TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

Nature. 2018 Nov;563(7732):508-513. doi: 10.1038/s41586-018-0665-2. Epub 2018 Oct 31.


A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP-the gene that encodes TDP-43-that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / chemistry
  • Amyloid / genetics
  • Amyloid / metabolism*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Female
  • Humans
  • Male
  • Mice
  • Models, Biological
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism
  • Regeneration*
  • Sarcomeres / metabolism
  • TDP-43 Proteinopathies / metabolism*
  • TDP-43 Proteinopathies / pathology


  • Amyloid
  • DNA-Binding Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • TARDBP protein, human
  • TDP-43 protein, mouse