Cross-Bridge Cycling Kinetics Slow at Longer Muscle Length in Tetanic Contracting Mouse Soleus Muscle

Abstract

Muscle contraction results from force-generating cross-bridge interactions between myosin and actin. Cross-bridge cycling kinetics underlie fundamental properties of muscle contraction, such as total force production and energetics, and factors that influence cross-bridge kinetics at the molecular level can propagate to critically alter whole-muscle function. Reciprocally, whole-muscle properties, including movement and the length of the muscle, can influence kinetics on the cross-bridge level. Previous research using single-molecule and single-fiber experiments has suggested that cross-bridge cycling is strain-dependent, and that increasing the strain on cross-bridges may slow their cycling rate and prolong their attachment duration. However, whether this property is maintained in whole-muscle to affect cross-bridge behavior under various strains and muscle lengths remains unclear. Here, we estimated cross-bridge cycling kinetics using small-amplitude step-length perturbations (1% total muscle-tendon length) in electrically-activated mouse soleus muscles. We separated the resulting force response into distinct phases associated with cross-bridge detachment and cross-bridge recruitment rates. The initial, fast single-exponential force decay is dominated by myosin detachment events and the slower force recovery phase is dominated by cross-bridge recruitment events. We found that cross-bridge detachment kinetics were ∼30% slower when muscles were stretched 10% longer than optimal length (Lo) (t1/2=8.75 ms vs 6.65 ms at Lo, 17°C). Detachment kinetics were ∼35% faster at 10% shorter length (t1/2=4.25ms at 90% of Lo). These findings suggest that cross-bridge kinetics vary with muscle length during intact, tetanic contraction in skeletal muscle, which may follow from strain-dependent mechanisms of cross-bridge cycling and could intrinsically modulate whole muscle force-generation and energetics during locomotion. This study advances our understanding of the classic Length-Tension relationship of skeletal muscle and implies that strain-dependent cross-bridge kinetics contribute another feedback pathway between whole-muscle function and cross-bridge activity.