Abstract
Circulating levels of glucocorticoids are increased in many traumatic and muscle-wasting conditions that include insulin-dependent diabetes, acidosis, infection, and starvation. On the basis of indirect findings, it appeared that these catabolic hormones are required to stimulate Ub (ubiquitin)-proteasome-dependent proteolysis in skeletal muscles in such conditions. The present studies were performed to provide conclusive evidence for an activation of Ub-proteasome-dependent proteolysis after glucocorticoid treatment. In atrophying fast-twitch muscles from rats treated with dexamethasone for 6 days, compared with pair-fed controls, we found (i) increased MG132-inhibitable proteasome-dependent proteolysis, (ii) an enhanced rate of substrate ubiquitination, (iii) increased chymotrypsin-like proteasomal activity of the proteasome, and (iv) a co-ordinate increase in the mRNA expression of several ATPase (S4, S6, S7 and S8) and non-ATPase (S1, S5a and S14) subunits of the 19 S regulatory complex, which regulates the peptidase and the proteolytic activities of the 26 S proteasome. These studies provide conclusive evidence that glucocorticoids activate Ub-proteasome-dependent proteolysis and the first in vivo evidence for a hormonal regulation of the expression of subunits of the 19 S complex. The results suggest that adaptations in gene expression of regulatory subunits of the 19 S complex by glucocorticoids are crucial in the regulation of the 26 S muscle proteasome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / biosynthesis
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Adenosine Triphosphatases / genetics
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Animals
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Chymotrypsin / metabolism
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Culture Techniques
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Cysteine Endopeptidases / biosynthesis
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism
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Cysteine Proteinase Inhibitors / pharmacology
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Dexamethasone / pharmacology*
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Endopeptidases / biosynthesis
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Endopeptidases / genetics
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Gene Expression Regulation
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Glucocorticoids / pharmacology*
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Leupeptins / pharmacology
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Male
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Multienzyme Complexes / biosynthesis
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Multienzyme Complexes / genetics
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Multienzyme Complexes / metabolism
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Muscle Fibers, Fast-Twitch / drug effects
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Muscle Fibers, Fast-Twitch / metabolism*
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Muscle Proteins / metabolism
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism*
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Muscular Atrophy / etiology
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Peptide Hydrolases / biosynthesis*
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Peptide Hydrolases / genetics
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Proteasome Endopeptidase Complex
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Protein Subunits / biosynthesis
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Protein Subunits / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Ubiquitins / metabolism
Substances
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Cysteine Proteinase Inhibitors
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Glucocorticoids
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Leupeptins
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Multienzyme Complexes
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Muscle Proteins
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Protein Subunits
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RNA, Messenger
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Ubiquitins
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Dexamethasone
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Endopeptidases
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Peptide Hydrolases
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Chymotrypsin
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease
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26S proteasome non-ATPase regulatory subunit 13
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Adenosine Triphosphatases
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde