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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/L994    most recent 90404.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Google Scholar Articles by Supinski, G. S. Articles by Callahan, L. A. PubMed PubMed Citation Articles by Supinski, G. S. Articles by Callahan, L. A.

Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction

Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, Kentucky

Submitted 30 July 2008 ; accepted in final form 14 April 2009

Infections produce severe respiratory muscle dysfunction. It is known that the proteasome proteolytic system is activated in skeletal muscle in sepsis, and it has been postulated that this degradative pathway is responsible for inducing skeletal muscle weakness and wasting. The objective of this study was to determine if administration of proteasomal inhibitors (MG132, epoxomicin, bortezomib) can prevent sepsis-induced diaphragm weakness. Rats were given either 1) saline (0.5 ml ip), 2) endotoxin (12 mg/kg ip), 3) endotoxin plus MG132 (2.5 mg/kg), 4) endotoxin plus epoxomicin (1 µmol/kg), or 5) endotoxin plus bortezomib (0.05 mg/kg). Animals were killed either 48 or 96 h after injections, and assessments were made of diaphragm proteolysis, force-frequency relationships, mass, protein content, and caspase activation. Endotoxin increased proteolysis (P <0.001). MG132, epoxomicin, and bortezomib each prevented the endotoxin-induced increase in proteolysis (P <0.01). Endotoxin induced severe reductions in diaphragm force generation by 48 h (P <0.01); none of the proteasomal inhibitors prevented loss of force. Endotoxin induced significant reductions in diaphragm mass and protein content by 96 h (P <0.01); neither MG132 nor epoxomicin prevented loss of mass or protein, but bortezomib attenuated the reduction in protein content (P <0.05). Endotoxin increased diaphragm caspase-3 activity (P <0.01); caspase-3 activity remained high when either MG132, epoxomicin, or bortezomib were given. These data suggest proteasomal inhibitors are not an adequate treatment to prevent endotoxin-induced diaphragmatic dysfunction.

caspase; sepsis; skeletal muscle

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				S. K. Powers Calpain and caspase-3 are required for sepsis-induced diaphragmatic weakness J Appl Physiol, November 1, 2009; 107(5): 1369 - 1369. [Full Text] [PDF]

				G. S. Supinski, X. Ji, and L. A. Callahan The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activation Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R825 - R834. [Abstract] [Full Text] [PDF]