Oxidative Stress in Desminopathies and Myotilinopathies: A Link between Oxidative Damage and Abnormal Protein Aggregation

Abstract

Myotilinopathies and desminopathies are subgroups of myofibrillar myopathies (MFM) caused by mutations in myotilin and desmin genes, respectively. They are characterized by the presence of protein aggregates in muscle cells. As oxidation of proteins facilitates their aggregation and makes them more resistant to proteolysis, the present study was geared to analyze oxidative stress in MFM. For this purpose, markers of glycoxidation, lipoxidation and nitration were examined with gel electrophoresis and Western blotting, single immunohistochemistry, and double- and triple-labeling immunofluorescence and confocal microscopy in muscle biopsies from patients suffering from myotilinopathy and desminopathy. Increased levels of glycation-end products (AGEs), N-carboxymethyl-lysine (CML) and N-carboxyethyl-lysine (CEL), malondialdehyde-lysine (MDAL), 4-hydroxynonenal (HNE) and nitrotyrosine (N-tyr) were found in MFM. Furthermore, aberrant expression of AGE, CML, CEL, MDAL and HNE, as well as of neuronal, inducible and endothelial nitric oxide synthases (nNOS, iNOS, eNOS), and superoxide dismutase 2 (SOD2), was found in muscle fibers containing protein aggregates in myotilinopathies and desminopathies. AGE, ubiquitin and p62 co-localized in several muscle fibers in MFM. As oxidized proteins are vulnerable to misfolding and are resistant to degradation by the UPS, the present observations support a link between oxidative stress, protein aggregation and abnormal protein deposition in MFMs.