Glucocorticoids regulate mRNA levels for subunits of the 19 S regulatory complex of the 26 S proteasome in fast-twitch skeletal muscles.
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.
Combaret
Lydie
L
Human Nutrition Research Center of Clermont-Ferrand, and Nutrition and Protein Metabolism Unit, Institut National de la Recherche Agronomique, 63122 Ceyrat, France.
Taillandier
Daniel
D
Dardevet
Dominique
D
Béchet
Daniel
D
Rallière
Cécile
C
Claustre
Agnès
A
Grizard
Jean
J
Attaix
Didier
D
D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002918:Chymotrypsin / Q000378:metabolism; D046508:Culture Techniques; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D010450:Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology; D010447:Peptide Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014452:Ubiquitins / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D005938:Glucocorticoids; D007976:Leupeptins; D009097:Multienzyme Complexes; D009124:Muscle Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D014452:Ubiquitins; D003907:Dexamethasone; D010450:Endopeptidases; D010447:Peptide Hydrolases; D002918:Chymotrypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C119011:26S proteasome non-ATPase regulatory subunit 13; D000251:Adenosine Triphosphatases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde