Proteasome Inhibition and Aggresome Formation in Sporadic Inclusion-Body Myositis and in Amyloid-Beta Precursor Protein-Overexpressing Cultured Human Muscle Fibers

Am J Pathol. 2005 Aug;167(2):517-26. doi: 10.1016/s0002-9440(10)62994-x.


The 26S proteasome system is involved in eliminating various proteins, including ubiquitinated misfolded/unfolded proteins, and its inhibition results in cellular accumulation of protein aggregates. Intramuscle-fiber ubiquitinated multiprotein-aggregates are characteristic of sporadic inclusion-body myositis (s-IBM) muscle fibers. Two major types of aggregates exist, containing either amyloid-beta (Abeta) or phosphorylated tau (p-tau). We have now asked whether abnormalities of the 26S proteasome contribute to s-IBM pathogenesis and whether the multiprotein aggregates have features of aggresomes. Using cultured human muscle fibers we also studied the effect of amyloid-beta precursor protein (AbetaPP) overexpression on proteasome function and the influence of proteasome inhibition on aggresome formation. We report that in s-IBM muscle biopsies 26S proteasome subunits were immunodetected in the gamma-tubulin-associated aggresomes, which also contained Abeta, p-tau, ubiquitin, and HSP70. In addition, a) expression of proteasome subunits was greatly increased, b) the 20Salpha proteasome subunit co-immunoprecipitated with AbetaPP/Abeta, and c) the three major proteasomal proteolytic activities were reduced. In cultured muscle fibers, AbetaPP-overexpressing fibers displayed diminished proteasomal proteolytic activities, and addition of proteasome inhibitor strikingly increased aggresome formation. Accordingly, proteasome dysfunction in s-IBM muscle fibers may play a role in accumulation of misfolded, potentially cytotoxic proteins and may be induced by increased intracellular AbetaPP/Abeta.

Publication types

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

MeSH terms

  • Amyloid beta-Protein Precursor / metabolism*
  • Cells, Cultured
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Muscle Fibers, Skeletal / metabolism*
  • Myositis, Inclusion Body / metabolism*
  • Myositis, Inclusion Body / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors*
  • Ubiquitin / metabolism
  • tau Proteins / metabolism


  • Amyloid beta-Protein Precursor
  • HSP70 Heat-Shock Proteins
  • Proteasome Inhibitors
  • Ubiquitin
  • tau Proteins
  • Proteasome Endopeptidase Complex