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 (approximately 30-40%) and cross-bridge cycling kinetics (approximately 20%) in CHF.
Myosin content was approximately 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.