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Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats

Deptartments of ¹Pulmonary Diseases, ²Intensive Care Medicine, ³Cardiology and ⁴Cardio-Thoracic Surgery and ⁵Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and ⁶Deptartment of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington

Submitted 19 January 2007 ; accepted in final form 14 April 2007

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 Ca²⁺ 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 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). Ca²⁺ 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 30% (P < 0.05) and 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 Ca²⁺ sensitivity and slows cross-bridge cycling kinetics in diaphragm fibers.

skinned muscle single fibers; cross-bridge cycling kinetics; Ca²⁺ sensitivity; proteasome; caspase-3

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