Myofibrillar myopathies through the microscope: From diagnosis to molecular pathogenesis

Myofibrillar myopathies (MFMs) are a group of neuromuscular disorders with the common histological features of myofibrillar dissolution, Z-disk disintegration and accumulation of myofibrillar degradation products.  Mutations in genes encoding proteins of the Z-disk, a structural element of the striated muscle, have been reported in patients with MFMs. Nevertheless, in most of the cases the causative gene defect is still unknown. Microscopic studies conducted on skeletal muscle biopsy are fundamental to establish the diagnosis of MFMs and cannot be substituted by any other kind of laboratory investigation. Standard histological stains allow to visualize the granular or hyaline inclusions in the sarcoplasm, indicating the accumulation of misfolded proteins. Fluorescence microscopy analysis performed on muscle sections immunolabeled with antibodies against desmin, αB-crystallin and myotilin is used to detect protein aggregates. Transmission electron microscopy (TEM) is crucial in the diagnostic workout to demonstrate the presence of Z-disk streaming and myofibrillar dissolution.  Even if the pathogenetic mechanisms of MFMs are still under investigation, microscopic studies have been played a key role to define the protein composition of the aggregates and to characterize the abnormal molecular processes occurring in the disease.