Identification of pathways controlling muscle protein metabolism in uremia and other catabolic conditions.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Du
Jie
J
Department of Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1064, USA.
Mitch
William E
WE
D000818:Animals; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D009132:Muscles / Q000201:enzymology / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014511:Uremia / Q000378:metabolism*
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D010447:Peptide Hydrolases