Tau Phosphorylation in Myotilinopathies and Desminopathies

Tau expression and tau phosphorylation were examined in muscle biopsies of sporadic inclusion body myositis (sIBM), myotilinopathies and desminopathies compared with controls. A panel of anti-tau antibodies including 3Rtau, 4Rtau, phospho-specific tau Thr181, Ser262, Ser396, Ser422 and antibody AT8 (recognizing phosphorylation sites Ser202 and Thr205) and Alzh50 (conformation-dependent) showed diffuse staining in scattered fibers and peripheral or central aggregates in sIBM, myotilinopathies and desminopathies when compared with controls. This was accompanied by significantly increased tau expresion on western blots immunostained with PHF1 antibody, which recognizes a band of 120 kDa corresponding to big tau and several bands of lower molecular weight between 60 and 70 kDa, in sIBM and some myotilinopatyhy cases. Increased tau accumulation is not accompanied by increased tau mRNA expression levels but by increased focal immunoreactivity in damaged fibers which is variable from one case to another. Increased tau immunoreactivity is associated with increased focal expression of several kinases known to be involved in tau phosphorylation in vitro such as AKT-P, MAPK/ERK-P, GSK-3 Ser9, GSK-3 Tyr, and stress kinases SAPK/JNK-P and p38-P. These findings confirm previous observations in sIBM, but also demonstrate tau hyper-phosphorylation and abnormal deposition in damaged muscular fibers in myotilinopathies and desminopathies. Furthermore, the present findings suggest the involvement of varied kinases in the process of tau hyper-phosphorylation. GSK-3 appears to be a cardinal kinase. In addition, activation of stress kinases SAPK/JNK and p38 link previously described oxidative stress with tau phosphorylation in sIBM and myofibrillar myopathies. On the basis of these data, sIBM, myotilinopathies and desminopathies can be considered secondary tauopathies affecting the skeletal muscle.