Document Detail

Identification of pathways controlling muscle protein metabolism in uremia and other catabolic conditions.
MedLine Citation:
PMID:  15931008     Owner:  NLM     Status:  MEDLINE    
PURPOSE OF REVIEW: Major progress has been made in defining two key steps that mediate muscle protein degradation in kidney disease and other catabolic conditions. These advances are identified and discussed. RECENT FINDINGS: Activation of caspase-3 in muscle was discovered to be the initial step in breaking down the complex structure of myofibrils. Caspase-3 cleaves the complex structure, yielding substrate proteins and protein fragments that are degraded by the ubiquitin-proteasome system. Activation of caspase-3 occurs when insulin receptor substrate-1-associated phosphatidylinositol 3 kinase activity is suppressed in different models of catabolic conditions. The E3 ubiquitin ligases, MAFbx (also called atrogin-1) and MuRF1, were previously shown to play an essential role in muscle wasting. Several reports show that the insulin receptor substrate-1-associated phosphatidylinositol 3 kinase/Akt pathway activates forkhead transcription factors to increase expression of MAFbx/atrogin-1 and MuRF1. This response induces muscle protein wasting. In addition, chronic activation of the transcription factor, nuclear factor-kappaB, induces muscle atrophy. SUMMARY: The insulin-like growth factor-1/insulin receptor substrate-1-associated phosphatidylinositol 3 kinase/Akt cellular signaling pathway coordinately regulates two proteolytic pathways, caspase-3 and the ubiquitin ligases MAFbx/atrogin-1 and MuRF1 to control muscle protein degradation. These pathways represent therapeutic targets in diseases that cause muscle wasting.
Jie Du; William E Mitch
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Current opinion in nephrology and hypertension     Volume:  14     ISSN:  1062-4821     ISO Abbreviation:  Curr. Opin. Nephrol. Hypertens.     Publication Date:  2005 Jul 
Date Detail:
Created Date:  2005-06-02     Completed Date:  2005-12-09     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9303753     Medline TA:  Curr Opin Nephrol Hypertens     Country:  England    
Other Details:
Languages:  eng     Pagination:  378-82     Citation Subset:  IM    
Department of Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1064, USA.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / metabolism
Insulin Receptor Substrate Proteins
Insulin-Like Growth Factor I / metabolism
Muscle Proteins / metabolism*
Muscles / enzymology,  metabolism
Peptide Hydrolases / metabolism
Phosphoproteins / metabolism
Signal Transduction / physiology*
Uremia / metabolism*
Reg. No./Substance:
0/IRS1 protein, human; 0/Insulin Receptor Substrate Proteins; 0/Muscle Proteins; 0/Phosphoproteins; 67763-96-6/Insulin-Like Growth Factor I; EC 3-Kinase; EC 3.4.-/Peptide Hydrolases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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