Muscle Length is a Determinant of Cross-Bridge Cycling Rate in Intact Cardiac Trabeculae: Studies from Rodents to Humans

Abstract

The rate of cross-bridge cycling, a fundamental determinant impacting cardiac output, is usually measured in permeabilized muscle preparations and under non-physiological conditions. In order to gain a better understanding of mechanisms that regulate this kinetic parameter, we developed a novel method for measuring rate of tension redevelopment (ktr), an index of cross-bridge cycling kinetics, in intact cardiac trabeculae under physiological conditions. We were able to measure ktr in rat, rabbit, canine and failing human cardiac trabeculae. The ktr at Lopt (optimal length) was 27.7 ± 3.3 s−1 for rats (n = 11), 12.4 ± 1.2 s−1 for rabbits (n = 6), 14.0 ± 1.8 for canine (n =2) and 14.5 ± 1.8 s−1 for failing human myocardium (n=3). using this technique we investigated the role of muscle length in regulation of cross-bridge cycling kinetics. In cardiac trabeculae isolated from Brown Norway rats (n=11), the ktr was measured twice at Lopt and at L90 (corresponding to 90% of optimal length) in each muscle. The ktr for the L90 was 45.1 ± 7.6 s−1 and it was significantly decreased to 27.7 ± 3.3 s−1 as the muscles were stretched to Lopt (P < 0.05). Duplicate ktr experiments at each muscle length did not show any differences between the measured rates (P = 0.84). Additionally, preliminary experiments suggest similar length-dependent modulation of ktr also exists in rabbit, canine, and failing human cardiac trabeculae. This novel technique permits studying cross-bridge cycling kinetics in intact cardiac muscles from various species. The observed slower rate at optimal length may elucidate the century old question of why contractile kinetics slow down with increased preload of the ventricle.