Sporadic Inclusion Body Myositis Correlates with Increased Expression and Cross-linking by Transglutaminases 1 and 2

Young-Chul Choi,Geon Tae Park,Tai-Seung Kim,Il-Nam Sunwoo,Peter M Steinert,Soo-Youl Kim

doi:10.1074/jbc.275.12.8703

Abstract

Sporadic inclusion body myositis (SIBM) is characterized by vacuolar degeneration of muscle fibers and intrafiber clusters of paired helical filaments with abnormal amyloid deposition. Because of their potential involvement in other degenerative disorders, we have examined the expression of transglutaminases (TGases) in normal and SIBM tissues. We report that at least two different enzymes, the ubiquitous TGase 2 as well as the TGase 1 enzyme, are present in muscle tissues. However, in comparison with normal tissue, the expression of TGases 1 and 2 was increased 2.5- and 4-fold in SIBM, accompanied by about a 20-fold higher total TGase activity. By immunohistochemical staining, in normal muscle, TGase 2 expression was restricted to some endomysial connective tissue elements, whereas TGase 1 and beta-amyloid proteins were not detectable. In SIBM muscle, both TGases 1 and 2 as well as amyloid proteins were brightly expressed and co-localized in the vacuolated muscle fibers, but none of these proteins colocalized with inflammatory cell markers. Next, we isolated high molecular weight insoluble proteins from SIBM muscle tissue and showed that they were cross-linked by about 6 residues/1000 residues of the isopeptide bond. Furthermore, by amino acid sequencing of solubilized tryptic peptides, they contain amyloid and skeletal muscle proteins. Together, these findings suggest that elevated expression of TGases 1 and 2 participate in the formation of insoluble amyloid deposits in SIBM tissue and in this way may contribute to progressive and debilitating muscle disease.

Highlights

Sporadic inclusion body myositis (SIBM) is characterized by vacuolar degeneration of muscle fibers and intrafiber clusters of paired helical filaments with abnormal amyloid deposition
Expression of TGases 1 and 2 Is Increased in SIBM Tissue—We ascertained three SIBM patients who had developed weakness of the quadriceps muscles, atrophy and weakness of the finger flexors, and weakness of foot extensors, all features classically seen in SIBM [20]
Total TGase activity was measured in tissue extracts and found to be 16-fold higher in biopsy samples from the SIBM patients compared with normal tissues (Fig. 1)

Summary

Introduction

Sporadic inclusion body myositis (SIBM) is characterized by vacuolar degeneration of muscle fibers and intrafiber clusters of paired helical filaments with abnormal amyloid deposition Because of their potential involvement in other degenerative disorders, we have examined the expression of transglutaminases (TGases) in normal and SIBM tissues. By amino acid sequencing of solubilized tryptic peptides, they contain amyloid and skeletal muscle proteins Together, these findings suggest that elevated expression of TGases 1 and 2 participate in the formation of insoluble amyloid deposits in SIBM tissue and in this way may contribute to progressive and debilitating muscle disease. Recent studies have suggested that overexpression of the ␤-amyloid precursor protein (␤-APP) and its abnormal deposition may induce a muscle fiber destruction [4, 5] In this regard there are molecular-pathologic similarities between SIBM and Alzheimer’s disease [3, 6]. With this in mind and the possible involvement of TGases in the pathology of neurodegenerative diseases, in this study we have investigated TGase expression in normal and SIBM muscle tissues

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Discussion

Conclusion