We propose that in MFM horses, altered cysteine metabolism and a deficiency of cysteine-containing antioxidants combined with a high capacity to oxidize fatty acids and generate ROS during aerobic exercise causes chronic oxidation and aggregation of key proteins such as desmin.
229th ENMC international workshop: Limb girdle muscular dystrophies - Nomenclature and reformed classification Naarden, the Netherlands, 17-19 March 2017.
Familial PAM includes myofibrillar myopathies defined by the presence of desmin-positive protein aggregates and degenerative intermyofibrillar network changes.
Skeletal muscle biopsy revealed the morphological picture of myofibrillar myopathy with sarcoplasmic aggregates, immunoreactive for desmin and other ectopic proteins on immunohistochemistry, appearing as granulofilamentous material at ultrastructural level.
Desmin-related cardiomyopathy is a heterogeneous group of myofibrillar myopathies characterized by aggregates of desmin and related proteins in myocytes.
Desminopathies belong to a family of muscle disorders called myofibrillar myopathies that are caused by Desmin mutations and lead to protein aggregates in muscle fibers.
Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy.
Three mutant desmin variants were detected directly on the protein level as components of the aggregates, suggesting their direct involvement in aggregate-formation and demonstrating for the first time that proteomic analysis can be used for direct identification of a disease-causing mutation in myofibrillar myopathy.
Here, we analyse myoblasts behaviour in the context of myofibrillar myopathy resulting from p.D399Ydesmin mutation which disorganizes the desmin IF network in muscle cells.
Dependent on the MFM causing mutation, different sets of proteins were revealed as genuine (accumulated) plaque components in independent technical replicates: (i) αB-crystallin, desmin, filamin A/C, myotilin, PRAF3, RTN2, SQSTM, XIRP1, and XIRP2 (patient with defined MFM mutation distinct from FHL1) or (ii) desmin, FHL1, filamin A/C, KBTBD10, NRAP, SQSTM, RL40, XIRP1, and XIRP2 (patient with FHL1 mutation).
Disease associated with mutations in filamin C rod domain leading to expression of a toxic protein presents with progressive proximal muscle weakness and shows focal destructive lesions of polymorphous aggregates containing desmin, myotilin and other proteins in the affected myofibres; these features correspond to the profile of myofibrillar myopathy.
While MFMs are partly caused by mutations in genes encoding for extramyofibrillar proteins (desmin, alphaB-crystallin, plectin) or myofibrillar proteins (myotilin, Z-band alternatively spliced PDZ-containing protein, filamin C, Bcl-2-associated athanogene-3, four-and-a-half LIM domain 1), a large number of these diseases are caused by still unresolved gene defects.
Skeletal and cardiac muscle from patients with primary desminopathies characteristically display cytoplasmic accumulation of desmin-immunoreactive material and myofibrillar changes.