Key result
Reducing load increases cardiac myosin working stroke size ~2.7-fold, independent of Ca2+ or sarcomere length.
Length- and Ca2+-dependent increases in peak force and power in the heart are fully explained by modulation of the number of attached myosin motors, not by changes in the intrinsic properties of the motor's working stroke.
Supports motor recruitment over intrinsic stroke changes for cardiac force modulation; extends intact-myocardium mechanokinetics but leaves open human translation.
The power in the myocardium sarcomere is generated by two bipolar arrays of the motor protein cardiac myosin II extending from the thick filament and pulling the thin, actin-containing filaments from the opposite sides of the sarcomere. Despite the interest in the definition of myosin-based cardiomyopathies, no study has yet been able to determine the mechanokinetic properties of this motor protein in situ. Sarcomere-level mechanics recorded by a striation follower is used in electrically stimulated intact ventricular trabeculae from the rat heart to determine the isotonic velocity transient following a stepwise reduction in force from the isometric peak force TP to a value T(0.8-0.2 TP). The size and the speed of the early rapid shortening (the isotonic working stroke) increase by reducing T from ∼3 nm per half-sarcomere (hs) and 1,000 s(-1) at high load to ∼8 nm⋅hs(-1) and 6,000 s(-1) at low load. Increases in sarcomere length (1.9-2.2 μm) and external [Ca(2+)]o (1-2.5 mM), which produce an increase of TP, do not affect the dependence on T, normalized for TP, of the size and speed of the working stroke. Thus, length- and Ca(2+)-dependent increase of TP and power in the heart can solely be explained by modulation of the number of myosin motors, an emergent property of their array arrangement. The motor working stroke is similar to that of skeletal muscle myosin, whereas its speed is about three times slower. A new powerful tool for investigations and therapies of myosin-based cardiomyopathies is now within our reach.
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Caremani et al. (2016) studied Healthy (basic science model) (n=8). Stepwise reduction in force (T), sarcomere length, and external Ca2+ vs. High load vs low load, varying sarcomere length and Ca2+ was evaluated on Size and speed of the early rapid shortening (isotonic working stroke). The size and speed of the cardiac myosin working stroke increased by reducing force from ~3 nm and 1,000 s(-1) at high load to ~8 nm and 6,000 s(-1) at low load, independently of sarcomere length and external Ca2+ concentration.
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