Molecular regulation of muscle cachexia: It may be more than the proteasome

Per Olof Hasselgren, Curtis Wray, Joshua Mammen

Research output: Contribution to journalReview articlepeer-review

111 Scopus citations

Abstract

Muscle cachexia induced by sepsis, severe injury, cancer, and a number of other catabolic conditions is mainly caused by increased protein degradation, in particular breakdown of myofibrillar proteins. Ubiquitin-proteasome-dependent proteolysis is the predominant mechanism of muscle protein loss in these conditions, but there is evidence that several other regulatory mechanisms may be important as well. Some of those mechanisms are reviewed in this article and they include pre-, para-, and postproteasomal mechanisms. Among preproteasomal mechanisms, mediators, receptor binding, signaling pathways, activation of transcription factors, and modification of proteins are important. Several paraproteasomal mechanisms may influence the trafficking of ubiquitinated proteins and their interaction with the proteasome, including the expression and activity of the COP9 signalosome, the carboxy terminus of heat shock protein 70-interacting protein (CHIP) and valosin-containing protein (VCP). Finally, because the proteasome does not degrade proteins completely into free amino acids but into peptides, postproteasomal degradation of peptides by the giant protease tripeptidyl peptidase II (TPP II) and various aminopeptidases is important in muscle catabolism. Thus, multiple mechanisms and regulatory steps may influence the breakdown of ubiquitinated muscle proteins by the 26S proteasome.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalBiochemical and Biophysical Research Communications
Volume290
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • COP9 signalosome
  • Cachexia
  • Muscle
  • Proteolysis
  • Transcription factors
  • Tripeptidyl peptidase II
  • Ubiquitin

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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