Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats.
Diaphragm weakness commonly occurs in patients with congestive heart failure (CHF) and is an independent predictor of mortality. However, the pathophysiology of diaphragm weakness is poorly understood. We hypothesized that CHF induces diaphragm weakness at the single-fiber level by decreasing myosin content. In addition, we hypothesized that myofibrillar Ca(2+) sensitivity is decreased and cross-bridge kinetics are slower in CHF diaphragm fibers. Finally, we hypothesized that loss of myosin in CHF diaphragm weakness is associated with increased proteolytic activities of caspase-3 and the proteasome. In skinned diaphragm single fibers of rats with CHF, induced by left coronary artery ligation, maximum force generation was reduced by approximately 35% (P < 0.01) compared with sham-operated animals for slow, 2a, and 2x fibers. In these CHF diaphragm fibers, myosin heavy chain content per half-sarcomere was concomitantly decreased (P < 0.01). Ca(2+) sensitivity of force generation and the rate constant of tension redevelopment were significantly reduced in CHF diaphragm fibers compared with sham-operated animals for all fiber types. The cleavage activity of the proteolytic enzyme caspase-3 and the proteasome were approximately 30% (P < 0.05) and approximately 60% (P < 0.05) higher, respectively, in diaphragm homogenates from CHF rats than from sham-operated rats. The present study demonstrates diaphragm weakness at the single-fiber level in a myocardial infarct model of CHF. The reduced maximal force generation can be explained by a loss of myosin content in all fiber types and is associated with activation of caspase-3 and the proteasome. Furthermore, CHF decreases myofibrillar Ca(2+) sensitivity and slows cross-bridge cycling kinetics in diaphragm fibers.
van Hees
Hieronymus W H
HW
Department of Pulmonary Diseases - 454, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. H.vanhees@long.umcn.nl
van der Heijden
Henricus F M
HF
Ottenheijm
Coen A C
CA
Heunks
Leo M A
LM
Pigmans
Cindy J C
CJ
Verheugt
Freek W A
FW
Brouwer
Rene M H J
RM
Dekhuijzen
P N Richard
PN
D000818:Animals; D002303:Cardiac Output, Low / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism*; D003964:Diaphragm / Q000503:physiopathology*; D008297:Male; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal; D018908:Muscle Weakness / Q000503:physiopathology*; D009218:Myosins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D053148:Caspase 3; D009218:Myosins