Ubiquitin-protein ligases in muscle wasting: multiple parallel pathways?
OBJECTIVE
Studies in a wide variety of animal models of muscle wasting have led to the concept that increased protein breakdown via the ubiquitin-proteasome pathway is responsible for the loss of muscle mass seen as muscle atrophy. The complexity of the ubiquitination apparatus has hampered our understanding of how this pathway is activated in atrophying muscles and which ubiquitin-conjugating enzymes in muscle are responsible.


RESULTS
Recent experiments have shown that two newly identified ubiquitin-protein ligases (E3s), atrogin-1/MAFbx and MURF-1, are critical in the development of muscle atrophy. Other in-vitro studies also implicated E2(14k) and E3alpha, of the N-end rule pathway, as playing an important role in the process.


CONCLUSIONS
It seems likely that multiple pathways of ubiquitin conjugation are activated in parallel in atrophying muscle, perhaps to target for degradation specific classes of muscle proteins. The emerging challenge will be to define the protein targets for, as well as inhibitors of, these E3s.
Lecker
Stewart H
SH
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. slecker@caregroup.harvard.edu
D000818:Animals; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009133:Muscular Atrophy / Q000201:enzymology*; D044843:SKP Cullin F-Box Protein Ligases; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases
D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; C465394:Ube2b protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; C440907:FBXO32 protein, human; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; C499084:Trim63 protein, mouse; C113474:UBR1 protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases