title: Molecular regulation of muscle cachexia: it may be more than the proteasome.
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.
authors.affiliation: Department of Surgery, University of Cincinnati, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0558, USA. hasselp@uc.edu
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Hasselgren
authors.forename: Curtis
authors.initials: C
authors.lastname: Wray
authors.forename: Joshua
authors.initials: J
authors.lastname: Mammen
mesh_terms: D000251:Adenosine Triphosphatases; D000626:Aminopeptidases; D000818:Animals; D000075686:COP9 Signalosome Complex; D002100:Cachexia / Q000235:genetics* / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D006801:Humans; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D046912:Multiprotein Complexes; D009132:Muscles / Q000293:injuries / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D018805:Sepsis; D012697:Serine Endopeptidases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D009097:Multienzyme Complexes; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011506:Proteins; D025801:Ubiquitin; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D000075686:COP9 Signalosome Complex; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein