TDP-43 accumulation is common in myopathies with rimmed vacuoles

Abstract

TAR-DNA-binding protein-43 (TDP-43) is a nuclear protein that is thought to play a regulatory role in gene expression. Ubiquitinated TDP-43 is found in cytoplasmic inclusions in motor neuron disease (MND), frontotemporal lobar degeneration (FTLD-TDP), and MND with FTLD [4]. This shared histopathological hallmark led to the classiWcation of a new class of diseases, the TDP-43-proteinopathies [3]. Recently, TDP-43-positive inclusions have been described in skeletal muscle in sporadic inclusion body myositis (sIBM) and in IBM due to mutations in the valosin-containing protein (VCP) [6]. These myopathies are accompanied by vacuolar changes commonly known as rimmed vacuoles (although these vacuoles are morphologically not always rimmed). These characteristic morphological changes are not exclusive to sIBM and IBM with VCP-mutations but are also found in oculopharyngeal muscular dystrophy (OPMD) [2] and distal myopathies with rimmed vacuoles (DMRV), both of which are hereditary myopathies with inclusion bodies. Although DMRV are a genetically heterogeneous group of diseases, the term is often used in the context of the Nonaka myopathy with mutations of the UDP-N-acetylglucosamine 2-epimerase/ N-acetylmannosamine kinase (GNE) gene [5]. We studied whether TDP-43 aggregates were present in muscle biopsies of sIBM, OPMD and DMRV or in myopathies without the mentioned vacuolar changes. TDP-43 immunostaining was present in some, but not all, rimmed vacuoles and/or basophilic Wbers in most biopsies from patients with sIBM (77.8%) and OPMD (83.3%) and in all biopsies from patients with DMRV (one with conWrmed GNE mutation) (Table 1). TDP-43 immunostaining was not detected in muscle biopsies from patients with myopathies without vacuolar changes. The pattern of TDP-43 staining was variable: in some biopsies only a single TDP-43 positive inclusion was visible even though more than one rimmed vacuole was present, and in other biopsies multiple TDP-43-positive aggregates were visualized. Both granular and more dot-like aggregates in rimmed vacuoles and basophilic Wbers were detected. The morphology of the aggregates was similar in sIBM, OPMD, and DMRV (Fig. 1a–c). Many aggregates also stained positive for ubiquitin (Fig. 1d–f). Occasionally subsarcolemmal TDP-43 staining was present in Wbers that did not exhibit rimmed vacuoles or subsarcolemmal basophilia (Fig. 1g). In conclusion, we conWrm the recent data of Weihl et al. [6], showing the presence of TDP-43-positive inclusions in the majority of muscle biopsies from patients with sIBM. However, we found TDP-43-positive aggregates not only in sIBM but also in other vacuolar myopathies. Thus TDP-43positive aggregates would seem to be a general phenomenon among the myopathies associated with rimmed vacuoles. This suggests that abnormal TDP-43 accumulation is more likely to be a common endpoint of (muscle) cell degeneration rather than a primary pathological mechanism underlying these myopathies. These Wndings may provide insight into the pathobiological relevance of TDP-43 B. Kusters and B. J. A. van Hoeve have contributed equally to this work.