Molecular mechanisms regulating protein turnover in muscle.
Loss of muscle mass is a risk factor for mortality in chronic renal failure (CRF). Catabolic signals (eg, acidosis, glucocorticoids, insulin resistance) present in CRF stimulate the ubiquitin-proteasome proteolytic pathway in muscle but the activation mechanism(s) have been elusive. We have identified distinct mechanisms that may work in concert to increase the degradation of muscle proteins. Glucocorticoids increase the transcription of genes encoding components of the ubiquitin-proteasome pathway, thereby increasing the proteolytic capacity of muscle cells. Another signal could be a decreased response to insulin because acute diabetes is a potent stimulus for protein degradation by the ubiquitin-proteasome pathway and CRF impairs insulin signaling in muscle. Together, these responses increase the breakdown of muscle, contributing to protein malnutrition in CRF.
Price
S R
SR
Renal Division, Emory University, Atlanta, GA, USA. medrp@emory.edu
Du
J D
JD
Bailey
J L
JL
Mitch
W E
WE
D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009135:Muscular Diseases / Q000209:etiology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism; D019282:Wasting Syndrome / Q000209:etiology / Q000378:metabolism*
D005938:Glucocorticoids; D009097:Multienzyme Complexes; D009124:Muscle Proteins; D016328:NF-kappa B; D014452:Ubiquitins; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex