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PMID: 7989581 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.

Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle.

The Journal of clinical investigation ·Vol. 94 ·No. 6 ·1994-12-00 ·Pages 2255-64

Tiao G, Fagan JM, Samuels N, James JH, Hudson K, Lieberman M, Fischer JE, Hasselgren PO

Abstract

We tested the role of different intracellular proteolytic pathways in sepsis-induced muscle proteolysis. Sepsis was induced in rats by cecal ligation and puncture; controls were sham operated. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Lysosomal proteolysis was assessed by using the lysosomotropic agents NH4Cl, chloroquine, leupeptin, and methylamine. Ca(2+)-dependent proteolysis was determined in the absence or presence of Ca2+ or by blocking the Ca(2+)-dependent proteases calpain I and II. Energy-dependent proteolysis was determined in muscles depleted of ATP by 2-deoxyglucose and 2.4-dinitrophenol. Muscle ubiquitin mRNA and the concentrations of free and conjugated ubiquitin were determined by Northern and Western blots, respectively, to assess the role of the ATP-ubiquitin-dependent proteolytic pathway. Total and myofibrillar protein breakdown was increased during sepsis by 50 and 440%, respectively. Lysosomal and Ca(2+)-dependent proteolysis was similar in control and septic rats. In contrast, energy-dependent total and myofibrillar protein breakdown was increased by 172% and more than fourfold, respectively, in septic muscle. Ubiquitin mRNA was increased severalfold in septic muscle. The results suggest that the increase in muscle proteolysis during sepsis is due to an increase in nonlysosomal energy-dependent protein breakdown, which may involve the ubiquitin system.

MeSH Terms
Animals Base Sequence Calcium/pharmacology Cecum/surgery Energy Metabolism Hydrolysis/drug effects Male Molecular Sequence Data Muscle Proteins/metabolism Muscle, Skeletal/drug effects,metabolism Protease Inhibitors/pharmacology RNA, Messenger/biosynthesis,genetics Rats Rats, Sprague-Dawley Sepsis/metabolism Ubiquitins/biosynthesis,genetics
Chemicals
Muscle Proteins Protease Inhibitors RNA, Messenger Ubiquitins Calcium
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Tiao G
Department of Surgery, University of Cincinnati, Ohio 45267.
Fagan J M
Samuels N
James J H
Hudson K
Lieberman M
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/JCI117588
Published
1994-12-00
Pages
2255-64
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC330052
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/JCI117588 PMC Full Text View journal details
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