Tripeptidyl-peptidase II expression and activity are increased in skeletal muscle during sepsis.
Ubiquitin-proteasome-dependent protein degradation plays a central role in sepsis-induced muscle wasting. Because the proteasome degrades proteins into small peptides rather than free amino acids, it is likely that additional mechanisms downstream of the proteasome are involved in sepsis-induced muscle proteolysis. Recent studies suggest that the extralysosomal peptidase tripeptidyl-peptidase II (TPP II) degrades peptides generated by the proteasome. We hypothesized that TPP II expression and activity are increased in skeletal muscle during sepsis. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. TPP II activity was determined by using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin (AAF-AMC). TPP II protein and gene expression were determined by Western blot and real-time PCR, respectively. Sepsis resulted in increased activity and protein and gene expression of TPP II in extensor digitorum longus muscles. This result was blunted by the glucocorticoid receptor antagonist RU 38486, indicating that glucocorticoids participate in the upregulation of TPP II in skeletal muscle during sepsis. The results suggest that proteolytic mechanisms downstream of the proteasome may be important for the complete degradation of muscle proteins during sepsis.
Wray
Curtis J
CJ
Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
Tomkinson
Birgitta
B
Robb
Bruce W
BW
Hasselgren
Per Olof
PO
D000626:Aminopeptidases; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D005938:Glucocorticoids / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006868:Hydrolysis; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000201:enzymology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D005938:Glucocorticoids; D006727:Hormone Antagonists; D009124:Muscle Proteins; D012333:RNA, Messenger; D015735:Mifepristone; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases