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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/L1260    most recent 00035.2008v1 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 PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by van Hees, H. W. H. Articles by Heunks, L. M. A. PubMed PubMed Citation Articles by van Hees, H. W. H. Articles by Heunks, L. M. A.

Proteasome inhibition improves diaphragm function in congestive heart failure rats

¹Department of Pulmonary Diseases, ²Intensive Care Medicine, ³Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; ⁴Department of Medicine, Baylor College of Medicine, Houston, Texas, and ⁵Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona

Submitted 18 January 2008 ; accepted in final form 15 April 2008

In congestive heart failure (CHF), diaphragm weakness is known to occur and is associated with myosin loss and activation of the ubiquitin-proteasome pathway. The effect of modulating proteasome activity on myosin loss and diaphragm function is unknown. The present study investigated the effect of in vivo proteasome inhibition on myosin loss and diaphragm function in CHF rats. Coronary artery ligation was used as an animal model for CHF. Sham-operated rats served as controls. Animals were treated with the proteasome inhibitor bortezomib (intravenously) or received saline (0.9%) injections. Force generating capacity, cross-bridge cycling kinetics, and myosin content were measured in diaphragm single fibers. Proteasome activity, caspase-3 activity, and MuRF-1 and MAFbx mRNA levels were determined in diaphragm homogenates. Proteasome activities in the diaphragm were significantly reduced by bortezomib. Bortezomib treatment significantly improved diaphragm single fiber force generating capacity (30–40%) and cross-bridge cycling kinetics (20%) in CHF. Myosin content was 30% higher in diaphragm fibers from bortezomib-treated CHF rats than saline. Caspase-3 activity was decreased in diaphragm homogenates from bortezomib-treated rats. CHF increased MuRF-1 and MAFbx mRNA expression in the diaphragm, and bortezomib treatment diminished this rise. The present study demonstrates that treatment with a clinically used proteasome inhibitor improves diaphragm function by restoring myosin content in CHF.

myosin; bortezomib; single fiber contractility; myosin