coincide or follow the skeletal muscle weakness. Cardiomyopathy includes arrhythmogenic type (with atrioventricular blocks, supraventricular and ventricular ectopic beats and tachycardia), hypertrophic, dilated or restrictive features (reviewed in Ferrer & Olive, 2008;Goldfarb & Dalakas, 2009;Schroder & Schoser, 2009;Selcen, 2011 (4%)) from biopsies show abnormal ectopic expression of desmin, B-crystallin, myotilin and dystrophin (Claeys et al, 2009;Schroder & Schoser, 2009;Selcen, 2011).…”

Myofibrillar Myopathies and the Z-Disk Associated Proteins

“…Displaced membranous organelles are also evident, either in the cytoplasm or within autophagic vacuoles. Affected areas of the cells are frequently devoid of oxidative enzymatic activity and mitochondria can be abnormally shaped and positioned [2][3][4][5]. Characterization of the protein aggregates using immunohistochemistry reveals the presence of a wide range of sarcomeric, extracellular, and ubiquitously expressed proteins including Myotilin, Desmin, B-Crystallin, Filamin C, BAG3, ZASP, Actin, Titin, Myosin, Xin, Dystrophin, sarcoglycans, Plectin, Delsolin, Ubiquitin, Neural cell adhesion modulator, Gelsolin, Syncoilin, Synemin, TAR DNAbinding protein 43, Heat-shock protein 27, and DNAJB2 [6].…”