Acta Neuropathologica Communications (Oct 2019)

Phosphorylated TDP-43 aggregates in skeletal and cardiac muscle are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions

  • Fumiaki Mori,
  • Mari Tada,
  • Tomoya Kon,
  • Yasuo Miki,
  • Kunikazu Tanji,
  • Hidekachi Kurotaki,
  • Masahiko Tomiyama,
  • Tomohiko Ishihara,
  • Osamu Onodera,
  • Akiyoshi Kakita,
  • Koichi Wakabayashi

DOI
https://doi.org/10.1186/s40478-019-0824-1
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 12

Abstract

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Abstract Background Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients. Aim The aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs. Material and methods Five regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7). Results Two types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration. Conclusion The present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.

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