Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 296, Issue 6, Pages L994-L1001Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.90404.2008
Keywords
caspase; sepsis; skeletal muscle
Categories
Funding
- National Heart, Lung, and Blood Institute [HL-80429, HL-81525, HL-63698, HL-80609, HL-69821]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL063698, R01HL080609, R01HL081525, R01HL069821, R01HL080429] Funding Source: NIH RePORTER
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Supinski GS, Vanags J, Callahan LA. Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction. Am J Physiol Lung Cell Mol Physiol 296: L994-L1001, 2009. First published April 17, 2009; doi: 10.1152/ajplung.90404.2008.-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 mu mol/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.
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