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PMID: 8567953 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids.

The Journal of clinical investigation ·Vol. 97 ·No. 2 ·1996-01-15 ·Pages 339-48

Tiao G, Fagan J, Roegner V, Lieberman M, Wang JJ, Fischer JE, Hasselgren PO

Abstract

Recent studies suggest that sepsis-induced increase in muscle proteolysis mainly reflects energy-ubiquitin-dependent protein breakdown. We tested the hypothesis that glucocorticoids activate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis. Rats underwent induction of sepsis by cecal ligation and puncture or were sham-operated and muscle protein breakdown rates were measured 16 h later. The glucocorticoid receptor antagonist RU 38486 or vehicle was administered to groups of septic and sham-operated rats. In other experiments, dexamethasone (2.5 or 10 mg/kg) was injected subcutaneously in normal rats. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Energy-dependent proteolysis was determined in incubated muscles depleted of energy with 2-deoxyglucose and 2,4-dinitrophenol. Levels of muscle ubiquitin mRNA and free and conjugated ubiquitin were determined by Northern and Western blot, respectively. RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates and blunted the increase in ubiquitin mRNA levels and free ubiquitin. Some, but not all, sepsis-induced changes in ubiquitin protein conjugates were inhibited by RU 38486. Injection of dexamethasone in normal rats increased energy-dependent proteolysis and ubiquitin mRNA levels. The results suggest that glucocorticoids regulate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis.

MeSH Terms
Animals Base Sequence Energy Metabolism Gene Expression Gene Expression Regulation/drug effects Glucocorticoids/physiology Hormone Antagonists/pharmacology Male Mifepristone/pharmacology Molecular Sequence Data Muscle Proteins/metabolism Muscles/metabolism Oligonucleotide Probes/chemistry RNA, Messenger/genetics Rats Rats, Sprague-Dawley Receptors, Glucocorticoid/antagonists & inhibitors Sepsis/metabolism Ubiquitins/genetics,physiology
Chemicals
Glucocorticoids Hormone Antagonists Muscle Proteins Oligonucleotide Probes RNA, Messenger Receptors, Glucocorticoid Ubiquitins Mifepristone
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Tiao G
Department of Surgery, University of Cincinnati Medical Center, Ohio 45267, USA.
Fagan J
Roegner V
Lieberman M
Wang J J
Fischer J E
Hasselgren P O
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI118421
Published
1996-01-15
Pages
339-48
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC507023
Subset
IM
Grants
NIAMS NIH HHS · AR-38867 · United States
NIDDK NIH HHS · DK-37908 · United States
NICHD NIH HHS · HD-20748 · United States
External Links
PubMed source DOI: 10.1172/JCI118421 PMC Full Text View journal details
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