Pathogenic considerations in sporadic inclusion-body myositis, a degenerative muscle disease associated with aging and abnormalities of myoproteostasis

J Neuropathol Exp Neurol. 2012 Aug;71(8):680-93. doi: 10.1097/NEN.0b013e31826183c8.


The pathogenesis of sporadic inclusion-body myositis (s-IBM) is complex; it involves multidimensional pathways and the most critical issues are still unresolved. The onset of muscle fiber damage is age related and the disease is slowly, but inexorably, progressive. Muscle fiber degeneration and mononuclear cell inflammation are major components of s-IBM pathology, but which is precedent and how they interrelate is not known. There is growing evidence that aging of the muscle fiber associated with intramyofiber accumulation of conformationally modified proteins plays a primary pathogenic role leading to muscle fiber destruction. Here, we review the presumably most important known molecular abnormalities that occur in s-IBM myofibers and that likely contribute to s-IBM pathogenesis. Abnormal accumulation within the fibers of multiprotein aggregates (several of which are congophilic and, therefore, generically called "amyloid") may result from increased transcription of several proteins, their abnormal posttranslational modifications and misfolding, and inadequate protein disposal, that is, abnormal "myoproteostasis," which is combined with and may be provoked or abetted by an aging intracellular milieu. The potential cytotoxicity of accumulated amyloid β protein (Aβ42) and its oligomers, phosphorylated tau in the form of paired helical filaments and α-synuclein, and the putative pathogenic role and cause of the mitochondrial abnormalities and oxidative stress are reviewed. On the basis of our experimental evidence, potential interventions in the complex, interwoven pathogenic cascade of s-IBM are suggested.

Publication types

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

MeSH terms

  • Aging / pathology*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / biosynthesis
  • Amyloid beta-Protein Precursor / genetics
  • Autophagy
  • Biopsy
  • Humans
  • Lithium Compounds / therapeutic use
  • Mitochondria, Muscle / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / pathology
  • Myositis, Inclusion Body / diagnosis
  • Myositis, Inclusion Body / drug therapy
  • Myositis, Inclusion Body / metabolism*
  • Myositis, Inclusion Body / pathology*
  • Peptide Fragments / metabolism
  • Phenylbutyrates / therapeutic use
  • Polyphenols / therapeutic use
  • Proteasome Endopeptidase Complex / metabolism
  • Proteostasis Deficiencies / diagnosis
  • Proteostasis Deficiencies / drug therapy
  • Proteostasis Deficiencies / metabolism*
  • Proteostasis Deficiencies / pathology*
  • alpha-Synuclein / metabolism
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Lithium Compounds
  • Muscle Proteins
  • Peptide Fragments
  • Phenylbutyrates
  • Polyphenols
  • alpha-Synuclein
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease